CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022567Orig1s000
`
`LABELING
`
`
`
`
`

`

`VIIBRYD™ (vilazodone hydrochloride) Tablets
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`VIIBRYD™ safely and effectively. See full prescribing information for
`VIIBRYD.
`
`VIIBRYD (vilazodone HCl) Tablets for oral administration
`Initial U.S. Approval: 2011
`
`
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`
`See full prescribing information for complete boxed warning.
`Increased risk of suicidal thinking and behavior in children, adolescents,
`and young adults taking antidepressants for major depressive disorder
`(MDD) and other psychiatric disorders (5.1).
`VIIBRYD is not approved for use in pediatric patients (8.4).
`
`__________________ INDICATIONS AND USAGE _________________
`VIIBRYD is indicated for the treatment of major depressive disorder (MDD).
`The efficacy of VIIBRYD was established in two 8-week, placebo-controlled
`trials in adult patients with MDD (1, 14).
` _______________ DOSAGE AND ADMINISTRATION ______________
`• The recommended dose for VIIBRYD is 40 mg once daily (2).
`• VIIBRYD should be titrated to the 40 mg dose, starting with an initial
`dose of 10 mg once daily for 7 days, followed by 20 mg once daily for an
`additional 7 days, and then increased to 40 mg once daily (2).
`• VIIBRYD should be taken with food. Administration without food can
`result in inadequate drug concentrations and may diminish effectiveness
`(2, 12.3).
`• When discontinuing treatment, reduce the dose gradually (2.4).
` ______________ DOSAGE FORMS AND STRENGTHS _____________
`VIIBRYD is available as 10 mg, 20 mg and 40 mg tablets (3).
`
`____________________CONTRAINDICATIONS ___________________
`• Monoamine Oxidase Inhibitors: Do not use VIIBRYD concomitantly
`with an MAOI or within 14 days of stopping or starting an MAOI (4.1).
`
`_______________ WARNINGS AND PRECAUTIONS_______________
`Clinical Worsening/Suicide Risk: Monitor patients for clinical worsening
`and suicidal thinking or behavior (5.1).
`Serotonin Syndrome or Neuroleptic Malignant (NMS)-like Syndrome:
`Can occur with treatment. Discontinue and initiate supportive treatment (5.2).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Seizures: Can occur with treatment. Use with caution in patients with a
`seizure disorder (5.3).
`Abnormal Bleeding: Treatment can increase the risk of bleeding. Use with
`caution in association with nonsteroidal anti-inflammatory drugs (NSAIDs),
`aspirin, or other drugs that affect coagulation (5.4).
`Activation of Mania/Hypomania: Can occur with treatment. Screen patients
`for bipolar disorder (5.5).
`Discontinuation of Treatment with VIIBRYD: A gradual reduction in dose
`is recommended rather than an abrupt cessation (5.6).
`Hyponatremia: Can occur in association with the syndrome of inappropriate
`antidiuretic hormone secretion (SIADH) (5.7).
` ____________________ADVERSE REACTIONS____________________
`The most common adverse reactions (incidence ≥ 5% and at least twice the
`rate of placebo) are: diarrhea, nausea, vomiting, and insomnia (6).
`To report SUSPECTED ADVERSE REACTIONS, contact Trovis
`Pharmaceuticals at 1-877-878-7200 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`____________________DRUG INTERACTIONS____________________
`MAOIs: Do not use VIIBRYD concomitantly with an MAOI or within 14
`days of stopping or starting an MAOI (4.1, 7.1).
`CYP3A4 inhibitors: The VIIBRYD dose should be reduced to 20 mg when
`co-administered with CYP3A4 strong inhibitors (7.3).
`CYP3A4 inducers: Concomitant use of VIIBRYD with inducers of CYP3A4
`can result in inadequate drug concentrations and may diminish effectiveness.
`The effect of CYP3A4 inducers on systemic exposure of vilazodone has not
`been evaluated (7.3).
` _______________ USE IN SPECIFIC POPULATIONS _______________
`Pregnancy: There are no controlled human data regarding VIIBRYD use
`during pregnancy. Use only if the potential benefits outweigh the potential
`risks (2.3, 8.1).
`Nursing Mothers: There are no human data regarding VIIBRYD
`concentrations in breast milk. Women should breast feed only if the potential
`benefits outweigh the potential risks (8.3, 2.3).
`Pediatric Use: The safety and efficacy of VIIBRYD in pediatric patients have
`not been studied (8.4).
`Geriatric Use: No dose adjustment is recommended on the basis of age (8.5).
`Hepatic Impairment: No dose adjustment is recommended in patients with
`mild or moderate hepatic impairment. VIIBRYD has not been studied in
`patients with severe hepatic impairment (8.6).
`Renal Impairment: No dose adjustment is recommended in patients with mild,
`moderate, or severe renal impairment. (8.7).
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: January 2010
`
`
`Reference ID: 2894777
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: <<SUICIDALITY AND ANTIDEPRESSANT DRUGS>>
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Initial Treatment of Major Depressive Disorder
`2.2 Maintenance/Continuation/Extended Treatment
`2.3 Dosing in Special Populations
`2.3 Discontinuing Treatment
`2.4 Monoamine Oxidase Inhibitors (MAOI)
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`4.1 Monoamine Oxidase Inhibitors
`5 WARNINGS AND PRECAUTIONS
`5.1
` Clinical Worsening and Suicide Risk
`5.2
`Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-
`like Reactions
`Seizures
`5.3
