These Highlights Do Not Include All The Information Needed To Use Vilazodone Hydrochloride Tablets Safely And Effectively. See Full Prescribing Information For

Patients receiving concomitant CYP3A4 inhibitors:

During concomitant use of a strong CYP3A4 inhibitor (e.g., itraconazole, clarithromycin, voriconazole), the vilazodone hydrochloride dose should not exceed 20 mg once daily. The original vilazodone hydrochloride dose level, can be resumed when the CYP3A4 inhibitor is discontinued [see Drug Interactions (7)].

MEDICATION GUIDE

Vilazodone (vil-AZ-oh-done) Hydrochloride

Tablets , for oral use

Dispense with Medication Guide available at https://www.apotex.com/products/us/mg.asp

What is the most important information I should know about vilazodone hydrochloride tablets?

Vilazodone hydrochloride tablets may cause serious side effects, including:

• Increased risk of suicidal thoughts or actions in some children, adolescents, and young adults. Vilazodone hydrochloride tablets and other antidepressant medicines may increase suicidal thoughts or actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed.

  Vilazodone hydrochloride tablets are not for use in children.

  • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a higher risk of having suicidal thoughts or actions. These include people who have (or have a family history of) depression, bipolar illness (also called manic-depressive illness) or have a history of suicidal thoughts or actions.

How can I watch for and try to prevent suicidal thoughts and actions ?

• • Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed.
  • Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call your healthcare provider or get emergency medical help right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you:

• • attempts to commit suicide
  • acting aggressive, being angry or violent
  • new or worse depression
  • panic attacks
  • new or worse irritability
  • an extreme increase in activity or talking (mania)
  • acting on dangerous impulses
  • thoughts about suicide or dying
  • new or worse anxiety
  • feeling agitated or restless
  • trouble sleeping (insomnia)
  • other unusual changes in behavior or mood

What are vilazodone hydrochloride tablets?

Vilazodone hydrochloride tablets are a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD) in adults. It is not known if vilazodone hydrochloride tablets are safe and effective for use in children for the treatment of MDD.

Who should not take vilazodone hydrochloride tablets?

Do not take vilazodone hydrochloride tablets if you:

• take a Monoamine Oxidase Inhibitor (MAOI)
• have stopped taking an MAOI in the last 14 days
• are being treated with the antibiotic linezolid or intravenous methylene blue

Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene blue.

Do not start taking an MAOI for at least 14 days after you stop treatment with vilazodone hydrochloride.

Before taking vilazodone hydrochloride tablets, tell your healthcare provider about all your medical conditions, including if you:

• have or have a family history of suicide, depression, bipolar disorder, mania or hypomania
• have or had bleeding problems
• have or had seizures or convulsions
• have high pressure in the eye (glaucoma)
• have low sodium levels in your blood
• drink alcohol
• are pregnant or plan to become pregnant. Taking vilazodone hydrochloride tablets late in pregnancy may lead to an increased risk of certain problems in your newborn. Talk to your healthcare provider about the risks to your baby if you take vilazodone hydrochloride tablets during pregnancy. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with vilazodone hydrochloride tablets.
  • There is a pregnancy registry for females who are exposed to vilazodone hydrochloride pregnancy. The purpose of the registry is to collect information about the health of females exposed to vilazodone hydrochloride and their baby. If you become pregnant during treatment with vilazodone hydrochloride, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants.
• are breastfeeding or plan to breastfeed. It is not known if vilazodone hydrochloride passes into breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with vilazodone hydrochloride tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Vilazodone hydrochloride and some medicines may affect each other causing possible serious side effects. Vilazodone hydrochloride may affect the way other medicines work and other medicines may affect the way vilazodone hydrochloride works.

Especially tell your healthcare provider if you take:

• MAOIs
• medicines used to treat migraine headaches known as triptans
• tricyclic antidepressants
• lithium
• tramadol, fentanyl, meperidine, methadone, or other opioids
• tryptophan
• buspirone
• amphetamines
• St. John's Wort
• medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and warfarin
• diuretics
• medicines used to treat mood, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)

Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take vilazodone hydrochloride tablets with your other medicines.

Do not start or stop any other medicines during treatment with vilazodone hydrochloride tablets without talking to your healthcare provider first. Stopping vilazodone hydrochloride tablets suddenly may cause you to have serious side effects. See, "What are the possible side effects of vilazodone hydrochloride tablets?"

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How should I take vilazodone hydrochloride tablets?

• Take vilazodone hydrochloride tablets exactly as your healthcare provider tell you to. Do not change your dose or stop taking vilazodone hydrochloride tablets without first talking to your healthcare provider.
• Your healthcare provider may need to change the dose of vilazodone hydrochloride until it is the right dose for you.
• Take vilazodone hydrochloride tablets 1 time each day with food.
• If you miss a dose of vilazodone hydrochloride tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of vilazodone hydrochloride tablets at the same time.
• If you take too much vilazodone hydrochloride tablets, call your healthcare provider or poison control center at 1-800-222-1222 right away, or get emergency treatment right away.

