Levomilnacipran: Package Insert and Label Information

LEVOMILNACIPRAN- levomilnacipran hydrochloride capsule, extended release
Amneal Pharmaceuticals LLC

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [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 is indicated for the treatment of major depressive disorder (MDD) in adults [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 DOSAGE AND ADMINISTRATION

2.1 General Instruction for Use

The recommended dose range for levomilnacipran extended-release capsule 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 Screen for Bipolar Disorder Prior to Starting Levomilnacipran Extended-release Capsules

Prior to initiating treatment with levomilnacipran extended-release capsules or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.8)].

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 capsule is 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 (7.1)].

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 white to off-white 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 white to off-white 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 white to off-white 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 white to off-white 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 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.

Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age Range

Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated

Increases Compared to Placebo

<18 years old

14 additional patients

18 to 24 years old

5 additional patients

Decreases Compared to Placebo

25 to 64 years old

1 fewer patient

≥65 years old

6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e. beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing levomilnacipran, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome

Selective-serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including levomilnacipran, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased 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, i.e. MAOIs [see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone.

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).

The concomitant use of levomilnacipran with MAOIs is contraindicated. In addition, do not initiate levomilnacipran in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking levomilnacipran, discontinue levomilnacipran before initiating treatment with the MAOI [see Dosage and Administration (2.5, 2.6) and Contraindications (4), Drug Interactions (7.1)].

Monitor all patients taking levomilnacipran for the emergence of serotonin syndrome. Discontinue treatment with levomilnacipran and any concomitant serotonergic agents immediately if the above events occur and initiate supportive symptomatic treatment. If concomitant use of levomilnacipran with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

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 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 mg 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.

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