NDC 65162-437 Levomilnacipran

Levomilnacipran

NDC Product Code 65162-437

NDC Code: 65162-437

Proprietary Name: Levomilnacipran Additional informationCallout TooltipWhat is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Levomilnacipran Additional informationCallout TooltipWhat is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.


Product Characteristics
Color(s):
YELLOW (C48330 - YELLOW CAP AND WHITE BODY)
YELLOW (C48330 - YELLOW CAP AND YELLOW BODY)
PINK (C48328 - PINK CAP AND WHITE BODY)
Shape: CAPSULE (C48336)
Size(s):
14 MM
16 MM
18 MM
Imprint(s):
AN;411
AN;414
AN;437
Score: 1

Code Structure
  • 65162 - Amneal Pharmaceuticals Llc
    • 65162-437 - Levomilnacipran

NDC 65162-437-03

Package Description: 30 CAPSULE, EXTENDED RELEASE in 1 BOTTLE

NDC Product Information

Levomilnacipran with NDC 65162-437 is a a human prescription drug product labeled by Amneal Pharmaceuticals Llc. The generic name of Levomilnacipran is levomilnacipran. The product's dosage form is capsule, extended release and is administered via oral form.

Labeler Name: Amneal Pharmaceuticals Llc

Dosage Form: Capsule, Extended Release - A solid dosage form in which the drug is enclosed within either a hard or soft soluble container made from a suitable form of gelatin, and which releases a drug (or drugs) in such a manner to allow a reduction in dosing frequency as compared to that drug (or drugs) presented as a conventional dosage form.

Product Type: Human Prescription Drug Additional informationCallout TooltipWhat kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.


Levomilnacipran Active Ingredient(s)

Additional informationCallout TooltipWhat is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • LEVOMILNACIPRAN HYDROCHLORIDE 80 mg/1

Inactive Ingredient(s)

Additional informationCallout TooltipAbout the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ALCOHOL (UNII: 3K9958V90M)
  • AMMONIA (UNII: 5138Q19F1X)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • ETHYLCELLULOSE (20 MPA.S) (UNII: BJG0S321QY)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • HYPROMELLOSES (UNII: 3NXW29V3WO)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • POVIDONE (UNII: FZ989GH94E)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • SHELLAC (UNII: 46N107B71O)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SUCROSE (UNII: C151H8M554)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • WATER (UNII: 059QF0KO0R)
  • ALCOHOL (UNII: 3K9958V90M)
  • AMMONIA (UNII: 5138Q19F1X)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • ETHYLCELLULOSE (20 MPA.S) (UNII: BJG0S321QY)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • HYPROMELLOSES (UNII: 3NXW29V3WO)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • POVIDONE (UNII: FZ989GH94E)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • SHELLAC (UNII: 46N107B71O)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SUCROSE (UNII: C151H8M554)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • WATER (UNII: 059QF0KO0R)
  • ALCOHOL (UNII: 3K9958V90M)
  • AMMONIA (UNII: 5138Q19F1X)
  • BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
  • ETHYLCELLULOSE (20 MPA.S) (UNII: BJG0S321QY)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • HYPROMELLOSES (UNII: 3NXW29V3WO)
  • ISOPROPYL ALCOHOL (UNII: ND2M416302)
  • POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
  • POVIDONE (UNII: FZ989GH94E)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • SHELLAC (UNII: 46N107B71O)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SUCROSE (UNII: C151H8M554)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TRIETHYL CITRATE (UNII: 8Z96QXD6UM)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

Additional informationCallout TooltipWhat are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

Additional informationCallout TooltipWhat is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Norepinephrine Uptake Inhibitors - [MoA] (Mechanism of Action)
  • Serotonin and Norepinephrine Reuptake Inhibitor - [EPC] (Established Pharmacologic Class)
  • Serotonin Uptake Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

Additional informationCallout TooltipWhat is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Amneal Pharmaceuticals Llc
Labeler Code: 65162
FDA Application Number: ANDA210790 Additional informationCallout TooltipWhat is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. Additional informationCallout TooltipWhat is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 02-04-2019 Additional informationCallout TooltipWhat is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 Additional informationCallout TooltipWhat is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N Additional informationCallout TooltipWhat is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Levomilnacipran Product Label Images

Levomilnacipran Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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 [see Warnings and Precautions (5.1)]. 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)].