What should I avoid while taking vilazodone hydrochloride tablets?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how vilazodone hydrochloride tablets affects you. Vilazodone hydrochloride tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly.
• Avoid drinking alcohol during treatment with vilazodone hydrochloride tablets.

What are the possible side effects of vilazodone hydrochloride tablets?

Vilazodone hydrochloride tablets may cause serious side effects, including:

• See, "What is the most important information I should know about vilazodone hydrochloride tablets?’’
• Serotonin Syndrome. A potentially life-threatening problem called serotonin syndrome can happen when vilazodone hydrochloride tablets are taken with certain other medicines. See, "Who should not take vilazodone hydrochloride tablets?" Stop taking vilazodone hydrochloride tablets and call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome:
  • agitation
  • confusion
  • fast heart beat
  • dizziness
  • flushing
  • tremors, stiff muscles, or muscle twitching
  • seizures
  • seeing or hearing things that are not real (hallucinations)
  • coma
  • blood pressure changes
  • sweating
  • high body temperature (hyperthermia)
  • loss of coordination
  • nausea, vomiting, diarrhea

• Increased risk of bleeding. Taking vilazodone hydrochloride tablets with aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin or blood thinners may add to this risk. Tell your healthcare provider right away about any unusual bleeding or bruising.
• Mania or hypomania (manic episodes) in people who have a history of bipolar disorder. Symptoms may include:
  • greatly increased energy
  • racing thoughts
  • unusually grand ideas
  • talking more or faster than usual
  • severe trouble sleeping
  • reckless behavior
  • excessive happiness or irritability

• Discontinuation syndrome. Suddenly stopping vilazodone hydrochloride tablets may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include:
  • nausea
  • changes in your mood
  • irritability and agitation
  • dizziness
  • electric shock sensation (paresthesia)
  • anxiety
  • confusion
  • sweating
  • headache
  • tiredness
  • problems sleeping
  • hypomania
  • ringing in your ears (tinnitus)
  • seizures

• Seizures (convulsions).
• Eye problems (angle-closure glaucoma): Vilazodone hydrochloride tablets may cause a certain type of eye problem called angle-closure glaucoma. Call your healthcare provider if you have changes in your vision or eye pain.
• Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood may be serious and may cause death. Elderly people may be at greater risk for this. Signs and Symptoms of low sodium levels in your blood may include:
  • headache
  • memory changes
  • weakness and unsteadiness on your feet which can lead to falls
  • difficulty concentrating
  • confusion

In severe or more sudden cases, signs and symptoms include:

• • hallucinations (seeing or hearing things that are not real)
  • seizures
  • respiratory arrest
  • fainting
  • coma
  • death

• Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including vilazodone hydrochloride tablets, may cause sexual problems. Symptoms in males may include:
  • delayed ejaculation or inability to have an ejaculation
  • problems getting or keeping an erection
  • decreased sex drive
  Symptoms in females may include:
  • decreased sex drive
  • delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with vilazodone hydrochloride tablets. There may be treatments your healthcare provider can suggest.

The most common side effects of vilazodone hydrochloride tablets include diarrhea, nausea or vomiting, trouble sleeping.

These are not all the possible side effects of vilazodone hydrochloride tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store vilazodone hydrochloride tablets?

• Store vilazodone hydrochloride tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep vilazodone hydrochloride tablets and all medicines out of the reach of children.

General information about the safe and effective use of vilazodone hydrochloride tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use vilazodone hydrochloride tablets for a condition for which it was not prescribed. Do not give vilazodone hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them. You may ask your healthcare provider or pharmacist for information about vilazodone hydrochloride that is written for healthcare professionals.

What are the ingredients in vilazodone hydrochloride tablets?

Active ingredient: vilazodone hydrochloride

Inactive ingredients: colloidal silicon dioxide, FD&C Blue #1 Aluminum Lake (40 mg only), Ferric Oxide Red (10 mg only) and FD&C Yellow #6 Aluminum Lake (20 mg only), lactose monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

R_x Only

APOTEX INC.

VILAZODONE HYDROCHLORIDE TABLETS

10 mg, 20 mg and 40 mg

Rev. 6

Package Label – Principal Display Panel – 10 mg Tablets 30 Bottle Label

Rx only NDC 60505-4372-3

Vilazodone Hydrochloride

tablets

10 mg

Vilazodone hydrochloride has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Vilazodone hydrochloride should be prescribed with caution in patients with a seizure disorder.

There is limited clinical trial experience regarding human overdose with vilazodone hydrochloride. The adverse reactions associated with overdose of vilazodone hydrochloride at doses of 200 to 280 mg (5 to 7 times the recommended dosage) as observed in clinical trials included serotonin syndrome, lethargy, restlessness, hallucinations, and disorientation.

