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 (Vilazodone hydrochloride) 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 (Vilazodone hydrochloride) is not approved for use in pediatric patients []

Viibryd (Vilazodone hydrochloride) is indicated for the treatment of major depressive disorder (MDD). The efficacy of Viibryd (Vilazodone hydrochloride) was established in two 8-week, randomized, double-blind, placebo-controlled trials in adult patients with a diagnosis of MDD .

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.

Viibryd (Vilazodone hydrochloride) 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

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.

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 [].

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 (Vilazodone hydrochloride) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose .

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 (Vilazodone hydrochloride) is not approved for use in treating bipolar depression.

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 (Vilazodone hydrochloride) . 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 (Vilazodone hydrochloride) with MAOIs intended to treat depression is contraindicated .

If concomitant treatment of Viibryd (Vilazodone hydrochloride) with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases .

The concomitant use of Viibryd (Vilazodone hydrochloride) with serotonin precursors (such as tryptophan) is not recommended .

Treatment with Viibryd (Vilazodone hydrochloride) 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.

The use of drugs that interfere with serotonin reuptake inhibition, including Viibryd (Vilazodone hydrochloride) , 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 (Vilazodone hydrochloride) and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.

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 (Vilazodone hydrochloride) . 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 .

The risk of using Viibryd (Vilazodone hydrochloride) in combination with other CNS-active drugs has not been systematically evaluated. Consequently, use caution when Viibryd (Vilazodone hydrochloride) 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 (Vilazodone hydrochloride) (e.g. SSRIs), or who have recently had SSRI therapy discontinued prior to initiation of an MAOI. Do not prescribe Viibryd (Vilazodone hydrochloride) concomitantly with an MAOI or within 14 days of discontinuing or starting an MAOI .

Serotonergic Drugs
Based on the mechanism of action of Viibryd (Vilazodone hydrochloride) and the potential for serotonin toxicity, also known as serotonin syndrome, caution is advised when Viibryd (Vilazodone hydrochloride) is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., MAOI, SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.) .

Figure 1. Impact of other drugs on Vilazodone PK
Inhibitors of CYP3A4
Metabolism by CYP3A4 is a major elimination pathway for vilazodone. Concomitant use of Viibryd (Vilazodone hydrochloride) and strong inhibitors of CYP3A4 (e.g., ketoconazole) can increase vilazodone plasma concentrations by approximately 50% (see Figure 1). The Viibryd (Vilazodone hydrochloride) dose should be reduced to 20 mg if co-administered with a strong inhibitor of CYP3A4. During co-administration with moderate inhibitors of CYP3A4 (e.g., erythromycin), the Viibryd (Vilazodone hydrochloride) dose should be reduced to 20 mg for patients with intolerable adverse events. No dose adjustment is recommended when Viibryd (Vilazodone hydrochloride) is co-administered with mild inhibitors of CYP3A4 (e.g., cimetidine).

Inducers of CYP3A4
Concomitant use of Viibryd (Vilazodone hydrochloride) with inducers of CYP3A4 has the potential to reduce vilazodone systemic exposure. However, the effect of CYP3A4 inducers on vilazodone plasma concentrations has not been evaluated.

Inhibitors of other CYP enzymes
Concomitant administration of Viibryd (Vilazodone hydrochloride) with inhibitors of CYP2C19 and CYP2D6 is not expected to alter plasma concentrations of vilazodone. These isoforms are minor elimination pathways in the metabolism of vilazodone. studies have shown that CYP1A2, CYP2A6, CYP2C9 and CYP2E1 have minimal contribution to the metabolism of vilazodone.

Drugs metabolized by CYP1A2, CYP2C9, CYP2D6, CYP3A4 or CYP2C19.
Coadministration of Viibryd (Vilazodone hydrochloride) with substrates for CYP1A2, CYP2C9, CYP3A4, or CYP2D6 is unlikely to result in clinically significant changes in the concentrations of the CYP substrates. A study in healthy subjects found that Viibryd (Vilazodone hydrochloride) (20 mg/day for 8-10 days) had no effect on the pharmacokinetics of caffeine, flurbiprofen, nifedipine or debrisoquine, probes for CYP1A2, CYP2C9, CYP3A4, and CYP2D6, respectively. Viibryd (Vilazodone hydrochloride) coadministration with mephenytoin to healthy subjects resulted in a small (11%) increase in mephenytoin biotransformation, suggestive of a minor induction of CYP2C19. studies have shown that Viibryd (Vilazodone hydrochloride) is a moderate inhibitor of CYP2C19 and CYP2D6.