`5.4 Abnormal Bleeding
`5.5 Activation of Mania/Hypomania
`5.6 Discontinuation of Treatment with VILAZODONE
`5.7
` Hyponatremia
`ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`DRUG INTERACTIONS
`7.1 Central Nervous System (CNS)-Active Agents
`7.2 Drugs that Interfere with Hemostasis (e.g., NSAIDs, aspirin, and
`warfarin)
`Potential for Other Drugs to Affect Vilazodone
`7.3
`Potential for Vilazodone to Affect Other Drugs
`7.4
`7.5 Drugs Highly Bound to Plasma Protein
`
`3
`4
`
`6
`
`7
`
`
`
`
`8
`
`9
`
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Impairment
`8.7 Renal Impairment
`8.8 Gender Effect
`DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse and Dependence
`10 OVERDOSAGE
`10.1 Human Experience
`10.2 Management of Overdose
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`14
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`PATIENT COUNSELING INFORMATION
`17.1
`Information for Patients
`17.2 Medication Guide
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`11
`12
`
`13
`
`17
`
`
`Reference ID: 2894777
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents,
`and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone
`considering the use of VIIBRYD or any other antidepressant in a child, adolescent, or young adult must balance this risk
`with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to
`placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and
`older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.
`Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for
`clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close
`observation and communication with the prescriber. VIIBRYD is not approved for use in pediatric patients [see Warnings
`and Precautions (5.1), Use in Specific Populations (8.4), and Patient Counseling Information (17.1)]
`
`
`
`
`INDICATIONS AND USAGE
`
` 1
`
`
`VIIBRYD is indicated for the treatment of major depressive disorder (MDD). The efficacy of VIIBRYD was established in two 8-week, randomized, double-blind,
`placebo-controlled trials in adult patients with a diagnosis of MDD [see Clinical Studies (14)].
`
`Major depressive disorder consists of one or more major depressive episodes. A major depressive episode (DSM-IV-TR) implies a prominent and relatively persistent
`(nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms:
`depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation,
`increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.
`
` 2
`
`
`
`DOSAGE AND ADMINISTRATION
`
`Initial Treatment of Major Depressive Disorder
`
`Maintenance/Continuation/Extended Treatment
`
`Dosing in Special Populations
`
`
`2.1
`
`The recommended dose for VIIBRYD is 40 mg once daily. VIIBRYD should be titrated, starting with an initial dose of 10 mg once daily for 7 days, followed by 20 mg
`once daily for an additional 7 days, and then an increase to 40 mg once daily. VIIBRYD should be taken with food. VIIBRYD blood concentrations (AUC) in the fasted
`state can be decreased by approximately 50% compared to the fed state, and may result in diminished effectiveness in some patients [see Pharmacokinetics (12.3)].
`
`2.2
`
`The efficacy of VIIBRYD has not been systematically studied beyond 8 weeks. It is generally agreed that acute episodes of major depressive disorder require several
`months or longer of sustained pharmacologic therapy. Patients should be reassessed periodically to determine the need for maintenance treatment and the appropriate
`dose for treatment.
`
`2.3
`
`Pregnant Women: Neonates exposed to serotonergic antidepressants late in the third trimester have developed complications requiring prolonged hospitalization,
`respiratory support, and tube feeding. When treating pregnant women with VIIBRYD, consider whether the potential benefits outweigh the potential risks of treatment
`[see Pregnancy (8.1)].
`
`Nursing Mothers: There are no clinical data regarding the effect of VIIBRYD on lactation and nursing [see Nursing Mothers (8.3)]. Breastfeeding in women treated
`with VIIBRYD should be considered only if the potential benefit outweighs the potential risk.
`
`Pediatric Patients: The safety and efficacy of VIIBRYD have not been studied in pediatric patients [see Pediatric Use (8.4)].
`
`Geriatric Patients: No dose adjustment is recommended on the basis of age [see Geriatric Use (8.5)].
`
`Hepatic Impairment: No dose adjustment is recommended in patients with mild or moderate hepatic impairment. VIIBRYD has not been studied in severe hepatic
`impairment [see Hepatic Impairment (8.6)].
`
`Renal Impairment: No dose adjustment is recommended in patients with mild, moderate, or severe renal impairment. [see Renal Impairment (8.7)].
`
`Gender: No dose adjustment is recommended on the basis of gender [see Gender Effect (8.8)].
`
`2.4
`
`Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as VIIBRYD. Gradual dose reduction is recommended, instead of abrupt
`discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing VIIBRYD. 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
`(5.6)].
`
`2.5
`
`At least 14 days must elapse between discontinuation of an MAOI and initiation of therapy with VIIBRYD. In addition, at least 14 days must be allowed after stopping
`VIIBRYD before starting an MAOI [see Contraindications (4.1)].
`
`Discontinuing Treatment
`
`Monoamine Oxidase Inhibitors (MAOI)
`
`
`Reference ID: 2894777
`
`3
`
`