For current information on the management of poisoning or overdose, contact a poison control center at 1-800-222-1222.

No specific antidotes for vilazodone are known. Removal of vilazodone by dialysis has not been studied; however, the high volume of distribution of vilazodone suggests that dialysis will not be effective in reducing vilazodone plasma concentrations.

Vilazodone hydrochloride tablets for oral administration contain polymorph Form IV vilazodone hydrochloride (HCl), a selective serotonin reuptake inhibitor and a 5HT_1A receptor partial agonist.  

Vilazodone Hydrochloride is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride with a molecular formula of C₂₆H₂₇N₅O₂.HCI. Its molecular weight is 477.99. The structural formula is:

Vilazodone hydrochloride tablets are available as 10 mg, 20 mg, and 40 mg film-coated tablets containing 10 mg, 20 mg, and 40 mg of vilazodone HCl, respectively.

In addition to the active ingredient, vilazodone hydrochloride tablets contain the following inactive ingredients: colloidal silicon dioxide, FD&C Blue #1 Aluminum Lake (40 mg only), Ferric Oxide Red (10 mg only) and FD&C Yellow #6 Aluminum Lake (20 mg only), lactose monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc.

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including vilazodone hydrochloride. Cases of serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue vilazodone hydrochloride and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs [see Use in Specific Populations (8.5)].

The safety and effectiveness of vilazodone hydrochloride 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 1,002 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 vilazodone hydrochloride 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 [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.2)].

Juvenile Animal Toxicity Data

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.

Based on a pharmacokinetic study, no dosage adjustment of vilazodone hydrochloride is recommended on the basis of age (see Figure 3). Results from pharmacokinetic study of a single 20 mg vilazodone hydrochloride dose in geriatric subjects (> 65 years-old) vs. younger subjects (24 to 55 years-old) demonstrated that the pharmacokinetics were generally similar between the two age groups [see Clinical Pharmacology (12.3)].

Clinical studies of vilazodone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 3,007 patients in clinical studies with vilazodone hydrochloride, 65 (2.2%) were 65 years of age or older, and 378 (12.6%) were 55 to 64 years of age. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.8)]. No other differences in adverse reactions were observed between geriatric and younger patients.

The efficacy of vilazodone hydrochloride as a treatment for major depressive disorder was demonstrated in four multicenter, randomized, double-blind, placebo-controlled studies in adult (18 to 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 vilazodone hydrochloride 40 mg (Studies 1 to 3) and one 10-week study (Study 4) evaluated the efficacy of vilazodone hydrochloride 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 vilazodone hydrochloride with food. Vilazodone hydrochloride 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. Vilazodone hydrochloride 20 mg and 40 mg demonstrated superiority over placebo as measured by improvement in CGI-S 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.

Vilazodone hydrochloride tablets are contraindicated in:

• Patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue, because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interactions (7)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1)].
• Serotonin Syndrome [see Warnings and Precautions (5.2)].
• Increased Risk of Bleeding [see Warnings and Precautions (5.3)].
• Activation of Mania or Hypomania [see Warnings and Precautions (5.4)].
• Discontinuation Syndrome [see Warnings and Precautions (5.5)].
• Seizures [see Warnings and Precautions (5.6)].
• Angle-Closure Glaucoma [see Warnings and Precautions (5.7)].
• Hyponatremia [see Warnings and Precautions (5.8)].
• Sexual Dysfunction [see Warnings and Precautions (5.9)].

• CYP3A4 Inhibitors: The vilazodone hydrochloride dose should not exceed 20 mg once daily when co-administered with strong CYP3A4 inhibitors (2.4, 7).
• CYP3A4 Inducers: Consider increasing vilazodone hydrochloride dosage by 2-fold, up to 80 mg once-daily over 1 to 2 weeks when used concomitantly with strong CYP3A4 inducers for greater than 14 days (2.4, 7).

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-HT_1A receptors (IC₅₀=2.1 nM) and is a 5-HT_1A receptor partial agonist.

Vilazodone activity is due primarily to the parent drug. The pharmacokinetics of vilazodone (5 mg to 80 mg) are dose-proportional. Accumulation of vilazodone after administration of single vilazodone hydrochloride 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 vilazodone hydrochloride 40 mg under fed conditions, the mean C_max value was 156 ng/mL, and the mean AUC _{( 0-24 hours )} value was 1,645 ng·h/mL.

Serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitor (SSRIs), including vilazodone hydrochloride, 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 vilazodone hydrochloride 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 vilazodone hydrochloride with MAOIs is contraindicated. In addition, do not initiate vilazodone hydrochloride 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 vilazodone hydrochloride, discontinue vilazodone hydrochloride before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.1)].

