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Drug Forecast

Vilazodone HCl (Viibryd)

A Serotonin Partial Agonist and Reuptake Inhibitor For the Treatment of Major Depressive Disorder
Martin Paspe Cruz PharmD, CGP, BCPP

INTRODUCTION

Major depressive disorder (MDD) affects approximately 121 million people worldwide, including almost 15 million American adults.1,2 Among all medical conditions, MDD is the leading cause of morbidity worldwide as well as the leading cause of disability in the U.S. in individuals 15 to 44 years of age.2,3 Antidepressants were the fourth most commonly prescribed drug class in 2009, with prescription sales in the U.S. reaching $9.9 billion.4

Patients with MDD present with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration. The underlying pathophysiology of MDD has not been clearly defined, although clinical studies suggest that the disorder results from a disturbance in serotonin (5-HT) and norepinephrine neurotransmission in the central nervous system (CNS).57

Successful pharmacological treatment of depression depends on such factors as tolerability and treatment resistance along with drug efficacy. Up to 50% of depressive patients do not respond adequately to initial pharmacotherapy.8 However, patients who do not respond to one antidepressant might derive benefit from another one, even if it belongs to the same therapeutic class.

Research continues to be directed toward the development of antidepressant drugs with improvements in efficacy and side-effect profiles. The clinical need exists for new antidepressants with novel mechanisms of action. Vilazodone (Viibryd, Forest/Trovis) offers a novel combination of selective serotonin reuptake inhibition and serotonergic (5-HT1A) receptor partial agonist activity.9 Because of these characteristics, vilazodone has been termed a serotonin partial agonist–reuptake inhibitor (SPARI). Vilazodone was approved by the FDA for the treatment of MDD in January 2011.10

DOSAGE AND ADMINISTRATION

Vilazodone tablets are available in 10-mg, 20-mg, and 40-mg strengths.9 The recommended dosage is 40 mg once daily. Vilazodone should be titrated, starting with an initial dosage 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.9

Vilazodone should be taken with food. If vilazodone is taken without food, inadequate drug concentrations may result and the drug’s effectiveness may be diminished.9

CHEMISTRY AND MECHANISM OF ACTION

The chemical formula for vilazodone HCl is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl) butyl]-1-piperazinyl]-, hydrochloride (1:1). The molecular formula is C26H27N5O2, and the molecular weight is 477.99.9,11 Vilazodone is a selective serotonin reuptake inhibitor (SSRI) and a 5-HT1A receptor partial agonist. Figure 1 depicts the drug’s structural formula.

The mechanism of the antidepressant effect of vilazodone is thought to be related to its enhancement of serotonergic activity in the CNS through selective inhibition of serotonin reuptake. Vilazodone binds with high affinity to the serotonin reuptake site but not to the norepinephrine or dopamine reuptake site. As a result, vilazodone potently and selectively inhibits the reuptake of serotonin.

Even though vilazodone is also a partial agonist at serotonergic 5-HT1A receptors, the net result of this activity on serotonergic transmission and its role in the antidepressant effect of vilazodone are not fully understood.9,11

CLINICAL PHARMACOLOGY

Vilazodone’s pharmacokinetic activity (5–80 mg) is dose-proportional. The terminal half-life is approximately 25 hours. When vilazodone is taken with food, the drug’s absolute bioavailability is 72%. After daily dosing of vilazodone 40 mg under fed conditions, the mean maximum plasma concentration (Cmax) at steady state was 156 ng/mL, and the mean area-under-the-curve (AUC0–24 hr) concentration was 1,645 ng • hours/mL. When vilazodone was administered with a high-fat or light meal, the Cmax was increased by approximately 147% to 160%, and the AUC concentration was increased by approximately 64% to 85%.9,11

If vomiting occurs within 7 hours after administration, the drug’s absorption is decreased by about 25%; however, a replacement dose is not required.9,11

Vilazodone has a large volume of distribution (value unknown). It is approximately 96% to 99% protein-bound.9,11

The drug is extensively metabolized in the liver, primarily via the cytochrome P450 (CYP) 3A4 isoenzyme. CYP2C19 and CYP2D6 are minor metabolic pathways. Non-CYP450 metabolism also occurs, possibly by carboxylesterase. Only 1% and 2% of the dose are recovered in urine and feces, respectively, as unchanged vilazodone.