`

`DOSAGE FORMS AND STRENGTHS
`
`
`
` 3
`
`
`VIIBRYD Tablets are available as 10 mg, 20 mg and 40 mg immediate-release, film-coated tablets.
`10 mg pink, oval tablet, debossed with 10 on one side
`20 mg orange, oval tablet, debossed with 20 on one side
`40 mg blue, oval tablet, debossed with 40 on one side
`
`
`
`CONTRAINDICATIONS
`
` 4
`
`
`Monoamine Oxidase Inhibitors
`4.1
`VIIBRYD must not be used concomitantly in patients taking MAOIs or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious,
`sometimes fatal, drug interactions with serotonergic drugs. These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea,
`vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid
`fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Allow at least 14 days after stopping VIIBRYD
`before starting an MAOI [see Drug Interactions (7.1)].
`
` 5
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`Clinical Worsening and Suicide Risk
`5.1
`Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and
`behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission
`occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has
`been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients
`during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs]
`and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD
`and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24;
`there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
`
`The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included
`a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other
`psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was
`considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences
`in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively
`stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are
`provided in Table 1.
`
`Table 1
`Age Range
`
`Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
`
`
`
`<18
`
`18-24
`
`
`
`25-64
`
`≥65
`
`Increases Compared to Placebo
`
`14 additional cases
`
`5 additional cases
`
`Decreases Compared to Placebo
`
`1 fewer case
`
`6 fewer cases
`
`
`No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect
`on suicide.
`
`It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled
`maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.
`
`All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality,
`and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or
`decreases.
`
`The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania,
`and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both
`psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of
`suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
`
`Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse,
`or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe,
`abrupt in onset, or were not part of the patient's presenting symptoms.
`
`If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be
`associated with certain symptoms [see Warnings and Precautions (5.6) and Dosage and Administration (2.4)].
`
`Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be
`alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as
`
`Reference ID: 2894777
`
`4
`
`