1 Indications And Usage

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.

2.1 General Instruction For Use

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.

2.2 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 extended-release capsules has not been established beyond 8 weeks.

2.3 Special Populations

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)].

2.4 Discontinuing Treatment

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)].

2.5 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 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)].

2.6 Use Of Levomilnacipran With Other Maois Such As Linezolid Or Methylene Blue

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)].

2.7 Use Of Levomilnacipran With Strong Inhibitors Of Cytochrome P450 (Cyp3a4) Enzyme

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)].

3 Dosage Forms And Strengths

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.

4 Contraindications

  • Hypersensitivity to levomilnacipran, milnacipran HCl or to any excipient in the formulation. The use of MAOIs intended to treat psychiatric disorders with levomilnacipran or within 7 days of stopping treatment with levomilnacipran is contraindicated because of an increased risk of serotonin syndrome. The use of levomilnacipran within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.5) and Warnings and Precautions (5.2)]. 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)].

5.1 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 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 RangeDrug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo<1814 additional cases18 to 245 additional casesDecreases Compared to Placebo25 to 641 fewer case≥656 fewer casesNo 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.

5.2 Serotonin Syndrome

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.

5.3 Elevated Blood Pressure

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 StatusPlaceboLevomilnacipran 40 to 120 mg/dayMean change from baseline to end of treatment, mm HgSystolic blood pressure (SBP)-0.4 3.0 Diastolic blood pressure (DBP)-0.0 3.2 Sustained Hypertension, % of patientsBroad 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 visits1.2 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 visits0.1 0.3 Upward Shifts in Hypertensive Statusa, % of patientsNormal/ Pre-hypertensive → Stage I/ Stage II7.1 10.4 a Normal Blood Pressure: SBP < 120 mm Hg and DBP < 80 mm HgPre-hypertension: SBP ≥ 120 mm Hg and ≤ 139 mm Hg or DBP ≥ 80 mm Hg and ≤ 89 mm HgStage I hypertension: SBP ≥ 140 mm Hg and ≤ 159 mm Hg or DBP ≥ 90 mm Hg and ≤ 99 mm HgStage II hypertension: SBP ≥ 160 mm Hg or DBP ≥ 100 mm HgIn 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.

5.4 Elevated Heart Rate

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.

5.5 Abnormal Bleeding

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.

5.6 Angle Closure Glaucoma

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.

5.7 Urinary Hesitation Or Retention

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.

5.8 Activation Of Mania/Hypomania

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.

5.9 Seizures

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.

5.10 Discontinuation Syndrome

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)].

5.11 Hyponatremia

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.

6 Adverse Reactions

  • The following adverse reactions are discussed in greater detail in other sections of the label. Hypersensitivity [see Contraindications (4)] Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1)] Serotonin Syndrome [see Warnings and Precautions (5.2)] Elevated Blood Pressure [see Warnings and Precautions (5.3)] Elevated Heart Rate [see Warnings and Precautions (5.4)] Abnormal Bleeding [see Warnings and Precautions (5.5)] Angle Closure Glaucoma [see Warnings and Precautions (5.6)] Urinary Hesitation or Retention [see Warnings and Precautions (5.7)] Activation of Mania/Hypomania [see Warnings and Precautions (5.8)] Seizure [see Warnings and Precautions (5.9)]Discontinuation Syndrome [see Warnings and Precautions (5.10)] Hyponatremia [see Warnings and Precautions (5.11)]

