especially when co-administered with other serotonergic agents
`(including triptans, tricyclic antidepressants, fentanyl, lithium,
`
`tramadol, tryptophan, buspirone and St. John’s Wort). If such
`
`symptoms occur, discontinue VIIBRYD and initiate supportive
`treatment. If concomitant use of VIIBRYD with other serotonergic
`drugs is clinically warranted, patients should be made aware of a
`
`potential increased risk for serotonin syndrome, particularly during
`treatment initiation and dose increases (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 Forest
`
`Laboratories, Inc. at 1-800-678-1605 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, 7.2).
` CYP3A4 inhibitors: The VIIBRYD dose should be reduced to 20
`
`
`mg when co-administered with CYP3A4 strong inhibitors (2.3, 7.5).
` CYP3A4 inducers: Based on clinical response, consider increasing
`
`the dose of VIIBRYD up to 2-fold when used concomitantly with
`strong CYP3A4 inducers (e.g., carbamazepine) for greater than 14
`days. The maximum daily dose should not exceed 80 mg. (2.3, 7.5).
`
`
`
`_______________ 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 (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).
` 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).
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`Medication Guide.
`
`
`Revised: 04/2014
`
`
`
`
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`
`See full prescribing information for complete boxed warning.
`· Increased risk of suicidal thinking and behavior in children,
`
`
`
` adolescents, and young adults taking antidepressants (5.1).
`· Monitor for worsening and emergence of suicidal thoughts and
` behaviors (5.1)
`
` · VIIBRYD is not approved for use in pediatric patients (8.4).
`
`
`
` _________________
`_________________
`RECENT MAJOR CHANGES
`
`12/2013
`Boxed Warning
`
`
`
`
`
`
`
`
`12/2013
`Dosage and Administration (2.3)
`
`
`
`
`
`
`04/2014
`
`Warnings and Precautions (5.2)
`
`
`
`
`
`
` __________________
`__________________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 (2.1).
`
`
`
` 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
`(2.1).
`
`
` VIIBRYD should be taken with food. Administration without food
`can result in inadequate drug concentrations and may diminish
`effectiveness (2.1, 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____________________
`
`
` Serotonin Syndrome and MAOIs: Do not use MAOIs intended to
`treat psychiatric disorders with VIIBRYD or within 14 days of
`
`stopping treatment with VIIBRYD. Do not use VIIBRYD within 14
`days of stopping an MAOI intended to treat psychiatric disorders. In
`
`addition, do not start VIIBRYD in a patient who is being treated with
`linezolid or intravenous methylene blue (4.1).
`
`
` _______________
`_______________ WARNINGS AND PRECAUTIONS
`
` Suicidal Thoughts and Behaviors in Children, Adolescents and
`Young Adults: Monitor patients for clinical worsening and suicidal
`thinking or behavior (5.1).
`
`
` Serotonin Syndrome: Serotonin syndrome has been reported with
`SSRIs and SNRIs, including VIIBRYD, both when taken alone, but
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3484427
`
`

