Vilazodone Hydrochloride

VIIBRYD® is indicated for the treatment of major depressive disorder (MDD) [see Clinical Studies].

Included as part of the PRECAUTIONS section.

Mechanism Of Action

The mechanism of the antidepressant effect of vilazodone is not fully understood but is thought to be related to its enhancement of serotonergic activity in the CNS through selective inhibition of serotonin reuptake. Vilazodone is also a partial agonist at serotonergic 5-HT1A receptors; however, the net result of this action on serotonergic transmission and its role in vilazodone's antidepressant effect are unknown.

Pharmacodynamics

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 (IC50= 1.6 nM). Vilazodone also binds selectively with high affinity to 5-HT1A receptors (IC50=2.1 nM) and is a 5-HT1A receptor partial agonist.

Treatment with VIIBRYD did not prolong the QTc interval. The effect of VIIBRYD [20, 40, 60, and 80 mg (2 times the recommended dosage)] 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). Thus, at doses of 2 times the recommended dosage, VIIBRYD did not prolong the QTc interval to a clinically relevant extent.

Pharmacokinetics

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 Cmax value 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 halflife of approximately 25 hours. The absolute bioavailability of vilazodone was 72% with food.Vilazodone AUC and Cmax in 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 Tmax 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.

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.

Drug Interaction Studies

Figure 1 below includes the impact of other drugs on the pharmacokinetics of vilazodone [see DRUG INTERACTIONS].

Figure 1: Effect of Other Drugs on Vilazodone Pharmacokinetics

In vitro studies 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 tested in vivo. Figure 2 below includes the impact of vilazadone on the pharmacokinetics of other drugs in vivo.

Figure 2: Impact of Vilazodone on Other Drug Pharmacokinetics

Studies In Specific 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).

Figure 3: Impact of Intrinsic Factors on Vilazodone Pharmacokinetics

Clinical Studies

The efficacy of VIIBRYD as a treatment for major depressive disorder was demonstrated in four multicenter, randomized, doubleblind, 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 1week 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.

Table 5: Summary of Results for the Primary Efficacy Endpoint - MADRS Total Score

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.

Do not use vilazodone if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Before you take vilazodone, tell your doctor if you have liver or kidney disease, a bleeding or blood clotting disorder, seizures, bipolar disorder, low levels of sodium in your blood, or a history of drug abuse or suicidal thoughts.

You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old. Your doctor will need to check you at regular visits for the first few months of treatment, or whenever your dose is changed.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Tell your doctor right away if you become pregnant while taking this medication. Vilazodone may cause heart defects or serious lung problems in a newborn if you take the medication during pregnancy. However, you may have a relapse of depression if you stop taking your antidepressant. Do not start or stop taking vilazodone during pregnancy without your doctor's advice.

Do not use vilazodone if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

You must wait at least 14 days after stopping an MAO inhibitor before you can take vilazodone. After you stop taking vilazodone, you must wait at least 14 days before you start taking an MAOI.

Tell your doctor about all other antidepressants you take, especially Celexa, Cymbalta, Desyrel, Effexor, Lexapro, Luvox, Oleptro, Prozac, Sarafem, Symbyax, Paxil, Pexeva, or Zoloft.

To make sure you can safely take vilazodone, tell your doctor if you have any of these other conditions:

• liver or kidney disease;
• a bleeding or blood clotting disorder;
• seizures or epilepsy;
• bipolar disorder (manic depression); or
• a history of drug abuse or suicidal thoughts.

Your family or other caregivers should also be alert to changes in your mood or symptoms. Your doctor will need to check you at regular visits for the first few months of treatment, or whenever your dose is changed.

You may have thoughts about suicide while taking an antidepressant, especially if you are younger than 24 years old. Tell your doctor if you have worsening depression or suicidal thoughts during the first several weeks of treatment, or whenever your dose is changed.

FDA pregnancy category C. Tell your doctor right away if you become pregnant while taking this medication. Vilazodone may cause heart defects or serious lung problems in a newborn if you take the medication during pregnancy. However, you may have a relapse of depression if you stop taking your antidepressant. Do not start or stop taking vilazodone during pregnancy without your doctor's advice.

It is not known whether vilazodone passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not give this medication to anyone under 18 years old without medical advice.

