Dosage & Administration
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Viibyrd Prescribing Information
In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater in antidepressant-treated patients than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.
Age Range (years) | Drug-Placebo Difference in Number of Patient s with Suicidal Thoughts or Behaviors per 1000 Patients Treated |
Increases Compared to Placebo | |
| <18 | 14 additional patients |
| 18-24 | 5 additional patients |
Decreases Compared to Placebo | |
| 25-64 | 1 fewer patient |
| ≥65 | 6 fewer patients |
It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.
Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing VIIBRYD, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
The safety and effectiveness of VIIBRYD have not been established in pediatric patients for the treatment of MDD.
Efficacy was not demonstrated in two adequate and well controlled, 8-week studies including a total of 1002 pediatric patients ages 7 years to 17 years of age with MDD. The following adverse reactions were reported in at least 5% of pediatric patients treated with VIIBRYD and occurred at a rate at least twice that for pediatric patients receiving placebo: nausea, vomiting, diarrhea, abdominal pain/discomfort, and dizziness.
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients
In a juvenile animal study, male and female rats were treated with vilazodone (10, 50, and 200 mg/kg/day) starting on postnatal day (PND) 21 through 90. A delay in the age of attainment of vaginal patency (i.e. sexual maturation) was observed in females starting at 50 mg/kg/day with a No Observed Adverse Effect Level (NOAEL) of 10 mg/kg/day. This NOAEL was associated with AUC levels similar to those measured at a maximum dose tested in pediatrics (30 mg). Adverse behavioral effects (lack of habituation in an acoustic startle test) were observed in males at 200 mg/kg and females starting at 50 mg/kg both during drug treatment and the recovery periods. The NOAEL for this finding was 50 mg/kg for males and 10 mg/kg for females, which was associated with AUC levels greater than (males) or similar (females), to those observed with the maximum dose tested in pediatric patients. An 8% decrease in femur mineral density was observed in female rats at 200 mg/kg, compared to the control group. The NOAEL for this finding was 50 mg/kg, which was associated with an AUC level greater than those measured at the maximum dose tested in pediatrics.
Warnings and Precautions (5.2 Serotonin Syndrome Serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitor (SSRIs), including VIIBRYD, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, meperidine, methadone, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ) and Drug Interactions ( 7 ) ] . Serotonin syndrome can also occur when these drugs are used alone. Symptoms of serotonin syndrome were noted in 0.1% of MDD patients treated with VIIBRYD in premarketing clinical trials.Serotonin syndrome signs and 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of VIIBRYD with MAOIs is contraindicated. In addition, do not initiate VIIBRYD in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking VIIBRYD, discontinue VIIBRYD before initiating treatment with the MAOI [ see Contraindications ( 4 ) , Drug Interactions ( 7.1 ) ]. Monitor all patients taking VIIBRYD for the emergence of serotonin syndrome. Discontinue treatment with VIIBRYD and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of VIIBRYD with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.000000000000000e+00 3 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including VIIBRYD, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, 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. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1 )] . Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.Inform patients about the increased risk of bleeding associated with the concomitant use of VIIBRYD and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing VIIBRYD. | 8/2023 |
VIIBRYD® is indicated for the treatment of major depressive disorder (MDD) in adults
The efficacy of VIIBRYD as a treatment for major depressive disorder was demonstrated in four 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. Three 8-week studies evaluated the efficacy of VIIBRYD 40 mg (Studies 1-3) and one 10-week study (Study 4) evaluated the efficacy of VIIBRYD 20 mg and 40 mg (see Table 5). In these studies, patients were randomized to either 20 mg or 40 mg, or placebo once daily with food. Patients were either titrated over 1 week to a dose of 20 mg daily or over 2 weeks to a dose of 40 mg once daily of VIIBRYD with food. VIIBRYD was superior to placebo in the improvement of depressive symptoms as measured by the change from baseline to endpoint visit in the Montgomery-Asberg Depression Rating Scale (MADRS) total score for both doses. The MADRS is a ten-item, clinician-rated scale used to assess severity of depressive symptoms. Scores on the MADRS range from 0 to 60, with higher scores indicating more severe depression. Clinical Global Impression - Severity (CGI-S) was evaluated in Studies 3 and 4. VIIBRYD 20 mg and 40 mg demonstrated superiority over placebo as measured by improvement in CGI-S score.