Monitor all patients taking vilazodone hydrochloride for the emergence of serotonin syndrome. Discontinue treatment with vilazodone hydrochloride and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of vilazodone hydrochloride with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

Use of SSRIs, including vilazodone hydrochloride, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of vilazodone hydrochloride and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

Vilazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14)].

The mechanism of action of vilazodone in the treatment of major depressive disorder 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-HT_1A receptors; however, the net result of this action on serotonergic transmission and its role in vilazodone's antidepressant effect are unknown.

Vilazodone hydrochloride is not a controlled substance.

Vilazodone hydrochloride has been systematically studied in animals and did not demonstrate abuse or dependence potential. While vilazodone hydrochloride has not been systematically studied in humans for its potential for abuse, there was no suggested evidence of drug-seeking behavior in the clinical studies.

• Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue vilazodone hydrochloride and serotonergic agents and initiate supportive treatment (5.2)
• Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk (5.3)
• Activation of Mania/Hypomania: Screen patients for bipolar disorder (5.4)
• Seizures: Can occur with treatment. Use with caution in patients with a seizure disorder (5.6)
• Angle Closure Glaucoma: Avoid use of antidepressants, including vilazodone hydrochloride, in patients with untreated anatomically narrow angles. (5.7)
•  Sexual Dysfunction: Vilazodone hydrochloride may cause symptoms of sexual dysfunction (5.9)

The pupillary dilation that occurs following use of many antidepressant drugs including vilazodone hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including vilazodone hydrochloride, in patients with untreated anatomically narrow angles.

• Recommended target dosage: 20 mg to 40 mg once daily with food (2.1, 12.3).
• 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 (2.1)
• Prior to initiating vilazodone hydrochloride, screen for bipolar disorder (2.2, 5.4)
• When discontinuing vilazodone hydrochloride, reduce dosage gradually (2.4, 5.5)

Vilazodone Hydrochloride Tablets are available as 10 mg, 20 mg and 40 mg film-coated tablets.

• 10 mg: Pink colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “14” on other side, free from physical defects.
• 20 mg: Orange colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “15” on other side, free from physical defects.
• 40 mg: Blue colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “16” on other side, free from physical defects.

Adverse 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)].

The following adverse reactions have been identified during post-approval use of vilazodone hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Reports of adverse reactions temporally associated with vilazodone hydrochloride that have been received since market introduction and that are not listed above include the following:

General Disorders and Administration Site Conditions: irritability

Nervous System Disorders: sleep paralysis

Psychiatric Disorders: hallucinations, suicide attempt, suicidal ideation

Skin and subcutaneous tissue disorders: rash, generalized rash, urticaria, drug eruption

Gastrointestinal System: acute pancreatitis

Respiratory, Thoracic and Mediastinal Disorders: anosmia, hyposmia

• Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the newborn (8.1).

Drugs that interfere with serotonin reuptake inhibition, including vilazodone hydrochloride, 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 vilazodone hydrochloride and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing vilazodone hydrochloride. 

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.

The most commonly observed adverse reactions in vilazodone hydrochloride-treated patients with major depressive disorder (MDD) in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were diarrhea, nausea, vomiting, and insomnia.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

Dosage and Administration

Instruct patients to take vilazodone hydrochloride with food and to follow prescribed dosage instructions [see Dosage and Administration (2.1, 2.3, 2.4, 2.5)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of vilazodone hydrochloride with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7)].

Increased Risk of Bleeding

Inform patients about the concomitant use of vilazodone hydrochloride tablets with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use of drugs that interfere with serotonin reuptake (e.g., vilazodone hydrochloride) and these medications has been associated with an increased risk of bleeding. Advise them to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.3)].  

Activation of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.4)].

Discontinuation Syndrome

Advise patients not to abruptly discontinue vilazodone hydrochloride tablets and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when vilazodone hydrochloride tablets are discontinued [see Warnings and Precautions (5.5)].

Seizures

Caution patients about using vilazodone hydrochloride if they have a history of a seizure disorder [see Warnings and Precautions (5.6)].

Sexual Dysfunction

Advise patients that use of vilazodone hydrochloride may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.9)].

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Adverse Reactions (6.2)].

Concomitant Medications

Advise patients to inform their health care providers if they are taking, or plan to take any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions (7.1)].

Pregnancy

• Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with vilazodone hydrochloride tablets [see Use in Specific Populations (8.1)].
• Advise patients that vilazodone hydrochloride tablets use late in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) [see Use in Specific Populations (8.1)].
• Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to vilazodone hydrochloride tablets during pregnancy [see Use in Specific Populations (8.1)].