6.1 Clinical Studies Experience

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 PatientsSystem Organ Class Preferred TermPlacebo(N =1040)%Levomilnacipran40 to 120 mg/d(N = 1583)%Gastrointestinal disordersNausea617Constipation39Vomiting15Cardiac disorders Tachycardiaa26Palpitations15Reproductive system and breast disordersbErectile dysfunctionc16Testicular paind<14Ejaculation disordere<15InvestigationsHeart rate increasedf16Blood pressure increasedg13Renal and urinary disordersUrinary hesitation04Skin and subcutaneous tissue disordersHyperhidrosis29Rashh02Vascular disordersHot flush13Hypotensioni13Hypertensionj13Metabolism and nutrition disordersDecreased appetite13a Tachycardia also includes: sinus tachycardia and postural orthostatic tachycardia syndromeb 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 dysfunctiond testicular pain includes: testicular pain, epididymitis, and seminal vesiculitise ejaculation disorder includes: ejaculation disorder, ejaculation delayed, ejaculation failure, and premature ejaculationf Heart rate increased also includes: orthostatic heart rate response increasedg Blood pressure increased also includes: blood pressure systolic increased, blood pressure diastolic increased and blood pressure orthostatic increasedh Rash also includes: rash generalized, rash maculo-papular, rash erythematous and rash maculari Hypotension also includes: orthostatic hypotension and dizziness posturalj Hypertension also includes: labile hypertensionN = number of patients in the Safety PopulationDose-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 ReactionsSystem Organ Class Preferred Term Placebo(N = 362)%Levomilnacipran40 mg/d(N = 366)%80 mg/d(N = 367)%120 mg/d(N = 180)%Urinary hesitation 0456Erectile dysfunctiona26810aPercentage is relative to the number of male patients.N = number of patients in the Safety PopulationOther 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

6.2    Postmarketing Experience

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.

7 Drug Interactions

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.

7.1 Monoamine Oxidase Inhibitors (Maois)

[see Dosage and Administration (2.5, 2.6), Contraindications (4), and Warnings and Precautions (5.2)]

7.2 Serotonergic Drugs

[see Dosage and Administration (2.5, 2.6), Contraindications (4), and Warnings and Precautions (5.2)]

7.3 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 is initiated or discontinued [see Warnings and Precautions (5.5)].

7.4 Potential For Other Drugs To Affect Levomilnacipran

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

7.5 Potential For Levomilnacipran To Affect 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).

7.6 Central Nervous System (Cns)-Active Agents

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.

8.1 Pregnancy

Pregnancy Category CRisk 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.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

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)].

8.5 Geriatric 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 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)].

8.6 Hepatic Impairment

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).

8.7 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 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)].

8.8 Gender

Dose adjustment based on gender is not recommended (see Figure 2).Figure 2: Effect of Intrinsic Factors on Levomilnacipran PK

9.1 Controlled Substance

Levomilnacipran is not a controlled substance.

9.2 Abuse

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).

9.3 Dependence

Levomilnacipran has not been systematically studied in animals or humans for its potential for dependence.

10.1 Human Experience

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.

10.2 Management Of Overdose

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.

11 Description

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.

12.1 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).

12.2 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 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.

12.3 Pharmacokinetics

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. MetabolismLevomilnacipran 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)].

13.1 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.

14.1 Treatment Of Major Depressive Disorder

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 MADRSStudy 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)Placebo31.0 (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.

16 How Supplied/Storage And Handling

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 65162-411-03Levomilnacipran 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 65162-960-03Levomilnacipran 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 65162-437-03Levomilnacipran 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 65162-455-03Storage and HandlingAll 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].

17 Patient Counseling Information

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 SyndromeCaution 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 RateAdvise 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 RetentionCaution 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)]. HyponatremiaAdvise 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, INDIADistributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807Rev. 02-2018-00