Study Number | Treatment Group | Number of Patients a | Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Difference b (95% CI) |
| Study 1 | VIIBRYD 40 mg/day | 198 | 30.8 (3.90) | -12.9 (0.77) | -3.2 (-5.2, -1.3) |
| Placebo | 199 | 30.7 (3.93) | -9.6 (0.76) | ||
| Study 2 | VIIBRYD 40 mg/day | 231 | 31.9 (3.50) | -13.3 (0.90) | -2.5 (-4.4, -0.6) |
| Placebo | 232 | 32.0 (3.63) | -10.8 (0.90) | ||
| Study 3 | VIIBRYD 40 mg/day | 253 | 30.7 (3.3) | -16.1 (0.64) | -5.1 (-6.9, -3.3) |
| Placebo | 252 | 30.9 (3.3) | -11.0 (0.65) | ||
| Study 4 | VIIBRYD 20 mg/day* | 288 | 31.3 (3.5) | -17.3 (0.63) | -2.6 (-4.3, -0.8) |
| VIIBRYD 40 mg/day* | 284 | 31.2 (3.8) | -17.6 (0.65) | -2.8 (-4.6, -1.1) | |
| Placebo | 281 | 31.4 (3.8) | -14.8 (0.62) |
SD = standard deviation; SE = standard error; LS Mean = least-square mean; CI = confidence interval
abased on patients who took study medication and had baseline and postbaseline MADRS assessments
bdifference (drug minus placebo) in least-square mean change from baseline to endpoint
* All VIIBRYD treatment dose groups remained statistically significant compared with placebo after adjusting for multiplicity
Baseline demographics information were generally similar across all treatment groups. 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.
- Recommended target dosage: 20 mg to 40 mg once daily with food (,2.1Dosagefor Treatment ofMajor Depressive Disorder
The recommended target dosage for VIIBRYD is 20 mg to 40 mg orally once daily with food
[see Clinical Pharmacology (12.3), Clinical Studies (14)]. To achieve the target dosage, titrate VIIBRYD as follows:- Start with an initial dosage of 10 mg once daily with food for 7 days,
- Then increase to 20 mg once daily with food.
- The dose may be increased up to 40 mg once daily with food after a minimum of 7 days between dosage increases.
If a dose is missed, it should be taken as soon as the patient remembers. If it is almost time for the next dose, the patient should skip the missed dose and take the next dose at the regular time. Two doses should not be taken at the same time.
)12.3PharmacokineticsVilazodone activity is due primarily to the parent drug. The pharmacokinetics of vilazodone (5 mg – 80 mg) are dose-proportional. Accumulation of vilazodone after administration of single VIIBRYD doses did not vary with dose, and steady-state was 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 40 mg under fed conditions, the mean Cmaxvalue was 156 ng/mL, and the mean AUC (0-24 hours) value was 1645 ng·h/mL.
AbsorptionVilazodone concentrations peaked at a median of 4-5 hours (Tmax) after VIIBRYD administration and declined with a terminal half-life of approximately 25 hours. The absolute bioavailability of vilazodone was 72% with food.Vilazodone AUC and Cmaxin the fasted state can be decreased by approximately 50% and 60%, respectively, compared to the fed state. Administration without food can result in inadequate drug concentrations and may reduce effectiveness.
Coadministration of VIIBRYD with ethanol or with a proton pump inhibitor (pantoprazole) did not affect the rate or extent of vilazodone absorption. In addition, neither the Tmaxnor 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.
DistributionVilazodone is widely distributed and approximately 96-99% protein-bound. Administration of VIIBRYD to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, because vilazodone is highly bound to plasma protein. The interaction between vilazodone and other highly protein-bound drugs has not been evaluated.
Metabolism and EliminationVIIBRYD 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.
Drug Interaction StudiesFigure 1 below includes the impact of other drugs on the pharmacokinetics of vilazodone
[see Drug Interactions (7)].Figure1. Effectof Other Drugs on Vilazodone PharmacokineticsIn vitrostudies indicate that vilazodone is unlikely to inhibit or induce the metabolism of substrates for CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 or 3A5, except for CYP2C8. The effect of vilazodone on CYP2C8 activity has not been testedin vivo. Figure 2 below includes the impact of vilazodone on the pharmacokinetics of other drugsin vivo.Figure 2. Impact of Vilazodone on Other Drug PharmacokineticsStudiesinSpecific Populations:The presence of mild to severe renal impairment or mild to severe hepatic impairment did not affect the apparent clearance of vilazodone (see Figure 3). There were no pharmacokinetic differences of vilazodone in geriatric patients compared to younger patients, or between males and females (see Figure 3).