`

`
`
` 
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
` 
` 
`
`1
`INDICATIONS AND USAGE
` 
` 
`2
`DOSAGE AND ADMINISTRATION
` 
`
`Initial Treatment of Major Depressive
`
`2.1
` 
`Disorder
`
` 
`2.2 Maintenance/Continuation/Extended
`
` 
`Treatment
`
`
`Concomitant Use of CYP3A4 Inhibitors
`
` 
`or CYP3A4 Inducers
`
` 
` 
`2.4 Discontinuing Treatment
`
` 
`
`2.5
`Switching a Patient To or From a
`
`Monoamine Oxidase Inhibitor (MAOI)
`
` 
`Intended to Treat Psychiatric Disorders
`
` 
`2.6 Use of VIIBRYD with Other MAOIs
`
` 
`
`such as Linezolid or Methylene Blue
`
` 
`DOSAGE FORMS AND STRENGTHS
` 
`CONTRAINDICATIONS
` 
` 
`
`4.1 Monoamine Oxidase Inhibitors (MAOIs)
`
` 
`WARNINGS AND PRECAUTIONS
`
` 
`
`Suicidal Thoughts and Behaviors in
`
`5.1
`
`Children, Adolescents, and Young
`
` 
`Adults
`
` 
` 
`Serotonin Syndrome
`
`5.2
` 
` 
`Seizures
`
`5.3
` 
` 
`5.4 Abnormal Bleeding
`
` 
` 
`5.5 Activation of Mania/Hypomania
`
` 
`
`
`5.6 Discontinuation of Treatment with
`
` 
`VIIBRYD
`
` 
` 
`5.7 Hyponatremia
`
` 
`ADVERSE REACTIONS
`
` 
`
`Clinical Studies Experience
`
`6.1
`
`
`6.2
`Post-marketing Experience
`
` 
`DRUG INTERACTIONS
`
` 
`Central Nervous System (CNS)-Active
`
`7.1
` 
`Agents
`
` 
` 
`7.2 Monoamine Oxidase Inhibitors (MAOIs)
`
` 
` 
`7.3
`Serotonergic Drugs
`
` 
`7.4 Drugs that Interfere with Hemostasis
`
` 
`
`(e.g., NSAIDs, Aspirin, and Warfarin)
`
`
`Potential for Other Drugs to Affect
`
` 
`Vilazodone
`
`
` 
`2.3
`
` 
`3
` 
`4
`
` 
`5
`
` 
`6
`
` 
`7
`
` 
`7.5
`
`
`
`Reference ID: 3484427
`
` 
`7.6
`
`
`Potential for Vilazodone to Affect Other
`
` 
`Drugs
`
` 
` 
`7.7 Drugs Highly Bound to Plasma Protein
`
` 
` 
`7.8
`Triptans
`
` 
` 
`7.9 Alcohol
`
` 
`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
`
` 
` 
`Controlled Substance
`
`9.1
` 
` 
`9.2 Abuse and Dependence
`
` 
`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
`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
`
` 
`8
`
` 
`9
`
` 
`10
`
` 
`11
` 
`12
`
` 
`13
`
` 
`14
` 
`16
`
` 
`17
`
`
`
`

`

`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`Antidepressants increased the risk of suicidal thoughts and
`
`behavior in children, adolescents, and young adults in short-
`term studies. These studies did not show an increase in the
`risk of suicidal thoughts and behavior with antidepressant
`use in patients over age 24; there was a reduction in risk
`with antidepressant use in patients aged 65 and older [see
`
`
`
`Warnings and Precautions (5.1)].
`
`In patients of all ages who are started on antidepressant
`
`
`therapy, monitor closely for clinical worsening and for
`emergence of suicidal thoughts and behaviors. Advise
`families and caregivers of the need for close observation and
`communication with the prescriber [see Warnings and
`Precautions (5.1)].
`
`
`VIIBRYD is not approved for use in pediatric patients [see
`
`Use in Specific Populations (8.4)].
`
`
` 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
`
`2.1
`Initial Treatment of Major Depressive Disorder
`
`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 Clinical
`
`
`Pharmacology (12.3)].
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`
`
`Maintenance/Continuation/Extended Treatment
`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
`
`Concomitant Use of CYP3A4 Inhibitors or
`
`
`
`
`CYP3A4 Inducers
`Patients receiving concomitant CYP3A4 inhibitors:
`
`
`Reduce the VIIBRYD dose to 20 mg if co-administered
`
`
`with a strong inhibitor of CYP3A4 (e.g., ketoconazole).
`
`During co-administration with moderate inhibitors of
`
`
`CYP3A4 (e.g., erythromycin), the VIIBRYD dose should be
`
`reduced to 20 mg for patients with intolerable adverse events.
`
`The VIIBRYD dose should be readjusted to the original level
`when CYP3A4 inhibitors are discontinued [see Drug
`
`
`Interactions (7.5)].
`
`
`Patients receiving concomitant CYP3A4 inducers:
`
`Based on clinical response, consider increasing the dose of
`
`
`
`
`
`VIIBRYD up to 2-fold when concomitantly used with strong
`
`CYP3A4 inducers (e.g., carbamazepine) for greater than 14
`days. The maximum daily dose should not exceed 80 mg. If
`CYP3A4 inducers are discontinued, reduce the VIIBRYD
`
`dose to the original level in 14 days [see Drug Interactions
`
`
`(7.5)].
`
`2.4
` Discontinuing Treatment
`
`
`
`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
`
`
`Switching a Patient To or From a Monoamine
`Oxidase Inhibitor (MAOI) Intended to Treat
`
`Psychiatric Disorders
`
`
`At least 14 days should elapse between discontinuation of an
`
`MAOI intended to treat psychiatric disorders and initiation of
`therapy with VIIBRYD. Conversely, at least 14 days should
`
`be allowed after stopping VIIBRYD before starting an MAOI
`intended to treat psychiatric disorders [see Contraindications
`
`(4.1)].
`
`2.6
`
`
`
`Use of VIIBRYD with Other MAOIs such as
`Linezolid or Methylene Blue
`Do not start VIIBRYD in a patient who is being treated with
`
`linezolid or intravenous methylene blue because there is an
`
`increased risk of serotonin syndrome. In a patient who
`
`requires more urgent treatment of a psychiatric condition,
`other interventions, including hospitalization, should be
`considered [see Contraindications (4.1)].
`
`
`
`
`
`
`Reference ID: 3484427
`
`

