Fetzima

Warnings and Precautions ( 5.2 , 5.5 ) 8/2023

1 INDICATIONS AND USAGE FETZIMA ® is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies ( 14 )]. Limitation of Use: FETZIMA is not approved for the management of fibromyalgia. The efficacy and safety of FETZIMA for the management of fibromyalgia have not been established. FETZIMA is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of Major Depressive Disorder (MDD) in adults ( 1 ). Limitation of Use : FETZIMA is not approved for the management of fibromyalgia. The efficacy and safety of FETZIMA for the management of fibromyalgia have not been established ( 1 ).

2 DOSAGE AND ADMINISTRATION Recommended dosage: 40 mg to 120 mg once daily with or without food ( 2.1 ). Initial dosage is 20 mg once daily for 2 days and then increase to 40 mg once daily ( 2.1 ). Based on clinical response and tolerability, increase dose in increments of 40 mg at intervals of 2 or more days ( 2.1 ). The maximum recommended dosage is 120 mg once daily ( 2.1 ). Take capsules whole; do not open, chew or crush ( 2.1 ) Renal impairment ( 2.3 ) : ○ Severe renal impairment: Maximum recommended dosage is 40 mg once daily. ○ Moderate renal impairment: Maximum recommended dosage is 80 mg once daily. Discontinuation : Reduce dose gradually whenever possible ( 2.4 ) 2.1 Recommended Dosage The recommended dosage range for FETZIMA is 40 mg to 120 mg once daily, with or without food. FETZIMA should be initiated at 20 mg once daily for 2 days and then increased to 40 mg once daily. Based on clinical response and tolerability, FETZIMA may be increased in increments of 40 mg at intervals of 2 or more days. The maximum recommended dosage is 120 mg once daily. Take FETZIMA at approximately the same time each day. Swallow FETZIMA whole; do not open, chew, or crush the capsule. 2.2 Screen for Bipolar Disorder Prior to Starting FETZIMA Prior to initiating treatment with FETZIMA 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 Dosage Recommendations for Patients with Renal Impairment End stage renal disease (ESRD): FETZIMA is not recommended; Severe renal impairment (creatinine clearance of 15 to 29 mL/min), the dosage should not exceed 40 mg once daily; Moderate renal impairment (creatinine clearance of 30 to 59 mL/min), the dosage should not exceed 80 mg once daily; Mild renal impairment (creatinine clearance of 60 to 89 mL/min): no dosage adjustment recommended [see Use in Specific Populations ( 8.7 )]. 2.4 Discontinuing Treatment with FETZIMA Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as FETZIMA. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing FETZIMA. 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 must elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with FETZIMA. Conversely, at least 7 days should be allowed after stopping FETZIMA before starting an MAOI antidepressant [see Contraindications ( 4 )] . 2.6 Dosage Recommendations for Use with Strong CYP3A4 Inhibitors The maximum recommended dosage of FETZIMA should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors [ s ee Drug Interactions ( 7.1 )] .

3 DOSAGE FORMS AND STRENGTHS FETZIMA (levomilnacipran) is available as 20 mg, 40 mg, 80 mg, and 120 mg extended-release capsules. Capsule Strength Capsule Color/Shape Capsule Markings 20 mg yellow cap white body black "FL" on cap black "20" on body 40 mg yellow cap yellow body black "FL" on cap black "40" on body 80 mg pink cap white body black "FL" on cap black "80" on body 120 mg pink cap pink body black "FL" on cap black "120" on body Extended-release capsules: 20 mg, 40 mg, 80 mg, and 120 mg ( 3 ).

4 CONTRAINDICATIONS 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. The use of FETZIMA 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 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 [see Dosage and Administration ( 2.6 ) and Warnings and Precautions ( 5.2 )] . Hypersensitivity to levomilnacipran, milnacipran HCl, or any excipient in the FETZIMA formulation ( 4 ). Do not use MAOIs intended to treat psychiatric disorders with FETZIMA or within 7 days of stopping treatment with FETZIMA. Do not use FETZIMA within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start FETZIMA in a patient who is being treated with linezolid or intravenous methylene blue ( 4 ).

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 )] Increased Risk of 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 )] Sexual Dysfunction [see Warnings and Precautions ( 5.12 )] The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) are: nausea, constipation, hyperhidrosis, heart rate increase, erectile dysfunction, ejaculation disorder, tachycardia, vomiting, and palpitations ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 e xposure The safety of FETZIMA was evaluated in 3,317 patients (18 to 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. In these studies, FETZIMA was given at doses ranging from 40 mg to 120 mg once daily and was given without regard to food. Adverse r eacti ons r eported as r easons for discontinuation of t reatment 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 a dverse r eactions in p lacebo- c ontrolled MDD s tudies The most commonly observed adverse reactions in FETZIMA-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, ejaculation disorder, tachycardia, vomiting, and palpitations. Table 3 shows the incidence of adverse reactions that occurred in ≥ 2% of FETZIMA-treated MDD patients and at least twice the rate of placebo in the placebo-controlled studies. Table 3 Adverse Reactions Occurring in ≥ 2% of FETZIMA-treated Patients and at Least Twice the rate of Placebo-treated Patients in Pooled MDD Studies System Organ Class Preferred Term Placebo (N =1040) % FETZIMA 40 mg to 120 mg per day (N = 1583) % Gastrointestinal disorders Nausea 6 17 Constipation 3 9 Vomiting 1 5 Cardiac disorders Tachycardia a 2 6 Palpitations 1 5 Reproductive system and breast disorders b Erectile dysfunction c 1 6 Testicular pain d <1 4 Ejaculation disorder e <1 5 Investigations Heart rate increased f 1 6 Blood pressure increased g 1 3 Renal and urinary disorders Urinary hesitation 0 4 Skin and s ub …