`

`the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and
`caregivers. Prescriptions for VIIBRYD should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of
`overdose [see also Patient Counseling Information (17.1)].
`
`Screening patients for bipolar disorder
`A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an
`episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
`symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms
`should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family
`history of suicide, bipolar disorder, and depression. It should be noted that VIIBRYD is not approved for use in treating bipolar depression.
`
`Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
`5.2
`The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions has been reported with antidepressants
`alone, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs that impair metabolism of serotonin (including MAOIs), or with
`antipsychotics or other dopamine antagonists. Symptoms of serotonin syndrome were noted in 0.1% of patients treated with VIIBRYD. Serotonin syndrome symptoms
`may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular
`aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can
`resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients
`should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
`
`The concomitant use of VIIBRYD with MAOIs intended to treat depression is contraindicated. [see Contraindications (4.1)].
`
`If concomitant treatment of VIIBRYD with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised,
`particularly during treatment initiation and dose increases [see Drug Interactions (7.1)].
`
`The concomitant use of VIIBRYD with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions (7.1)].
`
`
`Treatment with VIIBRYD and any concomitant serotonergic (SSRI, serotonin–norepinephrine reuptake inhibitor [SNRI], triptan, buspirone, tramadol, etc.) or
`antidopaminergic drugs, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be
`initiated.
`
`Seizures
`5.3
`VIIBRYD has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Like other
`antidepressants, VIIBRYD should be prescribed with caution in patients with a seizure disorder.
`
`Abnormal Bleeding
`5.4
`The use of drugs that interfere with serotonin reuptake inhibition, including VIIBRYD, may increase the risk of bleeding events. Concomitant use of aspirin,
`nonsteroidal anti-inflammatory drugs (NSAIDS), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and
`cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding
`events related to SSRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
`
`Patients should be cautioned about the risk of bleeding associated with the concomitant use of VIIBRYD and NSAIDs, aspirin, or other drugs that affect coagulation or
`bleeding.
`
`Activation of Mania/Hypomania
`5.5
`Symptoms of mania/hypomania were reported in 0.1% of patients treated with VIIBRYD in clinical studies. Activation of mania/hypomania has also been reported in a
`small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use VIIBRYD cautiously
`in patients with a history or family history of bipolar disorder, mania, or hypomania.
`
`Discontinuation of Treatment with VIIBRYD
`5.6
`There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the
`following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache,
`lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious
`discontinuation symptoms.
`
`Monitor patients for these symptoms when discontinuing VIIBRYD. Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease
`in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate
`[see Dosage and Administration, (2.4)].
`
`Hyponatremia
`5.7
`Although no cases of hyponatremia resulting from VIIBRYD treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with
`SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum
`sodium lower than110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs. Also, patients taking diuretics or
`who are otherwise volume depleted can be at greater risk. Discontinuation of VIIBRYD in patients with symptomatic hyponatremia and appropriate medical
`intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and
`unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma,
`respiratory arrest, and death.
`
`
`Clinical Studies Experience
`6.1
`The most commonly observed adverse reactions in VIIBRYD-treated MDD patients in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo)
`were: diarrhea, nausea, vomiting, and insomnia.
`
`Patient Exposure
`
`
`Reference ID: 2894777
`
`5
`
`
`
`ADVERSE REACTIONS
`
` 6
`
`

`

`The safety of VIIBRYD was evaluated in 2,177 patients (18-70 years of age) diagnosed with MDD who participated in clinical studies, representing 552 patient-years
`of exposure. In an open-label 52 week study at 40 mg daily, 599 patients were exposed to VIIBRYD for a total of 348 patient-years.
`
`The information presented in these sections was derived from studies of VIIBRYD 40 mg daily in major depressive disorder including: 1) 2 placebo-controlled 8-week
`studies in 861 patients, including 436 receiving vilazodone; and 2) an open-label 52-week study of 599 patients. These studies included a titration period of 10 mg daily
`for 7 days followed by 20 mg daily for 7 days. In these clinical trials, VIIBRYD was administered with food.
`
`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.
`
`Adverse reactions reported as reasons for discontinuation of treatment
`In the placebo-controlled studies of MDD there was no single adverse reaction leading to discontinuation in > 1% of the patients. Overall, 7.1% of the patients who
`received VIIBRYD discontinued treatment due to an adverse reaction, compared with 3.2% of placebo-treated patients in these studies.
`
`Common adverse reactions in placebo-controlled MDD studies
`Table 2 shows the incidence of common adverse reactions that occurred in ≥ 2% of VIIBRYD-treated MDD patients (and greater than in placebo-treated patients) in the
`placebo-controlled studies.
`
`Table 2: Common Adverse Reactions Occurring in ≥2% of VIIBRYD-treated Patients and > Placebo-treated Patients
`Placebo
`System Organ Class
`VIIBRYD
`
` Preferred Term
`40 mg/day
`N = 433
`N = 436
`
`Gastrointestinal disorders
` Diarrhea
`
` Nausea
`
` Dry mouth
`
` Vomiting
`
` Dyspepsia
`
` Flatulence
`
` Gastroenteritis
`
`Nervous system disorders
` Dizziness
`
` Somnolence
`
` Paresthesia
`
` Tremor
`
`Psychiatric disorders
` Insomnia
`
` Abnormal dreams
`
` Libido decreased
`
` Restlessness *
`
` Orgasm abnormal**
`
`General disorders
` Fatigue
`
` Feeling jittery
`
`Cardiac disorders
` Palpitations
`
`Musculoskeletal and connective tissue disorders
` Arthralgia
`
`Reproductive system and breast disorders
` Delayed ejaculation***
`
` Erectile dysfunction***
`
`Metabolism and nutrition disorders
`
`
`Reference ID: 2894777
`
`
`
`
`
`28
`
`23
`
`8
`
`5
`
`3
`
`3
`
`3
`
`
`
`9
`
`3
`
`3
`
`2
`
`
`
`6
`
`4
`
`4
`
`3
`
`3
`
`
`
`4
`
`2
`
`
`
`2
`
`
`
`3
`
`
`
`2
`
`2
`
`
`
`9
`
`5
`
`5
`
`1
`
`2
`
`2
`
`<1
`
`
`
`5
`
`2
`
`1
`
`0
`
`
`
`2
`
`1
`
`<1
`
`<1
`
`0
`
`
`
`3
`
`<1
`
`
`
`<1
`
`
`
`2
`
`
`
`0
`
`1
`
`
`
`6
`
`