`

` In some cases, a patient already receiving VIIBRYD therapy
`
`
`
` may require urgent treatment with linezolid or intravenous
`methylene blue. If acceptable alternatives to linezolid or
`intravenous methylene blue treatment are not available and the
`
`potential benefits of linezolid or intravenous methylene blue
`treatment are judged to outweigh the risks of serotonin
`
`
`syndrome in a particular patient, VIIBRYD should be stopped
`
`
`promptly, and linezolid or intravenous methylene blue can be
`
`administered. The patient should be monitored for symptoms
`
`
`of serotonin syndrome for 2 weeks or until 24 hours after the
`
`last dose of linezolid or intravenous methylene blue,
`
`
`whichever comes first. Therapy with VIIBRYD may be
`
`resumed 24 hours after the last dose of linezolid or
`
`intravenous methylene blue [see Warnings and Precautions
`(5.2)].
`
`
`The risk of administering methylene blue by non-intravenous
`
`
`routes (such as oral tablets or by local injection) or in
`
`
`intravenous doses much lower than 1 mg/kg with VIIBRYD is
`unclear. The clinician should, nevertheless, be aware of the
`
`possibility of emergent symptoms of serotonin syndrome with
`such use [see Warnings and Precautions (5.2)].
`
`
`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
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`CONTRAINDICATIONS
`
`
`4
`
`Monoamine Oxidase Inhibitors (MAOIs)
`4.1
`The use of MAOIs intended to treat psychiatric disorders with
`
`
`
`VIIBRYD or within 14 days of stopping treatment with
`
`VIIBRYD is contraindicated because of an increased risk of
`
`
`serotonin syndrome. The use of VIIBRYD 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 VIIBRYD 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)].
`
`5
`
`5.1
` Suicidal Thoughts and Behaviors in Children,
`
`
`Adolescents, and Young Adults
`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
`
`
`WARNINGS AND PRECAUTIONS
`
`Reference ID: 3484427
`
`
`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
`
`Increases Compared to Placebo
`14 additional cases
`5 additional cases
`
`Decreases Compared to Placebo
`
`1 fewer case
`
`6 fewer cases
`
`
`<18
`18-24
`
`25-64
`≥65
`
`
`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 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.
`
`
`
`
`
`
`
`Reference ID: 3484427
`
`
`5.2
`Serotonin Syndrome
`
`The development of a potentially life-threatening serotonin
`
`syndrome has been reported with SNRIs and SSRIs, including
`
`
`VIIBRYD, alone but particularly with concomitant use of
`
`other serotonergic drugs (including triptans, tricyclic
`antidepressants, fentanyl, lithium, tramadol, tryptophan,
`
`
`
`buspirone, and St. John’s Wort) and with drugs that impair
`
`
`
`metabolism of serotonin (in particular, MAOIs, both those
`intended to treat psychiatric disorders and also others, such as
`
`linezolid and intravenous methylene blue). Symptoms of
`
`serotonin syndrome were noted in 0.1% of MDD patients
`treated with VIIBRYD in premarketing clinical trials
`
`Serotonin syndrome symptoms may include mental status
`
`changes (e.g., agitation, hallucinations, delirium, and coma),
`autonomic instability (e.g., tachycardia, labile blood pressure,
`dizziness, diaphoresis, flushing, hyperthermia), neuromuscular
`
`symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia,
`
`
`incoordination), seizures, and/or gastrointestinal symptoms
`(e.g., nausea, vomiting, diarrhea). Patients should be
`
`monitored for the emergence of serotonin syndrome.
`
`
`
`The concomitant use of VIIBRYD with MAOIs intended to
`
`treat psychiatric disorders is contraindicated. VIIBRYD
`
`
`
`should also not be started in a patient who is being treated
`
`with MAOIs such as linezolid or intravenous methylene blue.
`
`
`All reports with methylene blue that provided information on
`the route of administration involved intravenous
`
`
`administration in the dose range of 1 mg/kg to 8 mg/kg. No
`
`reports involved the administration of methylene blue by other
`routes (such as oral tablets or local tissue injection) or at lower
`doses. There may be circumstances when it is necessary to
`
`
`initiate treatment with an MAOI such as linezolid or
`
`intravenous methylene blue in a patient taking VIIBRYD.
`
`VIIBRYD should be discontinued before initiating treatment
`
`with the MAOI [see Contraindications (4.1) and Dosage and
`
`
`Administration (2.5 and 2.6)].
`
`
`
`If concomitant use of VIIBRYD with other serotonergic drugs
`
`including, triptans, tricyclic antidepressants, fentanyl, lithium,
`tramadol, buspirone, tryptophan and St. John’s Wort is
`
`clinically warranted, patients should be made aware of a
`
`potential increased risk for serotonin syndrome, particularly
`
`during treatment initiation and dose increases.
`
`
`Treatment with VIIBRYD and any concomitant serotonergic
`
`
`
`agents, 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.
`
`
`

