Vilazodone Hydrochloride

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 tablets 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.

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue vilazodone hydrochloride tablets and serotonergic agents and initiate supportive treatment ( 5.2 ) Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk ( 5.3 ) Activation of Mania/Hypomania: Screen patients for bipolar disorder ( 5.4 ) Seizures: Can occur with treatment. Use with caution in patients with a seizure disorder ( 5.6 ) Angle Closure Glaucoma: Avoid use of antidepressants, including vilazodone hydrochloride tablets, in patients with untreated anatomically narrow angles ( 5.7 ) Sexual Dysfunction: Vilazodone hydrochloride tablets may cause symptoms of sexual dysfunction ( 5.9 ) 5.1 Suicidal Thoughts and Behavior 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 over 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater in antidepressant-treated patients 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 with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range (years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18 to 24 5 additional patients Decreases Compared to Placebo 25 to 64 1 fewer patient ≥65 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 studies 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 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 vilazodone hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitor (SSRIs), including vilazodone hydrochloride, 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, meperidine, methadone, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ) and Drug Interactions ( 7 )]. Serotonin syndrome can also occur when these drugs are used alone. Symptoms of serotonin syndrome were noted in 0.1% of MDD patients treated with vilazod…

4 CONTRAINDICATIONS Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4 ). 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 )].

7 DRUG INTERACTIONS CYP3A4 Inhibitors: The vilazodone hydrochloride dose should not exceed 20 mg once daily when co-administered with strong CYP3A4 inhibitors ( 2.4 , 7 ). CYP3A4 Inducers: Consider increasing vilazodone hydrochloride 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 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 increases the risk of serotonin syndrome. Vilazodone hydrochloride is 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 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 initiation. If serotonin syndrome occurs, consider discontinuation of vilazodone hydrochloride 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 may potentiate the risk of bleeding. Inform patients of the increased risk of bleeding with the concomitant use of vilazodone hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating, titrating, or discontinuing vilazodone hydrochloride [see Warnings and Precautions ( 5.3 )] . Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) The concomitant use of vilazodone hydrochloride and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of vilazodone hydrochloride alone [see Clinical Pharmacology ( 12.3 )] . The vilazodone hydrochloride 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 and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of vilazodone hydrochloride alone [see Clinical Pharmacology ( 12.3 )] . Based on clinical response, consider increasing the dosage of vilazodone hydrochloride, 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 increased digoxin concentrations [see Clinical Pharmacology ( 12.3 )] . Measure serum digoxin concentrations before initiating concomitant use of vilazodone hydrochloride. 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 is administered concomitantly [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]

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 SSRIs, 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 ( 5.3 ) and Clinical Considerations] . 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. Maternal Adverse Reactions Use of vilazodone hydrochloride in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.3 )] . 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 to 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 hea…

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 Accord Healthcare Inc. at 1-866-941-7875 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-treated patients 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 was 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 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-treated patients; and An open-label 52-week study of 599 vilazodone hydrochloride-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-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-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-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-treated Patients and Greater than the Rate of Placebo-treated Patients 1 Includes abdominal discomfort, abdominal pain upper, and abdominal pain. 2 Includes headache and tension headache 3 Includes restlessness, akathisia, and restless legs syndrome Sexual adverse reactions are presented in Table 3 System Organ Class Preferred Term Placebo N=967 Vilazodone hydrochloride 20 mg/day N=288 Vilazodone hydrochloride 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 disor…