7 DRUG INTERACTIONS Strong CYP3A4 inhibitors : Maximum recommended dosage is 80 mg once daily ( 7 ). 7.1 Drugs Having Clinically Important Interactions with FETZIMA Table 5 includes clinically important drug interactions with FETZIMA. Table 5: Clinically Important Drug Interactions with FETZIMA Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: Concomitant use of SSRIs and SNRIs including FETZIMA with MAOIs increases the risk of serotonin syndrome. Intervention: Concomitant use of FETZIMA is contraindicated: With an MAOI intended to treat psychiatric disorders or within 7 days of stopping treatment with FETZIMA. Within 14 days of stopping an MAOI intended to treat psychiatric disorders In a patient who is being treated with linezolid or intravenous methylene blue [see Dosage and Administration ( 2.5 , 2.6 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )] . Examples: selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact: Concomitant use of FETZIMA with other serotonergic drugs increases the risk of serotonin syndrome. Intervention: Monitor for symptoms of serotonin syndrome when FETZIMA is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, immediately discontinue FETZIMA and/or concomitant serotonergic drugs [ see Dosage and Administration ( 2.5 , 2.6 ) , Contraindications ( 4 ) , and Warnings and Precautions ( 5.2 ) ] . Examples: other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort Drugs that Interfere with Hemostasis Clinical Impact: Concomitant use of FETZIMA with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of FETZIMA on the release of serotonin by platelets. Intervention: Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when FETZIMA is initiated or discontinued [see Warnings and Precautions ( 5.5 )] . Examples: NSAIDs, aspirin, and warfarin Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of FETZIMA with strong CYP3A4 inhibitors increases levomilnacipran exposure [see Pharmacokinetics ( 12.3 )] . Intervention: The dose of FETZIMA should not exceed 80 mg once daily when used with strong CYP3A4 inhibitors [see Dosage and Administration ( 2.6 ). Examples: Ketoconazole, itraconazole, clarithromycin Alcohol Clinical Impact: Concomitant use of FETZIMA and alcohol may result in accelerated release of levomilnacipran. Intervention: Avoid concomitant use of FETZIMA and alcohol [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS Pregnancy : Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate. ( 8.1 ) 8.1 Pregnancy 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 . 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] . The available data on FETZIMA use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including FETZIMA, during pregnancy (see Clinical Considerations ). In animal reproduction studies, levomilnacipran was not associated with malformations 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/m 2 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 (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. 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 )] . Fetal/Neonatal adverse reactions Neonates exposed to SNRIs or SSRIs, including FETZIMA, 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 findings are consistent with either direct toxic effect of SSRIs and SNRIs 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 and 5.10 )]. Data Animal Data No malformations 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/m 2 basis. Fetal body w …

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).

11 DESCRIPTION FETZIMA contains levomilnacipran, a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in the form of hydrochloride salt with the chemical name of levomilnacipran hydrochloride is (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride. Its empirical formula is C 15 H 2 2 N 2 O∙HCl and its molecular weight is 282.8 g/mol. Levomilnacipran (Initial US approval: 2013) is the 1S,2R-enantiomer of milnacipran. The chemical structure of levomilnacipran hydrochloride is: FETZIMA extended-release capsules are intended for oral administration. Each FETZIMA capsule contains 23.0, 45.9, 91.8, or 137.8 mg of levomilnacipran hydrochloride equivalent to 20, 40, 80, or 120 mg of levomilnacipran, respectively. Inactive ingredients include ethylcellulose, hypromellose, povidone, sugar spheres, talc, titanium dioxide, and triethyl citrate. Inactive ingredients also include black iron oxide, red iron oxide (80 mg and 120 mg capsules only), shellac glaze, and yellow iron oxide (20 mg and 40 mg capsules only). The chemical structure of FETZIMA is levomilnacipran, which is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). The chemical name of levomilnacipran is (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride; its empirical formula is C15H23ClN2O and its molecular weight is 282.8 g/mol. Levomilnacipran (Initial US approval: 2013) is the 1S,2R-enantiomer of milnacipran.

10 OVERDOSAGE 10.1 Human Experience There is limited clinical experience with FETZIMA 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 FETZIMA 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.

16 HOW SUPPLIED/STORAGE AND HANDLING FETZIMA extended-release capsules are supplied in the following configurations: Capsule Strength Capsule Color/Shape Capsule Markings Package Configuration NDC Code 20 mg yellow cap white body black "FL" on cap black "20" on body Bottle / 30 count 0456-2220-30 Hospital Unit Dose (Blister) / 10 x 10 0456-2220-63 40 mg yellow cap yellow body black "FL" on cap black "40" on body Bottle / 30 count 0456-2240-30 Bottle / 90 count 0456-2240-90 Hospital Unit Dose (Blister) / 10 x 10 0456-2240-63 80 mg pink cap white body black "FL" on cap black "80" on body Bottle / 30 count 0456-2280-30 Bottle / 90 count 0456-2280-90 Hospital Unit Dose (Blister) /10 x 10 0456-2280-63 120 mg pink cap pink body black "FL" on cap black "120" on body Bottle / 30 count 0456-2212-30 Bottle / 90 count 0456-2212-90 Hospital Unit Dose (Blister) / 10 x 10 0456-2212-63 FETZIMA Titration Pack is supplied in the following configuration: Capsule Strength Capsule Color/Shape Capsule Markings Package Configuration NDC Code 20 mg yellow cap white body black "FL" on cap black "20" on body Titration Pack (Blister) containing two 20 mg capsules and twenty-six 40 mg capsules 0456-2202-28 40 mg yellow cap yellow body black "FL" on cap black "40" on body Storage and Handling All package configurations: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature] .