`

` Increased appetite
`*Includes restlessness, akathisia, and restless legs syndrome
`**Includes orgasm abnormal and anorgasmia
`***Male patients only (Placebo n=182; VIIBRYD n=170)
`
`Table 3: Sexual Adverse Reactions: Percentage in the Placebo-Controlled Studies
`
`2
`
`1
`
`
`Preferred Term
`
`Decreased libido
`
`Abnormal orgasm*
`
`Delayed ejaculation
`
`Erectile dysfunction
`
`Males
`
`Females
`
`VIIBRYD
`N= 170
`
`Placebo
`N= 182
`
`VIIBRYD
`N=266
`
`Placebo
`N=251
`
`5
`
`4
`
`2
`
`2
`
`0
`
`0
`
`0
`
`1
`
`3
`
`2
`
`−
`
`−
`
`<1
`
`0
`
`−
`
`−
`
`2
`
`0
`
`<1
`
`<1
`
`Sexual dysfunction
`− Not applicable
`*Includes anorgasmia
`
`Laboratory Tests
`VIIBRYD has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (including liver function tests), hematology
`and urinalysis, as measured in placebo-controlled studies. These studies include analysis of (1) mean change from baseline and (2) the proportion of patients meeting
`criteria for potentially clinically significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-
`controlled studies.
`
`ECG
`VIIBRYD has not been associated with any clinically significant effect on ECG parameters, including QT, QTc, PR and QRS intervals, or with any arrhythmogenic
`potential. ECGs were evaluated in a thorough QTc study at doses up to 80 mg daily with food and in the placebo-controlled studies [see Pharmacodynamics (12.2)].
`
`Vital Signs
`VIIBRYD has not been associated with any clinically significant effect on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in
`placebo-controlled studies. These studies included analyses of (1) change from baseline, and (2) the proportion of patients meeting criteria for potentially clinically
`significant changes from baseline. Results from a 52-week open-label study were consistent with the findings from the placebo-controlled studies.
`
`Weight
`VIIBRYD had no effect on body weight as measured by the mean change from baseline in the 8-week, placebo-controlled studies. The mean changes in weight were
`+0.16 kg in the VIIBRYD group and +0.18 kg in the placebo group. The proportions of patients with a weight gain > 7% were 0.9% in the VIIBRYD group and 1.2%
`in the placebo group. The proportions of patients with a weight decrease > 7% were 1.4% in the VIIBRYD group and 1.4% in the placebo group.
`
`Other adverse reactions observed in clinical studies
`The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so
`general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.
`
`Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent
`adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients:
`
`Cardiac disorders: infrequent: ventricular extrasystoles
`
`Eye disorders: frequent: vision blurred, dry eye; infrequent: cataracts
`
`General disorders: infrequent: feeling abnormal
`
`Metabolism and nutrition disorders: frequent: decreased appetite
`
`Nervous System: frequent: sedation, migraine; infrequent: dysgeusia
`
`Psychiatric disorders: infrequent: panic attack, mania
`
`Renal and Urinary disorder: infrequent: pollakiuria
`
`Skin and subcutaneous tissue disorders: frequent: hyperhidrosis, night sweats
`
`
` 7
`
`
`
`DRUG INTERACTIONS
`
`
`Central Nervous System (CNS)-Active Agents
`7.1
`The risk of using VIIBRYD in combination with other CNS-active drugs has not been systematically evaluated. Consequently, use caution when VIIBRYD is
`prescribed in combination with other CNS-active drugs.
`
`
`Reference ID: 2894777
`
`7
`
`

`

`Monoamine Oxidase Inhibitors (MAOI)
`Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from a MAOI and started on
`antidepressant(s) with pharmacological properties similar to VIIBRYD (e.g. SSRIs), or who have recently had SSRI therapy discontinued prior to initiation of an
`MAOI. Do not prescribe VIIBRYD concomitantly with an MAOI or within 14 days of discontinuing or starting an MAOI