Vilazodone Hydrochloride

Warnings and Precautions (5.9) 7/2021 Warnings and Precautions ( 5.2 , 5.3 ) 8/2023

1 INDICATIONS AND USAGE Vilazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies ( 14 )] . Vilazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended target dosage: 20 mg to 40 mg once daily with food. ( 2.1 , 12.3 ) To titrate: start with initial dosage of 10 mg once daily for 7 days, followed by 20 mg once daily. The dose may be increased up to 40 mg once daily after a minimum of 7 days between dosage increases. ( 2.1 ) Prior to initiating vilazodone hydrochloride tablets, screen for bipolar disorder. ( 2.2 , 5.4 ) When discontinuing vilazodone hydrochloride tablets, reduce dosage gradually. ( 2.4 , 5.5 ) 2.1 Dosage for Treatment of Major Depressive Disorder The recommended target dosage for vilazodone hydrochloride tablets is 20 mg to 40 mg orally once daily with food [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] . To achieve the target dosage, titrate vilazodone hydrochloride tablets as follows: Start with an initial dosage of 10 mg once daily with food for 7 days, Then increase to 20 mg once daily with food. The dose may be increased up to 40 mg once daily with food after a minimum of 7 days between dosage increases. If a dose is missed, it should be taken as soon as the patient remembers. If it is almost time for the next dose, the patient should skip the missed dose and take the next dose at the regular time. Two doses should not be taken at the same time. 2.2 Screen for Bipolar Disorder Prior to Starting Vilazodone Hydrochloride Tablets Prior to initiating treatment with vilazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.4 )] . 2.3 Switching to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of vilazodone hydrochloride tablets. In addition, at least 14 days must elapse after stopping vilazodone hydrochloride tablets before starting an MAOI antidepressant [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . 2.4 Dosage Adjustments with CYP3A4 Inhibitors or Inducers Patients receiving concomitant CYP3A4 inhibitors : During concomitant use of a strong CYP3A4 inhibitor (e.g., itraconazole, clarithromycin, voriconazole), the vilazodone hydrochloride tablets dose should not exceed 20 mg once daily. The original vilazodone hydrochloride tablet dose level, can be resumed when the CYP3A4 inhibitor is discontinued [see Drug Interactions ( 7 )] . Patients receiving concomitant CYP3A4 inducers : Based on clinical response, consider increasing the dosage of vilazodone hydrochloride tablets by 2-fold, up to a maximum 80 mg once daily, over 1 to 2 weeks in patients taking strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin) for greater than 14 days. If CYP3A4 inducers are discontinued, gradually reduce the vilazodone hydrochloride tablets dosage to its original level over 1 to 2 weeks [see Drug Interactions ( 7 )] . 2.5 Discontinuing Treatment with Vilazodone Hydrochloride Tablets Adverse reactions may occur upon discontinuation of vilazodone hydrochloride tablets [see Warnings and Precautions ( 5.5 )] . A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible. Vilazodone hydrochloride tablets should be down tapered from the 40 mg once daily dose to 20 mg once daily for 4 days, followed by 10 mg once daily for 3 days. Patients taking vilazodone hydrochloride tablets 20 mg once daily should be tapered to 10 mg once daily for 7 days.

3 DOSAGE FORMS AND STRENGTHS Vilazodone Hydrochloride Tablets are available as 10 mg, 20 mg, and 40 mg film-coated tablets. 10 mg, pink, elliptical shaped biconvex tablets de-bossed with “ IG ” on one side and “ 544 ” on other. 20 mg, orange, film coated, elliptical shaped biconvex tablets debossed with “ IG ” on one side and “ 545 ” on the other. 40 mg, blue, elliptical shaped biconvex tablets de-bossed with “ IG ” on one side and “ 546 ” on other. Tablets: 10 mg, 20 mg, and 40 mg ( 3 )