`

`
`
`5.4
`Abnormal Bleeding
`
`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.
`
`
`
`
`5.5
`Activation of Mania/Hypomania
`
`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.
`
`5.6
`Discontinuation of Treatment with VIIBRYD
`
`
`
`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 than 110 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,
`
`
`Reference ID: 3484427
`
`
`ADVERSE REACTIONS
`
`
`
`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.
`
`6
`
`The following adverse reactions are discussed in greater detail
`
`
`in other sections of the label.
`
` Clinical Worsening and Suicide Risk [see Warnings
`
`and Precautions (5.1)]
`
`
`
` Serotonin Syndrome [see Warnings and Precautions
`
`(5.2)]
`
`
`
`
` Seizure [see Warnings and Precautions (5.3)]
`
`
`
` Abnormal Bleeding [see Warnings and Precautions
`
`(5.4)]
`
` Activation of Mania/Hypomania [see Warnings and
`
`Precautions (5.5)]
`
`
`
` Discontinuation of Treatment with VIIBRYD [see
`
`Warnings and Precautions (5.5)]
`
`
`
` Hyponatremia [see Warnings and Precautions (5.7)]
`
`
`
`6.1
`Clinical Studies Experience
`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
`
`
`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
`
`System Organ Class
` Preferred Term
`
`VIIBRYD
`40 mg/day
`N = 436
`
`Placebo
`
`N = 433
`
`
`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***
`
`
`
`
`
`Reference ID: 3484427
`
`
`
`
`
`28
`23
`
`8
`5
`3
`3
`3
`
`9
`3
`3
`2
`
`