The presence of mild or moderate renal and hepatic impairment does not affect the clearance of vilazodone.9,11

PIVOTAL CLINICAL STUDIES

Clinical data supporting the efficacy of vilazodone in MDD were obtained from two 8-week, multicenter, double-blind, randomized, placebo-controlled studies in 869 adults (18–70 years of age) who met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD.9 The dose was titrated over a period of 2 weeks to a dose of 40 mg with food (n = 436) or placebo (n = 433) once daily. In both trials, vilazodone provided superior improvement in depressive symptoms, as measured by the mean change from baseline to week 8 in the Montgomery–Asberg Depression Rating Scale (MADRS), compared with placebo.

In study 1, the least-squares mean difference from placebo in the change from baseline was −3.2 (95% confidence interval [CI], −5.2 to −1.3) with vilazodone. In study 2, the mean difference was −2.5 (95% CI, −4.4 to −0.6).9

In these placebo-controlled studies, 7.1% of treated patients and 3.2% of placebo-treated patients discontinued therapy because of an adverse reaction. The most common adverse reactions in the vilazodone-treated patients (with an incidence of 5% or greater and at least twice the rate of placebo) included diarrhea (28%), nausea (23%), insomnia (6%), and vomiting (5%).9

DRUG–DRUG INTERACTIONS

Serious, sometimes fatal, drug interactions may occur if vilazodone is co-administered with a monoamine oxidase (MAO) inhibitor or within 14 days of discontinuing or initiating MAO inhibitor therapy. Because of vilazodone’s mechanism of action and the potential for serotonin toxicity (“serotonin syndrome”), caution is advised when vilazodone is coadministered with other serotonergic drugs, including MAO inhibitors, SSRIs, serotonin–norepinephrine reuptake inhibitors (SNRIs), buspirone (Buspar, Bristol-Myers Squibb), tramadol (Ultram, Janssen/PriCara), triptans, and tryptophan products.9

The manufacturer recommends that the vilazodone dose should not exceed 20 mg if it is given with strong CYP3A4 inhibitors, such as ketoconazole (Nizoral, Janssen), because use with these drugs can increase vilazodone plasma levels by approximately 50%. When vilazodone is coadministered with moderate CYP3A4 inhibitors, such as erythromycin, the dose should not exceed 20 mg in patients who have experienced intolerable adverse events. No dose adjustment is necessary when vilazodone is given with mild inhibitors of CYP3A4, such as cimetidine (Tagamet, GlaxoSmithKline).9

Although the effect of CYP3A4 inducers on vilazodone plasma levels has not been studied, the concomitant use of vilazodone and CYP3A4 inducers has the potential to reduce systemic exposure to vilazodone.9 The effects of other drugs on the pharmacokinetics of vilazodone are illustrated in Figure 2.

Serotonin release by platelets plays an important role in hemostasis. Studies show that the use of psychotropic drugs that interfere with serotonin uptake may increase the risk of upper gastrointestinal bleeding, and that this risk may be potentiated by the concurrent use of non-steroidal anti-inflammatory drugs or aspirin. Increased bleeding has occurred when SSRIs and SNRIs were coadministered with warfarin (Coumadin, Bristol-Myers Squibb). Patients receiving warfarin, therefore, should be carefully monitored when vilazodone therapy is initiated or discontinued.9

BOXED WARNING

The prescribing information for vilazodone includes a boxed warning regarding suicidality and antidepressant medications. In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults when compared with placebo. Vilazodone is not approved for use in pediatric patients.9

WARNINGS AND PRECAUTIONS

Patients should be monitored for clinical worsening, suicidality, and unusual changes in behavior while they are taking vilazodone. Clinicians should discontinue vilazodone and begin supportive treatment if serotonin syndrome or neuroleptic malignant syndrome (NMS) occurs during vilazodone therapy.