Drugs metabolized by CYP2C8
Coadministration of Viibryd (Vilazodone hydrochloride) with a CYP2C8 substrate may lead to an increase in concentration of the other drug. studies suggest that Viibryd (Vilazodone hydrochloride) may inhibit the biotransformation of substrates of CYP2C8. The effect of Viibryd (Vilazodone hydrochloride) on CYP2C8 activity has not been tested .

Induction of CYP isoforms
Viibryd (Vilazodone hydrochloride) did not induce CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 or 3A5 in an study in cultured human hepatocytes. Chronic administration of vilazodone is unlikely to induce the metabolism of drugs metabolized by these major CYP isoforms.

No dose adjustment is recommended on the basis of age (see Figure 2). Results from a single-dose (20 mg) pharmacokinetic study in elderly (> 65 years-old) vs. young (24-55 years-old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups.

Of the 2177 patients in clinical studies with Viibryd (Vilazodone hydrochloride) , 37 (1.7%) were 65 years of age or older, and 272 (12.5%) were 55 to 64 years of age.

Greater sensitivity of some older individuals cannot be ruled out .

Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event .

After adjustment for body weight, the systemic exposures between males and females are similar (see Figure 2) .

Figure 2. Impact of Intrinsic Factors on Vilazodone PK

Viibryd (Vilazodone hydrochloride) Tablets for oral administration contain polymorph Form IV vilazodone hydrochloride (HCl), a selective serotonin reuptake inhibitor and a 5HT receptor partial agonist.

Vilazodone HCl is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1). Its molecular weight is 477.99. The structural formula is:

In addition to the active ingredient, Viibryd (Vilazodone hydrochloride) Tablets contain lactose monohydrate, microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, FD&C Blue #1 (40 mg only), FD&C Yellow #6 (20 mg only) and FD&C Red #40 (10 mg only).

Vilazodone binds with high affinity to the serotonin reuptake site (Ki= 0.1 nM), but not to the norepinephrine (Ki=56 nM) or dopamine (Ki=37 nM) reuptake sites. Vilazodone potently and selectively inhibits reuptake of serotonin (IC= 1.6 nM). Vilazodone also binds selectively with high affinity to 5-HT receptors (IC=2.1 nM) and is a 5-HT receptor partial agonist.

Thorough QT Study: Treatment with Viibryd (Vilazodone hydrochloride) did not prolong the QTc interval. The effect of vilazodone (20, 40, 60, and 80 mg) on the QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg), parallel-group, thorough QTc study in 157 healthy subjects. The study demonstrated an ability to detect small effects. The upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc interval was below 10 msec, based on the individual correction method (QTcI). This is below the threshold for clinical concern. However, it is unknown whether 80 mg is adequate to represent a high clinical exposure condition.

Vilazodone activity is due primarily to the parent drug. The pharmacokinetics of vilazodone (5 mg – 80 mg) are dose-proportional. Accumulation of vilazodone is predictable from single dose data, does not vary with dose, and steady-state is achieved in about 3 days. Elimination of vilazodone is primarily by hepatic metabolism with a terminal half-life of approximately 25 hours. At steady-state, after daily dosing of Viibryd (Vilazodone hydrochloride) 40 mg under fed conditions, the mean C value is 156 ng/mL, and the mean AUC () value is 1645 ng•h/mL.

Absorption
Vilazodone concentrations peak at a median of 4-5 hours (T) after administration and decline with a terminal half-life of approximately 25 hours. The absolute bioavailability of vilazodone is 72% with food. Administration of Viibryd (Vilazodone hydrochloride) with food (high fat or light meal) increases oral bioavailability (C increased by approximately 147-160%, and AUC increased by approximately 64-85%).

Coadministration of Viibryd (Vilazodone hydrochloride) with ethanol or with a proton pump inhibitor (pantoprazole) did not affect the rate or extent of vilazodone absorption . In addition, neither the T nor terminal elimination rate of vilazodone was altered by coadministration with either pantoprazole or ethanol.

Absorption is decreased by approximately 25% if vomiting occurs within 7 hours of ingestion; no replacement dose is needed.