4 CONTRAINDICATIONS Vilazodone hydrochloride tablets are contraindicated in: Patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue, because of an increased risk of serotonin syndrome [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] . Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1)]. • Serotonin Syndrome [see Warnings and Precautions (5.2)]. • Increased Risk of Bleeding [see Warnings and Precautions (5.3)]. • Activation of Mania or Hypomania [see Warnings and Precautions (5.4)]. • Discontinuation Syndrome [see Warnings and Precautions (5.5)]. • Seizures [see Warnings and Precautions (5.6)]. • Angle-Closure Glaucoma [see Warnings and Precautions (5.7)]. • Hyponatremia [see Warnings and Precautions (5.8)]. • Sexual Dysfunction [see Warnings and Precautions (5.9)]. Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): diarrhea, nausea, vomiting, and insomnia (6) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions and varying lengths of time, 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 rates observed in practice. The most commonly observed adverse reactions in vilazodone hydrochloride tablets-treated with major depressive disorder (MDD) in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were diarrhea, nausea, vomiting, and insomnia. Patient Exposure The safety of vilazodone hydrochloride tablets were evaluated in 3,007 patients (18 to 70 years of age) diagnosed with MDD who participated in clinical studies, representing 676 patient-years of exposure. In an open-label 52 week study at 40 mg daily, 599 patients were exposed to vilazodone hydrochloride tablets for a total of 348 patient-years. The adverse reaction information presented below was derived from studies of vilazodone hydrochloride tablets 20 mg and 40 mg daily in patients with MDD including: • Four placebo-controlled 8 to 10-week studies in 2,233 patients, including 1,266 vilazodone hydrochloride tablets -treated patients; and • An open-label 52-week study of 599 vilazodone hydrochloride tablets -treated patients. These studies included a titration period of 10 mg daily for 7 days, followed by 20 mg daily for 7 days or to 40 mg daily over 2 weeks. In these clinical trials, vilazodone hydrochloride tablets were administered with food. Adverse reactions reported as reasons for discontinuation of treatment In these studies, 7.3% of the vilazodone hydrochloride tablets-treated patients discontinued treatment due to an adverse reaction, compared with 3.5% of placebo-treated patients. The most common adverse reaction leading to discontinuation in at least 1% of the vilazodone hydrochloride tablets-treated patients in the placebo-controlled studies was nausea (1.4%). Common adverse reactions in placebo-controlled MDD studies Table 2 shows the incidence of common adverse reactions occurring in ≥ 2% of vilazodone hydrochloride tablets-treated patients and greater than the rate of placebo-treated patients in MDD Studies. There were no dose-related adverse reactions between 20 mg and 40 mg reported. Table 2: Common Adverse Reactions Occurring in ≥2% of Vilazodone Hydrochloride Tablets-Treated Patients and Greater than the Rate of Placebo-Treated Patients System Organ Class Preferred Term Placebo N=967 Vilazodone Hydrochloride Tablets 20 mg/day N=288 Vilazodone Hydrochloride Tablets 40 mg/day N=978 Gastrointestinal disorders Diarrhea 10% 26% 29% Nausea 7% 22% 24% Dry mouth 5% 8% 7% Vomiting 2% 4% 5% Abdominal pain 1 3% 7% 4% Dyspepsia 2% 2% 3% Flatulence 1% 3% 3% Gastroenteritis 1% 1% 2% Abdominal distension 1% 2% 1% Nervous system disorders Headache 2 14% 15% 14% Dizziness 5% 6% 8% Somnolence 2% 4% 5% Paresthesia 1% 1% 2% Psychiatric disorders Insomnia 2% 7% 6% Abnor …

7 DRUG INTERACTIONS • CYP3A4 Inhibitors: The vilazodone hydrochloride tablet dose should not exceed 20 mg once daily when co-administered with strong CYP3A4 inhibitors (2.4, 7) • CYP3A4 Inducers: Consider increasing vilazodone hydrochloride tablets dosage by 2-fold, up to 80 mg once-daily over 1 to 2 weeks when used concomitantly with strong CYP3A4 inducers for greater than 14 days (2.4, 7) 7.1 Drugs Having Clinically Important Interactions With Vilazodone Hydrochloride Tablets Table 4: Clinically Important Drug Interactions with Vilazodone Hydrochloride Tablets Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of MAOIs and serotonergic drugs including vilazodone hydrochloride tablets increases the risk of serotonin syndrome. Vilazodone hydrochloride tablets are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)]. Other Serotonergic Drugs Concomitant use of vilazodone hydrochloride tablets with other serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during vilazodone hydrochloride tablets initiation. If serotonin syndrome occurs, consider discontinuation of vilazodone hydrochloride tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)]. Antiplatelet Agents and Anticoagulants Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with vilazodone hydrochloride tablets may potentiate the risk of bleeding. Inform patients of the increased risk of bleeding with the concomitant use of vilazodone hydrochloride tablets and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating, titrating, or discontinuing vilazodone hydrochloride tablets [see Warnings and Precautions (5.3)]. Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) The concomitant use of vilazodone hydrochloride tablets and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of vilazodone hydrochloride tablets alone [see Clinical Pharmacology (12.3)]. The vilazodone hydrochloride tablet dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin) The concomitant use of vilazodone hydrochloride tablets and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of vilazodone hydrochloride tablets alone [see Clinical Pharmacology (12.3)]. Based on clinical response, consider increasing the dosage of vilazodone hydrochloride tablets, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. Digoxin Digoxin is a narrow therapeutic index drug. Concomitant use of vilazodone hydrochloride tablets increased digoxin concentrations [see Clinical Pharmacology (12.3)] . Measure serum digoxin concentrations before initiating concomitant use of vilazodone hydrochloride tablets. Continue monitoring and reduce digoxin dose as necessary. 7.2 Drugs Having No Clinically Important Interactions With Vilazodone Hydrochloride Tablets Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and/or P-glycoprotein (except narrow therapeutic index drugs, e.g., digoxin), when vilazodone hydrochloride tablets are administered c …