Like other antidepressants, vilazodone should be used with caution in patients with a history of a seizure disorder. Treatment with vilazodone may also increase the risk of bleeding if the drug is taken with NSAIDs, aspirin, and other agents that affect coagulation. Vilazodone should not be stopped abruptly; the dose should be reduced gradually. Although no cases of hyponatremia were associated with vilazodone therapy in clinical studies, hyponatremia has occurred as a result of treatment with other SSRIs and SNRIs. Activation of mania or hypomania can occur with vilazodone therapy. Therefore, patients should be screened for bipolar disorder.9

CONTRAINDICATIONS

Because of the risk of serious, sometimes fatal, interactions with serotonergic drugs, vilazodone is contraindicated in patients taking concomitant MAO inhibitors or in those who have taken them within 14 days preceding vilazodone therapy.9

ADVERSE REACTIONS

The adverse reactions most commonly noted (with an incidence of 5% or greater and at least twice the rate of placebo) in MMD patients treated with vilazodone in pivotal placebo-controlled trials were diarrhea (28%), nausea (23%), insomnia (6%), and vomiting (5%). Other adverse effects included dizziness, dry mouth, fatigue, abnormal dreams, decreased libido, arthralgia, and palpitations (Table 1).9 During clinical studies, vilazodone was not associated with clinically significant effects on weight, vital signs, or electrocardiographic parameters.9

PATIENT MONITORING

Patients who are taking vilazodone should be monitored for clinical worsening and for suicidal thinking or behavior, especially during the initial few months and at times of dose increases or decreases).9

Serotonergic drugs such as vilazodone have been associated with symptoms upon discontinuation, including dysphoric mood, irritability, agitation, anxiety, and confusion. Patients should be monitored for these symptoms when discontinuing vilazodone.9

The most severe form of serotonin syndrome resembles NMS and is characterized by hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and alterations in mental status. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.9

Because of the potential for increased bleeding, patients receiving warfarin therapy should be carefully monitored when vilazodone is initiated or discontinued.9

P&T COMMITTEE CONSIDERATIONS

Vilazodone may be considered for addition to drug formularies as a novel treatment for MDD. The drug combines two mechanisms that can increase serotonin levels in the brain cortex (i.e., selective serotonin reuptake inhibition and partial agonism of the 5-HT1A receptor).

Because of its low incidence of sexual adverse effects, the manufacturer is promoting vilazodone as an alternative to other antidepressant drugs for men who have experienced antidepressant-induced erectile dysfunction.

COST

Viibryd is expected to cost $4.74 per dose for all strengths (10, 20, and 40 mg) or approximately $142.20 per month.12,13

CONCLUSION

Vilazodone’s mechanism of anti-depressant action enhances the release of serotonin across the brain’s serotonergic pathways by inhibiting the serotonin transporter (similar to SSRIs) and by simultaneously stimulating serotonin (5-HT1A) receptors via partial agonism (similar to the anxiolytic drug buspi rone). Because of this dual activity, vilazodone is considered to be a serotonin partial agonist–reuptake inhibitor (SPARI).

The efficacy of vilazodone in the treatment of adults with MMD was shown in two 8-week, randomized, double-blind, placebo-controlled trials. Vilazodone was found to be superior to placebo in improving depressive symptoms, as measured by MADRS scores. During these clinical trials, commonly observed adverse reactions included diarrhea, nausea, insomnia, and vomiting.

Further studies are needed to assess the efficacy and safety of vilazodone therapy beyond 8 weeks, because patients with acute episodes of MMD can require several months or longer of sustained pharmacological treatment.

