`
`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 (2.1).
`
`
`
`• 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
`
`• 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 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, 7.1).
`
`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 (2.3, 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 (2.3, 8.6).
`
`Renal Impairment: No dose adjustment is recommended in patients with mild,
`moderate, or severe renal impairment. (2.3, 8.7).
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`Revised: April 2011
`
`
`
`
`Reference ID: 3018048
`
`
`
`Page 1 of 14
`
`
`
`3
`
`4
`
`
`
`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
`
`
`2.4 Discontinuing Treatment
`
`
`
`2.5 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 VIIBRYD
`
`
`
` Hyponatremia
`
`5.7
`
`
`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
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`
`
`
`6
`
`
`7
`
`
`8
`
`
`9
`
`
`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: 3018048
`
`
`
`Page 2 of 14
`
`
`
`
`
`
`
`
`
` 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
`
`Initial Treatment of Major Depressive Disorder
`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 Clinical Pharmacology (12.3)].
`
`
`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.
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`Reference ID: 3018048
`
`
`
`Dosing in Special Populations
`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 Use in Specific Populations (8.1)].
`
`
`Nursing Mothers: There are no clinical data regarding the effect of VIIBRYD
`on lactation and nursing [see Use in Specific Populations (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 Use in Specific Populations (8.4)].
`
`Geriatric Patients: No dose adjustment is recommended on the basis of age
`[see Use in Specific Populations (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 Use in Specific Populations (8.6)].
`
`Renal Impairment: No dose adjustment is recommended in patients with mild,
`moderate, or severe renal impairment [see Use in Specific Populations (8.7)].
`
`
`Gender: No dose adjustment is recommended on the basis of gender [see Use
`
`in Specific Populations (8.8)].
`
`
`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
`Monoamine Oxidase Inhibitors (MAOI)
`
`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) and Drug Interactions (7.1)].
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`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
`
`5.1
`Clinical Worsening and Suicide Risk
`
`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
`Page 3 of 14
`
`WARNINGS AND PRECAUTIONS
`
`
`
`
`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
`Increases Compared to Placebo
`
`
`
`<18
`
`14 additional cases
`
`
`18-24
`
`5 additional cases
`
`
`
`Decreases Compared to Placebo
`
`25-64
`
`1 fewer case
`
`≥65
`
`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.
`
`
`
`
`
`
`Reference ID: 3018048
`
`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.
`
`
`5.2
`
`Serotonin Syndrome or Neuroleptic Malignant Syndrome
`
`(NMS)-like Reactions
`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.
`
`
`Page 4 of 14
`
`
`
`
`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.
`
`
`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.
`
`
`
`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.
`
`
`6
`
`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
`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.
`
`
`
`
`ADVERSE REACTIONS
`
`
`
`Reference ID: 3018048
`
`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***
`
`
`
`
`
`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
`
`Page 5 of 14
`
`
`
`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
`
`
`
`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.
`
`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 [see
`Contraindications (4.1)].
`
`Serotonergic Drugs
`Based on the mechanism of action of VIIBRYD and the potential for
`serotonin toxicity, also known as serotonin syndrome, caution is advised when
`VIIBRYD is coadministered with other drugs that may affect the serotonergic
`neurotransmitter systems (e.g., MAOI, SSRIs, SNRIs, triptans, buspirone,
`tramadol, and tryptophan products etc.) [see Warnings and Precautions (5.2)].
`
`7.2
`
`Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin,
`and Warfarin)
`Serotonin release by platelets plays an important role in hemostasis.
`Epidemiological studies of case-control and cohort design have demonstrated
`an association between use of psychotropic drugs that interfere with serotonin
`reuptake and the occurrence of upper gastrointestinal bleeding. These studies
`have also shown that concurrent use of an NSAID or aspirin may potentiate
`this risk of bleeding. Altered anticoagulant effects, including increased
`bleeding, have been reported when SSRIs and SNRIs are coadministered with
`warfarin. Patients receiving warfarin therapy should be carefully monitored
`when VIIBRYD is initiated or discontinued [see Warnings and Precautions
`(5.4)].
`
`7.3 Potential for Other Drugs to Affect Vilazodone
`
`Figure 1. Impact of other drugs on Vilazodone PK
`
`
`Change due to
`
`PK
`
`Fold Change and 90% CI
`
`Recommendation
`
`Ethanol:
`
`CYP3A4 Inhibitors:
`Ketoconazole
`
`Proton Pump Inhibitors:
`Pantoprazole
`
`Cmax
`AUC
`
`Cmax
`AUC
`
`Cmax
`AUC
`
`No dose adjustment
`
`Maximum dose: 20 mg
`
`No dose adjustment
`
`1.50 2.00
`1.00
`0.50
`Change relative to reference
`Page 6 of 14
`
`
`
`
`
`
`
`DRUG INTERACTIONS
`
` 7
`
`
`
`
`Metabolism and nutrition disorders
`2
` 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
`
`
`
`1
`
`
`Preferred
`Term
`
`D