Vilazodone hydrochloride tablets are supplied in the following configurations:  

10 mg: Pink colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “14” on other side, free from physical defects

60505-4372-3: 30-count bottles

20 mg: Orange colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “15” on other side, free from physical defects

60505-4373-3: 30-count bottles

40 mg: Blue colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “16” on other side, free from physical defects

60505-4374-3: 30-count bottles

Blister Package:

10 mg: 100 (10 x 10) Unit-dose tablets NDC 60505-4372-0

20 mg: 100 (10 x 10) Unit-dose tablets NDC 60505-4373-0

40 mg: 100 (10 x 10) Unit-dose tablets NDC 60505-4374-0

Vilazodone hydrochloride tablets should be stored at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

In patients with bipolar disorder, treating a depressive episode with vilazodone hydrochloride 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 vilazodone hydrochloride. Prior to initiating treatment with vilazodone hydrochloride, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration (2.2)].

No dosage adjustment of vilazodone hydrochloride is necessary on the basis of gender, renal function (mild to severe renal impairment, glomerular filtration rate: 15 to 90 mL/minute), or hepatic function (mild to severe hepatic impairment, Child-Pugh score: 5 to 15 [see Clinical Pharmacology (12.3)].

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and  young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)] . Vilazodone hydrochloride tablets is not approved for use in pediatric patients [see Use in Specific Populations (8.4 )] .

The recommended target dosage for vilazodone hydrochloride 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 vilazodone hydrochloride 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.

Adverse reactions may occur upon discontinuation of vilazodone hydrochloride [see Warnings and Precautions (5.5)]. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible. Vilazodone hydrochloride should be down tapered from the 40 mg once daily dose to 20 mg once daily for 4 days, followed by 10 mg once daily for 3 days. Patients taking vilazodone hydrochloride 20 mg once daily should be tapered to 10 mg once daily for 7 days.

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 1,000 patients treated are provided in Table 1.

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 vilazodone hydrochloride, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of vilazodone hydrochloride. In addition, at least 14 days must elapse after stopping vilazodone hydrochloride before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)].

Prior to initiating treatment with vilazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.4)].  

Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and/or P-glycoprotein (except narrow therapeutic index drugs, e.g., digoxin), when vilazodone hydrochloride is administered concomitantly [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Patients receiving concomitant CYP3A4 inhibitors:

During concomitant use of a strong CYP3A4 inhibitor (e.g., itraconazole, clarithromycin, voriconazole), the vilazodone hydrochloride dose should not exceed 20 mg once daily. The original vilazodone hydrochloride dose level, can be resumed when the CYP3A4 inhibitor is discontinued [see Drug Interactions (7)].

MEDICATION GUIDE

Vilazodone (vil-AZ-oh-done) Hydrochloride

Tablets , for oral use

Dispense with Medication Guide available at https://www.apotex.com/products/us/mg.asp

What is the most important information I should know about vilazodone hydrochloride tablets?

Vilazodone hydrochloride tablets may cause serious side effects, including:

• Increased risk of suicidal thoughts or actions in some children, adolescents, and young adults. Vilazodone hydrochloride tablets and other antidepressant medicines may increase suicidal thoughts or actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed.

  Vilazodone hydrochloride tablets are not for use in children.

  • Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a higher risk of having suicidal thoughts or actions. These include people who have (or have a family history of) depression, bipolar illness (also called manic-depressive illness) or have a history of suicidal thoughts or actions.

How can I watch for and try to prevent suicidal thoughts and actions ?

• • Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed.
  • Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call your healthcare provider or get emergency medical help right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you:

• • attempts to commit suicide
  • acting aggressive, being angry or violent
  • new or worse depression
  • panic attacks
  • new or worse irritability
  • an extreme increase in activity or talking (mania)
  • acting on dangerous impulses
  • thoughts about suicide or dying
  • new or worse anxiety
  • feeling agitated or restless
  • trouble sleeping (insomnia)
  • other unusual changes in behavior or mood

What are vilazodone hydrochloride tablets?

Vilazodone hydrochloride tablets are a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD) in adults. It is not known if vilazodone hydrochloride tablets are safe and effective for use in children for the treatment of MDD.

Who should not take vilazodone hydrochloride tablets?

Do not take vilazodone hydrochloride tablets if you:

• take a Monoamine Oxidase Inhibitor (MAOI)
• have stopped taking an MAOI in the last 14 days
• are being treated with the antibiotic linezolid or intravenous methylene blue

Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene blue.

Do not start taking an MAOI for at least 14 days after you stop treatment with vilazodone hydrochloride.