Figure3: Impact of Intrinsic Factors on Vilazodone Pharmacokinetics - Start with an initial dosage of 10 mg once daily with food for 7 days,
- To titrate: start with initial dosage of 10 mg once daily for 7 days, followed by 20 mg once daily. The dose may be increased up to 40 mg once daily after a minimum of 7 days between dosage increases ()2.1Dosagefor Treatment ofMajor Depressive Disorder
The recommended target dosage for VIIBRYD is 20 mg to 40 mg orally once daily with food
[see Clinical Pharmacology (12.3), Clinical Studies (14)]. To achieve the target dosage, titrate VIIBRYD as follows:- Start with an initial dosage of 10 mg once daily with food for 7 days,
- Then increase to 20 mg once daily with food.
- The dose may be increased up to 40 mg once daily with food after a minimum of 7 days between dosage increases.
If a dose is missed, it should be taken as soon as the patient remembers. If it is almost time for the next dose, the patient should skip the missed dose and take the next dose at the regular time. Two doses should not be taken at the same time.
- Start with an initial dosage of 10 mg once daily with food for 7 days,
- Prior to initiating VIIBRYD, screen for bipolar disorder (,2.2Screen for Bipolar Disorder Prior to Starting VIIBRYD
Prior to initiating treatment with VIIBRYD
or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania[seeWarnings and Precautions (5.4)].)5.000000000000000e+004Activation of ManiaorHypomaniaIn patients with bipolar disorder, treating a depressive episode with VIIBRYD or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were excluded; however, symptoms of mania or hypomania were reported in 0.1% of undiagnosed patients treated with VIIBRYD. Prior to initiating treatment with VIIBRYD, screen patients for any personal or family history of bipolar disorder, mania, or hypomania
[see Dosage and Administration (2.2)]. - When discontinuing VIIBRYD, reduce dosage gradually (,2.000000000000000e+004Dosage Adjustments withCYP3A4 Inhibitors or InducersPatients receiving concomitant CYP3A4 inhibitors:
During concomitant use of a strong CYP3A4 inhibitor (e.g., itraconazole, clarithromycin, voriconazole), the VIIBRYD dose should not exceed 20 mg once daily. The original VIIBRYD dose level, can be resumed when the CYP3A4 inhibitor is discontinued
[see Drug Interactions (7)].Patients receiving concomitant CYP3A4 inducers:Based on clinical response, consider increasing the dosage of VIIBRYD by 2-fold, up to a maximum 80 mg once daily, over 1 to 2 weeks in patients taking strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin) for greater than 14 days. If CYP3A4 inducers are discontinued, gradually reduce the VIIBRYD dosage to its original level over 1 to 2 weeks
[see Drug Interactions (7)].)5.000000000000000e+005DiscontinuationSyndromeAdverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible
[see Dosage and Administration (2.5)].
VIIBRYD Tablets are available as 10 mg, 20 mg and 40 mg 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
No dosage adjustment of VIIBRYD is necessary on the basis of gender, renal function (mild to severe renal impairment, glomerular filtration rate: 15-90 mL/minute), or hepatic function (mild to severe hepatic impairment, Child-Pugh score: 5-15
Vilazodone activity is due primarily to the parent drug. The pharmacokinetics of vilazodone (5 mg – 80 mg) are dose-proportional. Accumulation of vilazodone after administration of single VIIBRYD doses did not vary with dose, and steady-state was 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 40 mg under fed conditions, the mean Cmaxvalue was 156 ng/mL, and the mean AUC (0-24 hours) value was 1645 ng·h/mL.
Vilazodone concentrations peaked at a median of 4-5 hours (Tmax) after VIIBRYD administration and declined with a terminal half-life of approximately 25 hours. The absolute bioavailability of vilazodone was 72% with food.Vilazodone AUC and Cmaxin the fasted state can be decreased by approximately 50% and 60%, respectively, compared to the fed state. Administration without food can result in inadequate drug concentrations and may reduce effectiveness.
Coadministration of VIIBRYD with ethanol or with a proton pump inhibitor (pantoprazole) did not affect the rate or extent of vilazodone absorption. In addition, neither the Tmaxnor 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.
Vilazodone is widely distributed and approximately 96-99% protein-bound. Administration of VIIBRYD to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, because vilazodone is highly bound to plasma protein. The interaction between vilazodone and other highly protein-bound drugs has not been evaluated.
VIIBRYD 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.
Figure 1 below includes the impact of other drugs on the pharmacokinetics of vilazodone
The presence of mild to severe renal impairment or mild to severe hepatic impairment did not affect the apparent clearance of vilazodone (see Figure 3). There were no pharmacokinetic differences of vilazodone in geriatric patients compared to younger patients, or between males and females (see Figure 3).