Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

FETZIMA (NDA-204168)

(LEVOMILNACIPRAN HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/19/2024 (SUPPL-12)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

Before taking FETZIMA, tell your healthcare provider about all your medical conditions, including if you:

…

There is a pregnancy registry for women who are exposed to FETZIMA during pregnancy. The purpose of the registry is to collect information about the health of women exposed to FETZIMA and their baby. If you become pregnant during treatment with FETZIMA, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visit online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants.

08/18/2023 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

Additions and/or revisions underlined:

Serotonin-norepinephrine reuptake inhibitors (SNRIs), including FETZIMA, 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, meperidine, methadone, 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.

…

5.5 Increased Risk of Bleeding

Additions and/or revisions underlined:

… Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of FETZIMA and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.1)].

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Respiratory, thoracic and mediastinal disorders: Anosmia, Hyposmia

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.5) and Clinical Considerations].

…

Maternal Adverse Reactions

Use of FETZIMA in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5)].

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of FETZIMA with other serotonergic agents (including triptans, tricyclic antidepressants, opioids, lithium, amphetamines, tryptophan, buspirone, and St. John’s Wort supplements) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

…

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

…

Especially tell your healthcare provider if you take:

…

tramadol, fentanyl, meperidine, methadone, or other opioids
…

03/24/2023 (SUPPL-10)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

FETZIMA is contraindicated:

in patients with hypersensitivity to levomilnacipran, milnacipran HCl, or to any excipient in the formulation.
with the use of MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA is contraindicated because of an increased risk of serotonin syndrome.

…

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

Revision to Table 1; please refer to label for complete information

5.3 Elevated Blood Pressure

Addition of “with FETSIMA (in Adults)” to the title of Table 2; please refer to label for complete information.

Additions and/or revisions underlined:

…

Table 2 shows the mean changes in blood pressure, sustained hypertension, and upward shifts in hypertensive status that were observed in FETZIMA-treated adult patients in the short-term placebo-controlled studies.

…

In the short-term, placebo-controlled MDD studies in adults, 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 adult patients exposed to one-year, open-label treatment of FETZIMA (doses range from 40- 120 mg once daily), the mean change from initiation of treatment in systolic BP was 3.9 mm Hg and diastolic BP was 3.1 mm Hg.

In short-term, placebo- and active-controlled MDD studies in pediatric patients 7 years to less than 18 years of age, treatment with FETZIMA was associated with the occurrence of new-onset hypertension (two systolic and/or diastolic BP measurements in the stage I hypertension range and/or one measurement in the stage II range) in 36.2% of treated patients compared with 20.7% of patients randomized to placebo. Elevations in either systolic or diastolic BP leading to measures at or above the stage II hypertension threshold occurred in 12.1% of pediatric patients treated with FETZIMA and 7.5% of patients randomized to placebo. Sustained hypertension (three or more consecutive systolic or diastolic BP measurements at or above the stage I hypertension threshold) occurred in 15% of pediatric patients treated with FETZIMA and 4% of patients randomized to placebo. The safety and effectiveness of FETZIMA have not been established in pediatric patients for the treatment of MDD.

…

5.6 Angle Closure Glaucoma

Additions and/or revisions underlined:

The pupillary dilation that occurs following use of many antidepressant drugs including FETZIMA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including FETZIMA, in patients with anatomically narrow angles.

5.8 Activation of Mania/Hypomania

Additions and/or revisions underlined:

Symptoms of mania/hypomania were reported in 0.2% of FETZIMA-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. Prior to initiating treatment with FETZIMA, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

6 Adverse Reactions

6.1 Clinical Trials Experience

Addition of “in Pooled MDD Studies” to Table 3 title; please refer to label for complete information.

Additions and/or revisions underlined:

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 FETZIMA (40 mg to 120 mg) discontinued treatment due to an adverse reaction, 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 FETZIMA-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 reactions in FETZIMA-treated MDD patients in placebo- controlled studies (incidence greater than or equal to 5% and at least twice the rate of placebo) were: nausea, constipation, hyperhidrosis, heart rate increased, erectile dysfunction, ejaculation disorder, tachycardia, vomiting, and palpitations.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants.

…

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of FETZIMA have not been established in pediatric patients for the treatment of major depressive disorder (MDD).

The safety and efficacy of FETZIMA were evaluated in two randomized, double-blind, placebo- and active-controlled 8-week trials in pediatric patients with MDD, one in patients 7 to 17 years of age (flexible-dose study) and the other in patients 12 to 17 years of age (fixed-dose study). The primary efficacy endpoint for both studies was the change from baseline to week 8 in the Children’s Depression Rating Scale-Revised (CDRS-R) total score. The CDRS-R assesses the severity of depression and change in depressive symptoms in children and adolescents with depression.