Before taking vilazodone hydrochloride tablets, tell your healthcare provider about all your medical conditions, including if you:

• have or have a family history of suicide, depression, bipolar disorder, mania or hypomania
• have or had bleeding problems
• have or had seizures or convulsions
• have high pressure in the eye (glaucoma)
• have low sodium levels in your blood
• drink alcohol
• are pregnant or plan to become pregnant. Taking vilazodone hydrochloride tablets late in pregnancy may lead to an increased risk of certain problems in your newborn. Talk to your healthcare provider about the risks to your baby if you take vilazodone hydrochloride tablets during pregnancy. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with vilazodone hydrochloride tablets.
  • There is a pregnancy registry for females who are exposed to vilazodone hydrochloride pregnancy. The purpose of the registry is to collect information about the health of females exposed to vilazodone hydrochloride and their baby. If you become pregnant during treatment with vilazodone hydrochloride, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants.
• are breastfeeding or plan to breastfeed. It is not known if vilazodone hydrochloride passes into breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with vilazodone hydrochloride tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Vilazodone hydrochloride and some medicines may affect each other causing possible serious side effects. Vilazodone hydrochloride may affect the way other medicines work and other medicines may affect the way vilazodone hydrochloride works.

Especially tell your healthcare provider if you take:

• MAOIs
• medicines used to treat migraine headaches known as triptans
• tricyclic antidepressants
• lithium
• tramadol, fentanyl, meperidine, methadone, or other opioids
• tryptophan
• buspirone
• amphetamines
• St. John's Wort
• medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and warfarin
• diuretics
• medicines used to treat mood, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)

Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take vilazodone hydrochloride tablets with your other medicines.

Do not start or stop any other medicines during treatment with vilazodone hydrochloride tablets without talking to your healthcare provider first. Stopping vilazodone hydrochloride tablets suddenly may cause you to have serious side effects. See, "What are the possible side effects of vilazodone hydrochloride tablets?"

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How should I take vilazodone hydrochloride tablets?

• Take vilazodone hydrochloride tablets exactly as your healthcare provider tell you to. Do not change your dose or stop taking vilazodone hydrochloride tablets without first talking to your healthcare provider.
• Your healthcare provider may need to change the dose of vilazodone hydrochloride until it is the right dose for you.
• Take vilazodone hydrochloride tablets 1 time each day with food.
• If you miss a dose of vilazodone hydrochloride tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of vilazodone hydrochloride tablets at the same time.
• If you take too much vilazodone hydrochloride tablets, call your healthcare provider or poison control center at 1-800-222-1222 right away, or get emergency treatment right away.

What should I avoid while taking vilazodone hydrochloride tablets?

• Do not drive, operate heavy machinery, or do other dangerous activities until you know how vilazodone hydrochloride tablets affects you. Vilazodone hydrochloride tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly.
• Avoid drinking alcohol during treatment with vilazodone hydrochloride tablets.

What are the possible side effects of vilazodone hydrochloride tablets?

Vilazodone hydrochloride tablets may cause serious side effects, including:

• See, "What is the most important information I should know about vilazodone hydrochloride tablets?’’
• Serotonin Syndrome. A potentially life-threatening problem called serotonin syndrome can happen when vilazodone hydrochloride tablets are taken with certain other medicines. See, "Who should not take vilazodone hydrochloride tablets?" Stop taking vilazodone hydrochloride tablets and call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome:
  • agitation
  • confusion
  • fast heart beat
  • dizziness
  • flushing
  • tremors, stiff muscles, or muscle twitching
  • seizures
  • seeing or hearing things that are not real (hallucinations)
  • coma
  • blood pressure changes
  • sweating
  • high body temperature (hyperthermia)
  • loss of coordination
  • nausea, vomiting, diarrhea

• Increased risk of bleeding. Taking vilazodone hydrochloride tablets with aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), warfarin or blood thinners may add to this risk. Tell your healthcare provider right away about any unusual bleeding or bruising.
• Mania or hypomania (manic episodes) in people who have a history of bipolar disorder. Symptoms may include:
  • greatly increased energy
  • racing thoughts
  • unusually grand ideas
  • talking more or faster than usual
  • severe trouble sleeping
  • reckless behavior
  • excessive happiness or irritability

• Discontinuation syndrome. Suddenly stopping vilazodone hydrochloride tablets may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include:
  • nausea
  • changes in your mood
  • irritability and agitation
  • dizziness
  • electric shock sensation (paresthesia)
  • anxiety
  • confusion
  • sweating
  • headache
  • tiredness
  • problems sleeping
  • hypomania
  • ringing in your ears (tinnitus)
  • seizures

• Seizures (convulsions).
• Eye problems (angle-closure glaucoma): Vilazodone hydrochloride tablets may cause a certain type of eye problem called angle-closure glaucoma. Call your healthcare provider if you have changes in your vision or eye pain.
• Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood may be serious and may cause death. Elderly people may be at greater risk for this. Signs and Symptoms of low sodium levels in your blood may include:
  • headache
  • memory changes
  • weakness and unsteadiness on your feet which can lead to falls
  • difficulty concentrating
  • confusion

In severe or more sudden cases, signs and symptoms include:

• • hallucinations (seeing or hearing things that are not real)
  • seizures
  • respiratory arrest
  • fainting
  • coma
  • death

• Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including vilazodone hydrochloride tablets, may cause sexual problems. Symptoms in males may include:
  • delayed ejaculation or inability to have an ejaculation
  • problems getting or keeping an erection
  • decreased sex drive
  Symptoms in females may include:
  • decreased sex drive
  • delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with vilazodone hydrochloride tablets. There may be treatments your healthcare provider can suggest.