General

• Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor and initiation of vilazodone and vice versa.1 (See Contraindications and Serotonin Syndrome or Neuroleptic Malignant Syndrome [NMS]-like Reactions under Cautionsand also see Specific Drugs under Interactions.)

• Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.1 12 14 15 (See Worsening of Depression and Suicidality Risk under Cautions.)

• Avoid abrupt discontinuance.1 5 Taper dosage gradually and monitor for withdrawal symptoms.1 5 If intolerable symptoms occur following dosage reduction or discontinuance, consider reinstituting previously prescribed dosage, then resume more gradual dosage reductions.1 (See Withdrawal of Therapy under Cautions.)

Administration

Oral Administration

Administer immediate-release tablets orally once daily with food.1 Taking the drug without food may result in inadequate drug concentrations and reduced efficacy.1 (See Food under Pharmacokinetics.)

Dosage

Available as vilazodone hydrochloride; dosage expressed in terms of the salt.1

Adults

Titrate up to recommended target dosage of 40 mg once daily to reduce risk of adverse effects (particularly GI effects).1 29 30 Manufacturer recommends 10 mg once daily initially for 7 days, followed by 20 mg once daily for an additional 7 days, and 40 mg once daily thereafter.1 29 30 May use the Viibryd patient starter kit for initial 1-month titration period.1

If used with a potent CYP3A4 inhibitor, dosage adjustment required; dosage adjustment also may be required if used with a moderate CYP3A4 inhibitor.1 30 (See Interactions.)

Optimum duration not established; may require several months or longer of sustained antidepressant therapy.1 5 Although manufacturer states that long-term efficacy (i.e., >8 weeks) not studied,1 long-term therapy at a dosage of 40 mg once daily was effective and well tolerated in a 52-week, open-label trial.4 Periodically reassess need for continued therapy and appropriateness of dosage.1

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild or moderate hepatic impairment; not studied in patients with severe hepatic impairment.1 8

Renal Impairment

No dosage adjustment required in patients with mild, moderate, or severe renal impairment.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustment not necessary.1

Gender

Dosage adjustment based on gender not necessary.1

Metabolized by CYP isoenzymes, principally by 3A4 with minor contributions from CYP2C19 and CYP2D6 and non-CYP (possibly by carboxylesterase) pathways.1

Did not induce CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4, or 3A5 in an in vitro study.1

Moderate inhibitor of CYP2C19 and CYP2D6.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma vilazodone concentrations).1 19 Reduce vilazodone dosage to 20 mg once daily if used concomitantly with a potent CYP3A4 inhibitor.1 19 30 Reduce vilazodone dosage to 20 mg once daily if used concomitantly with a moderate CYP3A4 inhibitor and patient experiences intolerable adverse effects.1 30 Vilazodone dosage adjustment not necessary when used concurrently with a mild CYP3A4 inhibitor.1 30

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased vilazodone AUC).1 11

CYP2C19 or CYP2D6 inhibitors: Clinically important pharmacokinetic interaction unlikely.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Drugs metabolized by CYP1A2, 2C9, 2D6, or 3A4: Clinically important pharmacokinetic interaction unlikely.1

Drugs metabolized by CYP2C19: Potential pharmacokinetic interaction (possible increased plasma concentrations of CYP2C19 substrate).1

Drugs metabolized by CYP2C8: Potential pharmacokinetic interaction (possible increased plasma concentrations of CYP2C8 substrate).1

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions) with serotonergic drugs.1 Avoid concomitant use or exercise caution.1 If serotonin syndrome or NMS occurs, immediately discontinue vilazodone and any concurrently administered antidopaminergic or serotonergic agents and initiate supportive and symptomatic treatment.1 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome [NMS]-like Reactions under Cautions.)

Drugs Affecting Hemostasis

Potential pharmacologic interaction (increased risk of bleeding) if used concurrently with drugs that affect coagulation or bleeding; use with caution.1 (See Abnormal Bleeding under Cautions.)

Drugs Highly Bound to Plasma Protein

Potential pharmacokinetic interaction (possible increased free concentrations of other highly protein bound drugs if used concurrently with vilazodone).1

Specific Drugs

Storage

Oral

25°C (may be exposed to 15–30°C).1