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the newborn (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 register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org clinical-and-research-programs/pregnancyregistry/antidepressants/. Risk Summary There are no adequate and well-controlled studies of vilazodone hydrochloride in pregnant women. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. In animal reproduction studies, oral administration of vilazodone during the period of organogenesis at doses up to 48 and 17 times the maximum recommended human dose (MRHD) in rats and rabbits, respectively, resulted in decreased fetal body weight gain and delayed skeletal ossification but no teratogenic effects were observed. Decreased fetal body weight and delayed skeletal ossification were not observed at doses up to 10 and 4 times the MRHD in rats and rabbits, respectively [see Data ] . Clinical Considerations Disease-associated maternal and/or embryo/fetal risk A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal adverse reactions Exposure to SSRIs and SNRIs, including vilazodone hydrochloride, in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). Monitor neonates who were exposed to vilazodone hydrochloride in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [see Data ] . Data Human Data Third Trimester Exposure Neonates exposed to SSRIs or SNRIs late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on post-marketing reports. 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 SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome [see Warnings and Precautions ( 5.2 )] . Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20 th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997 - 2005 found a PPHN risk ratio of 2.4 …

12.1 Mechanism of action The mechanism of the action of vilazodone in the treatment of major depressive disorder is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through selective inhibition of serotonin reuptake. Vilazodone is also a partial agonist at serotonergic 5-HT 1A receptors; however, the net result of this action on serotonergic transmission and its role in vilazodone’s antidepressant effect are unknown.

11 DESCRIPTION Vilazodone hydrochloride tablets for oral administration contain polymorph Form IV vilazodone hydrochloride (HCl), a selective serotonin reuptake inhibitor and a 5HT 1A receptor partial agonist. Vilazodone HCl is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1 H -indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1). It has a molecular formula C 26 H 27 N 5 O 2 . HCl and its molecular weight is 477.99. The structural formula is: Vilazodone hydrochloride tablets are available as 10 mg, 20 mg, and 40 mg film-coated tablets containing 10 mg, 20 mg, and 40 mg of vilazodone HCl, respectively. In addition to the active ingredient, vilazodone hydrochloride tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3350, polyvinyl alcohol – part hydrolyzed, talc and titanium dioxide. Additionally, the 10 mg tablets contain iron oxide red, the 20 mg tablets contain iron oxide red and iron oxide yellow, and the 40 mg tablets contain FD&C Blue #2/indigo carmine aluminum lake. formula

10 OVERDOSAGE There is limited clinical trial experience regarding human overdose with vilazodone hydrochloride tablets. The adverse reactions associated with overdose of vilazodone hydrochloride tablets at doses of 200 to 280 mg (5 to 7 times the recommended dosage) as observed in clinical trials included serotonin syndrome, lethargy, restlessness, hallucinations, and disorientation. For current information on the management of poisoning or overdose, contact a poison control center at 1-800-222-1222. No specific antidotes for vilazodone are known. Removal of vilazodone by dialysis has not been studied; however, the high volume of distribution of vilazodone suggests that dialysis will not be effective in reducing vilazodone plasma concentrations.

16 HOW SUPPLIED/STORAGE AND HANDLING Vilazodone hydrochloride tablets 10 mg are pink, oval, film-coated, biconvex tablets debossed with ‘497’ on one side and plain on other side. Bottle of 30 NDC 46708-232-30 Bottle of 90 NDC 46708-232-90 Bottle of 500 NDC 46708-232-71 Bottle of 1000 NDC 46708-232-91 Vilazodone hydrochloride tablets 20 mg are orange, oval, film-coated, biconvex tablets debossed with ‘498’ on one side and ‘L’ on other side. Bottle of 30 NDC 46708-233-30 Bottle of 90 NDC 46708-233-90 Bottle of 500 NDC 46708-233-71 Bottle of 1000 NDC 46708-233-91 Vilazodone hydrochloride tablets 40 mg are light blue, oval, film-coated, biconvex tablets debossed with ‘499’ on one side and ‘L’ on other side. Bottle of 30 NDC 46708-234-30 Bottle of 90 NDC 46708-234-90 Bottle of 500 NDC 46708-234-71 Bottle of 1000 NDC 46708-234-91 Vilazodone hydrochloride tablets should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].