The most common side effects of vilazodone hydrochloride tablets include diarrhea, nausea or vomiting, trouble sleeping.

These are not all the possible side effects of vilazodone hydrochloride tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store vilazodone hydrochloride tablets?

• Store vilazodone hydrochloride tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep vilazodone hydrochloride tablets and all medicines out of the reach of children.

General information about the safe and effective use of vilazodone hydrochloride tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use vilazodone hydrochloride tablets for a condition for which it was not prescribed. Do not give vilazodone hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them. You may ask your healthcare provider or pharmacist for information about vilazodone hydrochloride that is written for healthcare professionals.

What are the ingredients in vilazodone hydrochloride tablets?

Active ingredient: vilazodone hydrochloride

Inactive ingredients: colloidal silicon dioxide, FD&C Blue #1 Aluminum Lake (40 mg only), Ferric Oxide Red (10 mg only) and FD&C Yellow #6 Aluminum Lake (20 mg only), lactose monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

R_x Only

APOTEX INC.

VILAZODONE HYDROCHLORIDE TABLETS

10 mg, 20 mg and 40 mg

Rev. 6

Package Label – Principal Display Panel – 10 mg Tablets 30 Bottle Label

Rx only NDC 60505-4372-3

Vilazodone Hydrochloride

tablets

10 mg

Vilazodone hydrochloride has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Vilazodone hydrochloride should be prescribed with caution in patients with a seizure disorder.

There is limited clinical trial experience regarding human overdose with vilazodone hydrochloride. The adverse reactions associated with overdose of vilazodone hydrochloride at doses of 200 to 280 mg (5 to 7 times the recommended dosage) as observed in clinical trials included serotonin syndrome, lethargy, restlessness, hallucinations, and disorientation.

For current information on the management of poisoning or overdose, contact a poison control center at 1-800-222-1222.

No specific antidotes for vilazodone are known. Removal of vilazodone by dialysis has not been studied; however, the high volume of distribution of vilazodone suggests that dialysis will not be effective in reducing vilazodone plasma concentrations.

Vilazodone hydrochloride tablets for oral administration contain polymorph Form IV vilazodone hydrochloride (HCl), a selective serotonin reuptake inhibitor and a 5HT_1A receptor partial agonist.  

Vilazodone Hydrochloride is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride with a molecular formula of C₂₆H₂₇N₅O₂.HCI. Its molecular weight is 477.99. The structural formula is:

Vilazodone hydrochloride tablets are available as 10 mg, 20 mg, and 40 mg film-coated tablets containing 10 mg, 20 mg, and 40 mg of vilazodone HCl, respectively.

In addition to the active ingredient, vilazodone hydrochloride tablets contain the following inactive ingredients: colloidal silicon dioxide, FD&C Blue #1 Aluminum Lake (40 mg only), Ferric Oxide Red (10 mg only) and FD&C Yellow #6 Aluminum Lake (20 mg only), lactose monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc.

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including vilazodone hydrochloride. Cases of serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue vilazodone hydrochloride and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs [see Use in Specific Populations (8.5)].

The safety and effectiveness of vilazodone hydrochloride 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 1,002 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 vilazodone hydrochloride 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 [see Boxed Warning, Warnings and Precautions (5.1), and Adverse Reactions (6.2)].

Juvenile Animal Toxicity Data

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.

Based on a pharmacokinetic study, no dosage adjustment of vilazodone hydrochloride is recommended on the basis of age (see Figure 3). Results from pharmacokinetic study of a single 20 mg vilazodone hydrochloride dose in geriatric subjects (> 65 years-old) vs. younger subjects (24 to 55 years-old) demonstrated that the pharmacokinetics were generally similar between the two age groups [see Clinical Pharmacology (12.3)].

Clinical studies of vilazodone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 3,007 patients in clinical studies with vilazodone hydrochloride, 65 (2.2%) were 65 years of age or older, and 378 (12.6%) were 55 to 64 years of age. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.8)]. No other differences in adverse reactions were observed between geriatric and younger patients.

The efficacy of vilazodone hydrochloride as a treatment for major depressive disorder was demonstrated in four multicenter, randomized, double-blind, placebo-controlled studies in adult (18 to 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 vilazodone hydrochloride 40 mg (Studies 1 to 3) and one 10-week study (Study 4) evaluated the efficacy of vilazodone hydrochloride 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 vilazodone hydrochloride with food. Vilazodone hydrochloride 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. Vilazodone hydrochloride 20 mg and 40 mg demonstrated superiority over placebo as measured by improvement in CGI-S 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.