Medication Guide

  • Levomilnacipran (lee" voe mil na' si pran) Extended-Release CapsulesRead 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: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness 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. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness). Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment. Levomilnacipran extended-release capsules are not approved for use in children. Talk to your child’s healthcare provider for more information. How can I watch for and try to prevent suicidal thoughts and actions?Pay close attention to any changes in mood, behavior, thoughts, or feelings, especially sudden changes. This is very important when an antidepressant medicine is started or when the dose is changed. Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. 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: attempts to commit suicide acting on dangerous impulses acting aggressive, being angry, or violent thoughts about suicide or dying new or worsening depression new or worsening anxiety feeling very agitated or restless panic attacks trouble sleeping new or worsening irritability an extreme increase in activity or talking (mania) other unusual changes in behavior or mood 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: agitation, hallucinations, coma or other changes in mental status problems controlling your movements or muscle twitching fast heartbeat high or low blood pressure sweating or fever nausea or vomiting diarrhea muscle stiffness or tightness What else do I need to know about antidepressant medicines? Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider, not just antidepressant medications. Antidepressant medicines have other side effects. Talk to your healthcare provider about the possible side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines (including prescription, over-the-counter, vitamins and herbal supplements) to show your healthcare provider. Do not start new medicines without first checking with your healthcare provider. Never stop an antidepressant medicine without first talking to your healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. 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: are allergic to levomilnacipran, milnacipran HCl, or any of the ingredients in levomilnacipran extended-release capsules. See the end of this Medication Guide for a complete list of ingredients in levomilnacipran extended-release capsules. take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene blue. have taken an MAOI within 14 days unless directed by your healthcare provider 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: have high blood pressure have heart problems have or had bleeding problems have or had urinary retention or problems urinating have mania or bipolar disorder (manic depression) have or had seizures or convulsions have low salt (sodium) levels in your blood have kidney problems drink alcohol are pregnant or plan to become pregnant. It is not known if levomilnacipran extended-release capsules will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if levomilnacipran passes into breast milk. Talk to your healthcare provider if you are or plan to breast feed your baby while taking levomilnacipran extended-release capsules. 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: medicines used to treat migraine headache (triptans) medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, fentanyl, tryptophan, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), buspirone, amphetamines, or antipsychotics sibutramine tramadol over-the-counter supplements such as tryptophan or St. John’s Wort nonsteroidal anti-inflammatory drugs (NSAIDS) aspirin warfarin (Coumadin®, Jantoven®) diuretics 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? Take levomilnacipran extended-release capsules exactly as your healthcare provider tells you to take it. Take levomilnacipran extended-release capsules at about the same time each day. Your healthcare provider may need to change the dose of levomilnacipran extended-release capsules until it is the right dose for you. Do not start or stop taking levomilnacipran extended-release capsules without talking to your healthcare provider first. Stopping levomilnacipran extended-release capsules suddenly can cause side effects. Levomilnacipran extended-release capsules may be taken with or without food. Swallow levomilnacipran extended-release capsules whole. Do not chew, crush, or cut levomilnacipran extended-release capsules. If you miss a dose of levomilnacipran extended-release capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of levomilnacipran extended-release capsules at the same time. If you take too much levomilnacipran extended-release capsules, call your healthcare provider or your poison control center at 1-800-222-1222, or go to the nearest hospital emergency room right away. What should I avoid while taking levomilnacipran extended-release capsules? Levomilnacipran extended-release capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how levomilnacipran extended-release capsule affects you. You should not drink alcohol while taking levomilnacipran extended-release capsules. See “What should I tell my healthcare provider before 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: high blood pressure (hypertension). Your healthcare provider should evaluate your blood pressure before and while you are taking levomilnacipran extended-release capsules. If you have high blood pressure, it should be controlled before you start taking levomilnacipran extended-release capsules.increased heart rate (palpitations). Your healthcare provider should evaluate your heart rate before and while you are taking levomilnacipran extended-release capsules. abnormal bleeding or bruising. Levomilnacipran extended-release capsules may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti-inflammatory drug (NSAID), or aspirin. visual problems eye pain changes in vision swelling or redness in or around eye 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.urinary hesitation and retention (difficulty urinating or unable to urinate)hypomania (manic episodes). Symptoms of manic episodes include: greatly increased energy severe problems sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritabilitytalking more or faster than usual seizures or convulsions discontinuation symptoms: Do not stop levomilnacipran extended-release capsules without first talking to your healthcare provider. Stopping levomilnacipran extended-release capsules suddenly may cause serious symptoms including: anxiety irritability high or low mood feeling restless or sleepy headache sweating nausea dizziness electric shock-like sensations tremor confusionlow levels of salt (sodium) in your blood. Symptoms of this may include: headache, difficulty concentrating, memory changes, confusion, weakness and unsteadiness on your feet. Symptoms of severe or sudden cases of low salt levels in your blood may include: hallucinations (seeing or hearing things that are not real), fainting, seizures and coma. If not treated, severe low sodium levels could cause death. The most common side effects of levomilnacipran extended-release capsules include: nausea or vomiting constipation sweating erectile dysfunction 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, INDIADistributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807Rev. 02-2018-00

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