Figures and Table

Chemical structure of vilazodone HCl. (From Viibryd prescribing information.9)

Effects of other drugs on vilazodone pharmacokinetics. AUC = area under the curve; CI = confidence interval; Cmax = maximum plasma concentration; PK = pharmacokinetics. (From Viibryd prescribing information.9)

Common Adverse Reactions Occurring in 2% or More Of Vilazodone-Treated Patients Compared With Placebo-Treated Patients

Vilazodone 40 mg/day (n = 436) % Placebo (n = 433) %
Gastrointestinal disorders
  Diarrhea 28 9
  Nausea 23 5
  Dry mouth 8 5
  Vomiting 5 1
  Dyspepsia 3 2
  Flatulence 3 2
  Gastroenteritis 3 <1
Nervous system disorders
  Dizziness 9 5
  Somnolence 3 2
  Paresthesia 3 1
  Tremor 2 0
Psychiatric disorders
  Insomnia 6 2
  Abnormal dreams 4 1
  Libido decreased 4 <1
  Restlessness* 3 <1
  Orgasm abnormal 3 0
General disorders
  Fatigue 4 3
  Feeling jittery 2 <1
Cardiac disorders
  Palpitations 2 < 1
Musculoskeletal and connective-tissue disorders
  Arthralgia 3 2
Reproductive-system and breast disorders
  Delayed ejaculation 2 0
  Erectile dysfunction 2 1
Metabolism and nutrition disorders
  Decreased appetite 2 1

*Includes restlessness, akathisia, and restless legs syndrome.

Includes orgasm abnormal and anorgasmia.

Male patients only (vilazodone, n = 170; placebo, n = 182).

From Viibryd prescribing information.9

References

  1. Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of twelve-month DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Arch Gen Psychiatry 2005;62;(6):617–627.
  2. World Health Organization. Depression. Available at: www.who.int/mental_health/management/depression/definition/en. Accessed November 8, 2011.
  3. World Health Organization. The World Health Report 2004: Statistical Annex. Annex Table 3: Burden of disease in DALYs by cause, sex, and mortality stratum in WHO regions, estimates for 2002. Available at: www.who.int/whr/2004/annex/topic/en/annex_3_en.pdf. Accessed November 8, 2011.
  4. IMS Health reports U.S. prescription sales grew 5.1 percent in 2009, to $300.3 billion, April 1, 2010. Available at: www.imshealth.com. Accessed November 8, 2011.
  5. Richelson E. Serotonin: And what about its side effects?. Depress Anxiety 1998;7;(Suppl 1):18–20.
  6. Blier P. Norepinephrine and selective norepinephrine reuptake inhibitors in depression and mood disorders: Their pivotal roles. J Psychiatry Neurosci 2001;26;(Suppl):S1–S2.
  7. Goldstein DJ. Duloxetine in the treatment of major depressive disorder. Neuropsychiatr Dis Treat 2007;3;(2):193–209.
  8. Hirschfield RMA, Montgomery SA, Aguglia E, et al. Partial response and non-response to antidepressant therapy: Current approaches and treatment options. J Clin Psychiatry 2002;63:826–837.
  9. Viibryd® (vilazodone HCl) Tablets, prescribing information St. Louis: Forest Laboratories. April 2011;Available at: www.frx.com/pi/viibryd_pi.pdf. Accessed November 8, 2011.
  10. FDA approves Viibryd to treat major depressive disorder January 212011;Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm240642.htm. Accessed November 8, 2011.
  11. Thomson Reuters Drugdex. Vilazodone Available at: https://www.thomsonreuters.com/products_services/healthcare/healthcare_products/a-z/drugdex_system. Accessed July 1, 2011.
  12. Fallon Community Health Plan. Available at: www.fchp.org/ppact/Viibryd_CIA_052011.pdf. Accessed December 19, 2011.
  13. restat, Issue 109, May 2011. Available at: www.restat.com/media/restat/pdf/costimpact/Viibryd_CIA_052011.pdf. Accessed December 19, 2011.