FETZIMA was not superior to placebo in either study. The most commonly observed adverse reactions in pediatric patients 7 to 17 years of age randomized to FETZIMA were similar to those observed in adults [see Adverse Reactions (6.1)].

FETZIMA was associated with an increase in blood pressure in placebo- and active-controlled trials in pediatric patients with MDD. Increases in blood pressure in pediatric patients treated with FETZIMA led to a higher proportion of pediatric patients developing new-onset and sustained hypertension when compared to adults [see Warnings and Precautions (5.3)].

Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Juvenile Animal Toxicity Data

In a juvenile animal study, male and female rats were treated with 10, 35, or 120 mg/kg/day of levomilnacipran by oral gavage from post-natal day 21 to 90. At 120 mg/kg/day, there was a decrease in bone mineral density in both males and females and a decrease in mean tibia length in females. These effects were not completely resolved at the end of the recovery period. There was a delay in sexual maturation in females treated with 120 mg/kg/day; however, there was no effect on fertility. The no observed adverse effect level (NOAEL) for all these findings was 35 mg/kg/day.

8.7 Renal Impairment

Additions and/or revisions underlined:

Renal excretion plays a predominant role in the elimination of levomilnacipran. FETZIMA is not recommended for use in patients with end stage renal disease.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensive changes; please refer to label for complete information

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Suicide Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

…

Concomitant Medication

Instruct patients not to take FETZIMA with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping FETZIMA before starting an MAOI [see Contraindications (4)]. Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for drug-drug interactions [see Drug Interactions (7.1)].

…

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of FETZIMA with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, amphetamines, tryptophan, buspirone, and St. John’s Wort supplements) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)]. Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Elevated Blood Pressure and Heart Rate

…

Increased Risk of Bleeding

Caution patients about the concomitant use of FETZIMA and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation because combined use has been associated with an increased risk of bleeding. Advise patients to inform their healthcare provider if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.5)].

…

Urinary Hesitation or Retention

Caution patients about the risk of urinary hesitation and retention while taking FETZIMA, particularly in patients prone to obstructive urinary disorders. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [see Warnings and Precautions (5.7)].

…

Discontinuation Syndrome

Advise patients not to abruptly stop taking FETZIMA without first talking with their healthcare provider. Patients should be aware that discontinuation effects may occur when suddenly stopping FETZIMA and they should monitor for discontinuation symptoms [see Warnings and Precautions (5.10)].

Hyponatremia

Advise patients that hyponatremia has been reported as a result of treatment with FETZIMA. Advise patients of the signs and symptoms of hyponatremia [see Warnings and Precautions (5.11)].

…

09/20/2021 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Sexual Dysfunction

(Newly added subsection)

Use of SNRIs, including Fetzima, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of Fetzima and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Sexual Dysfunction [see Warnings and Precautions (5.12)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Sexual problems (dysfunction). Taking serotonin and norepinephrine reuptake inhibitors (SNRIs), including Fetzima, may cause sexual problems.
Symptoms in males may include:

Delayed ejaculation or inability to have an ejaculation
Problems getting or keeping an erection
Decreased sex drive

Symptoms in females may include:

Decreased sex drive
Delayed orgasm or inability to have an orgasm
Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with FETZIMA. There may be treatments your healthcare provider can suggest.
…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Sexual Dysfunction

Advise patients that use of Fetzima may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.12)].

…

10/07/2019 (SUPPL-6)

Approved Drug Label (PDF)

Boxed Warning

Revised and now reads:

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.

FETZIMA is not approved for use in pediatric patients.

5 Warnings and Precautions

Additions and/or revisions underlined:

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 1000 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 New title of pre-existing table.

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 FETZIMA, 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 FETZIMA, 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 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 FETZIMA with MAOIs is contraindicated. In addition, do not initiate FETZIMA 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 FETZIMA, discontinue FETZIMA before initiating treatment with the MAOI

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

5.5 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake, including FETZIMA, may increase the risk of bleeding events. …

Inform patients about the risk of bleeding associated with the concomitant use of FETZIMA and NSAIDs, aspirin, or other drugs that affect coagulation.

5.6 Angle Closure Glaucoma

Newly added paragraph to subsection:

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.

5.11 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including FETZIMA. …

6 Adverse Reactions

Additions and/or revisions to bulleted line listing underlined:

Increased Risk of Bleeding

Additions and/or revisions underlined:

6.1 Clinical Trials Experience

Patient exposure

The safety of FETZIMA was evaluated in 3,317 patients (18-78 years of age) diagnosed with MDD who participated in clinical studies, representing 1,186 patient-years of exposure. Among the 3,317 FETZIMA-treated patients, 1,583 were exposed to FETZIMA 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 3,317 patients exposed to at least one dose of FETZIMA, 895 patients were exposed to FETZIMA for at least 6 months and 367 were exposed for one year.