Distribution
Vilazodone is widely distributed and approximately 96-99% protein-bound

Metabolism and Elimination
Viibryd (Vilazodone hydrochloride) is extensively metabolized through CYP and non-CYP pathways (possibly by carboxylesterase), with only 1% of the dose recovered in the urine and 2% of the dose recovered in the feces as unchanged vilazodone. CYP3A4 is primarily responsible for its metabolism among CYP pathways, with minor contributions from CYP2C19 and CYP2D6. studies with human microsomes and human hepatocytes indicate that vilazodone is unlikely to inhibit or induce the metabolism of other CYP (except for CYP2C8) substrates; and an study with probe substrates for CYP2C19, 2D6 and 3A4 showed vilazodone did not alter the pharmacokinetics of the probe substrates. However, an study with probe substrate for CYP2C19 demonstrated a minor induction of CYP2C19. Strong inhibitors of CYP3A4 (e.g., ketoconazole) can reduce the metabolism of vilazodone and increase exposure. Conversely, inducers of CYP3A4 can decrease vilazodone exposure .

The presence of mild or moderate renal impairment, or mild or moderate hepatic impairment did not affect the apparent clearance of vilazodone.

The efficacy of Viibryd (Vilazodone hydrochloride) as a treatment for major depressive disorder was established in two 8-week, multicenter, randomized, double-blind, placebo-controlled studies in adult (18-70 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. In these studies, patients were titrated over 2 weeks to a dose of 40 mg of Viibryd (Vilazodone hydrochloride) with food (n=436) or placebo (n = 433) once daily. Viibryd (Vilazodone hydrochloride) was superior to placebo in the improvement of depressive symptoms as measured by the mean change from baseline to Week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Examination of population subgroups based on age (there were few patients over 65), gender, and race did not reveal any clear evidence of differential responsiveness.

Viibryd (Vilazodone hydrochloride) (vilazodone HCl) Tablets are supplied in the following configurations:

10 mg, pink, oval tablet, debossed with 10 on one side
     0456-1110-30: 30-count bottles

20 mg, orange, oval tablet, debossed with 20 on one side
     0456-1120-30: 30-count bottles

40 mg, blue, oval tablet, debossed with 40 on one side
     0456-1140-30: 30-count bottles

Patient Starter Kit
     0456-1100-31: blister card containing 30 tablets:

          

          

          

See Medication Guide ()

Advise patients and their caregivers about the benefits and risks associated with treatment with Viibryd (Vilazodone hydrochloride) and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.

Suicide Risk
Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down [].

Dosing and Administration
Instruct patients to take Viibryd (Vilazodone hydrochloride) with food. When initiating treatment with Viibryd (Vilazodone hydrochloride) the dose should be titrated, starting with a 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.

Concomitant Medication
Instruct patients not to take Viibryd (Vilazodone hydrochloride) with an MAOI or within 14 days of stopping an MAOI and to allow 14 days after stopping Viibryd (Vilazodone hydrochloride) before starting an MAOI [].

Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
Caution patients about the risk of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions, particularly with the concomitant use of Viibryd (Vilazodone hydrochloride) and triptans, tramadol, tryptophan supplements, other serotonergic agents, or antipsychotic drugs [].

Seizures
Caution patients about using Viibryd (Vilazodone hydrochloride) if they have a history of a seizure disorder []. Patients with a history of seizures were excluded from clinical studies.

Abnormal Bleeding
Caution patients about the concomitant use of Viibryd (Vilazodone hydrochloride) and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of abnormal bleeding [].

Activation of Mania/Hypomania
Advise patients and their caregivers to observe for signs of activation of mania/hypomania [].

Discontinuation of Treatment
Advise patients not to stop taking Viibryd (Vilazodone hydrochloride) without talking first with their healthcare provider. Patients should be aware that discontinuation effects may occur when suddenly stopping Viibryd (Vilazodone hydrochloride) [].

Hyponatremia
Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking Viibryd (Vilazodone hydrochloride) [].

Alcohol
Advise patients to avoid alcohol while taking Viibryd (Vilazodone hydrochloride) [].

Allergic Reactions
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.

Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with Viibryd (Vilazodone hydrochloride) [].

Nursing Mothers
Advise patients to notify their healthcare provider if they are breastfeeding an infant and would like to continue or start Viibryd (Vilazodone hydrochloride) [].

Interference with Cognitive and Motor Performance
Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that Viibryd (Vilazodone hydrochloride) therapy does not adversely affect their ability to engage in such activities.

Distributed by Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA

Licensed from Merck KGaA, Darmstadt, Germany

Viibryd (Vilazodone hydrochloride) ™ is a trademark of Forest Laboratories, Inc. © 2011 Forest Laboratories, Inc.