6.2 Postmarketing Experience

The following adverse reaction has been identified during post-approval use of FETZIMA or other selective serotonin and norepinephrine reuptake inhibitors. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: Takotsubo cardiomyopathy

7 Drug Interactions

7.1 Drugs Having Clinically Important Interactions with FETZIMA

Table 5 includes clinically important drug interactions with FETZIMA. Newly added table; please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; please refer to label for complete information.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are no available data on the presence of levomilnacipran in human milk; however, racemic milnacipran is present in human milk. There are no reports on the effects of levomilnacipran or milnacipran on the breastfed infant or the effects on milk production.

However, there are reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to SSRIs or SNRIs through breast milk (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FETZIMA and any potential adverse effects on the breastfed child from FETZIMA or from the underlying maternal conditions.

Clinical Considerations

Infants exposed to FETZIMA should be monitored for agitation, irritability, poor feeding and poor weight gain.

Data

Milnacipran, a racemic mixture that contains levomilnacipran (the 1S,2R-enantiomer of milnacipran), is present in the milk of lactating women treated with milnacipran. In a lactation pharmacokinetic study with milnacipran, a single, oral dose of 50 mg milnacipran HCl tablet was administered to 8 lactating women who were at least 12 weeks postpartum and weaning their infants. The milk/plasma AUC ratio of milnacipran was 1.85 ± 0.38. The maximum estimated weight-adjusted daily infant dose for milnacipran from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 5% of the maternal weight-adjusted dose based on peak plasma concentrations.

8.5 Geriatric Use

… Of the total number of subjects in the 8-week clinical studies of FETZIMA, 2.8% of patients were age 65 or older …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Has been reformatted; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Suicide Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during treatment and when the dose is adjusted up or down.

Serotonin Syndrome

Increased Risk of Bleeding

Caution patients about the concomitant use of FETZIMA and NSAIDs …

Pregnancy

Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with FETZIMA.
Advise patients that FETZIMA use in late pregnancy may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding.
Advise women that there is a risk of relapse with discontinuation of antidepressants.
Advise patient that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to FETZIMA during pregnancy.
Lactation
Advise breastfeeding women using FETZIMA to monitor infants for sedation, agitation, irritability, poor feeding and poor weight gain and to seek medical care if they notice these signs.
Interference with Cognitive and Motor Performance
Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that FETZIMA therapy does not adversely affect their ability to engage in such activities.

12/19/2017 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Newly added subsection)

Besides these reactions reported under treatment with FETZIMA, 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 FETZIMA.

This adverse reaction includes: Takotsubo cardiomyopathy.

01/04/2017 (SUPPL-4)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

• Hypersensitivity to levomilnacipran, milnacipran HCl or to any excipient in the formulation.

• The use of MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA is contraindicated because of an increased risk of serotonin syndrome. The use of FETZIMA within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting FETZIMA 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.

5 Warnings and Precautions

5.2 Serotonin Syndrome

(additions underlined)

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, diaphoresis,myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

…

If concomitant use of FETZIMA 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.

5.4 Elevated Heart Rate

(additions underlined)

SNRIs including FETZIMA have been associated with increased heart rate. Heart rate should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. Pre- existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with FETZIMA. For patients who experience a sustained increase in heart rate while receiving FETZIMA, discontinuation or other appropriate medical intervention should be considered.

5.7 Urinary Hesitation or Retention

(addition underlined)

The noradrenergic effect of SNRIs including FETZIMA, can affect urethral resistance. In the controlled short-term studies, urinary hesitation occurred in 4%, 5% and 6% of FETZIMA- treated patients receiving doses of 40, 80 and 120 mg, respectively, compared to no patients in the placebo group. Caution is advised in the use of FETZIMA in patients prone to obstructive urinary disorders. If symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment with FETZIMA, consideration should be given to the possibility that they might be drug-related, and discontinuation or other appropriate medical intervention should be considered.

7 Drug Interactions

7.3 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

(additions underlined)

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 FETZIMA is initiated or discontinued.

8 Use in Specific Populations

8.3 Nursing Mothers

(additions underlined)

It is not known if FETZIMA 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 FETZIMA, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(addition underlined)

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of FETZIMA and triptans, tramadol, amphetamines, tryptophan supplements, other serotonergic agents, or antipsychotic drugs.

MEDICATION GUIDE

(addition underlined)

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