Vilazodone hydrochloride tablets are contraindicated in:

• Patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue, because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interactions (7)].

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1)].
• Serotonin Syndrome [see Warnings and Precautions (5.2)].
• Increased Risk of Bleeding [see Warnings and Precautions (5.3)].
• Activation of Mania or Hypomania [see Warnings and Precautions (5.4)].
• Discontinuation Syndrome [see Warnings and Precautions (5.5)].
• Seizures [see Warnings and Precautions (5.6)].
• Angle-Closure Glaucoma [see Warnings and Precautions (5.7)].
• Hyponatremia [see Warnings and Precautions (5.8)].
• Sexual Dysfunction [see Warnings and Precautions (5.9)].

• CYP3A4 Inhibitors: The vilazodone hydrochloride dose should not exceed 20 mg once daily when co-administered with strong CYP3A4 inhibitors (2.4, 7).
• CYP3A4 Inducers: Consider increasing vilazodone hydrochloride dosage by 2-fold, up to 80 mg once-daily over 1 to 2 weeks when used concomitantly with strong CYP3A4 inducers for greater than 14 days (2.4, 7).

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-HT_1A receptors (IC₅₀=2.1 nM) and is a 5-HT_1A receptor partial agonist.

Vilazodone activity is due primarily to the parent drug. The pharmacokinetics of vilazodone (5 mg to 80 mg) are dose-proportional. Accumulation of vilazodone after administration of single vilazodone hydrochloride 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 vilazodone hydrochloride 40 mg under fed conditions, the mean C_max value was 156 ng/mL, and the mean AUC _{( 0-24 hours )} value was 1,645 ng·h/mL.

Serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitor (SSRIs), including vilazodone hydrochloride, 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 vilazodone hydrochloride 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 vilazodone hydrochloride with MAOIs is contraindicated. In addition, do not initiate vilazodone hydrochloride 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 vilazodone hydrochloride, discontinue vilazodone hydrochloride before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.1)].

Monitor all patients taking vilazodone hydrochloride for the emergence of serotonin syndrome. Discontinue treatment with vilazodone hydrochloride and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of vilazodone hydrochloride with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

Use of SSRIs, including vilazodone hydrochloride, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of vilazodone hydrochloride and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

Vilazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14)].

The mechanism of action of vilazodone in the treatment of major depressive disorder 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-HT_1A receptors; however, the net result of this action on serotonergic transmission and its role in vilazodone's antidepressant effect are unknown.

Vilazodone hydrochloride is not a controlled substance.

Vilazodone hydrochloride has been systematically studied in animals and did not demonstrate abuse or dependence potential. While vilazodone hydrochloride has not been systematically studied in humans for its potential for abuse, there was no suggested evidence of drug-seeking behavior in the clinical studies.

• Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue vilazodone hydrochloride and serotonergic agents and initiate supportive treatment (5.2)
• Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk (5.3)
• Activation of Mania/Hypomania: Screen patients for bipolar disorder (5.4)
• Seizures: Can occur with treatment. Use with caution in patients with a seizure disorder (5.6)
• Angle Closure Glaucoma: Avoid use of antidepressants, including vilazodone hydrochloride, in patients with untreated anatomically narrow angles. (5.7)
•  Sexual Dysfunction: Vilazodone hydrochloride may cause symptoms of sexual dysfunction (5.9)

The pupillary dilation that occurs following use of many antidepressant drugs including vilazodone hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including vilazodone hydrochloride, in patients with untreated anatomically narrow angles.

• Recommended target dosage: 20 mg to 40 mg once daily with food (2.1, 12.3).
• 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 (2.1)
• Prior to initiating vilazodone hydrochloride, screen for bipolar disorder (2.2, 5.4)
• When discontinuing vilazodone hydrochloride, reduce dosage gradually (2.4, 5.5)

Vilazodone Hydrochloride Tablets are available as 10 mg, 20 mg and 40 mg film-coated tablets.

• 10 mg: Pink colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “14” on other side, free from physical defects.
• 20 mg: Orange colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “15” on other side, free from physical defects.
• 40 mg: Blue colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “16” on other side, free from physical defects.

Adverse 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)].

The following adverse reactions have been identified during post-approval use of vilazodone hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Reports of adverse reactions temporally associated with vilazodone hydrochloride that have been received since market introduction and that are not listed above include the following:

General Disorders and Administration Site Conditions: irritability

Nervous System Disorders: sleep paralysis

Psychiatric Disorders: hallucinations, suicide attempt, suicidal ideation

Skin and subcutaneous tissue disorders: rash, generalized rash, urticaria, drug eruption

Gastrointestinal System: acute pancreatitis

Respiratory, Thoracic and Mediastinal Disorders: anosmia, hyposmia

• Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the newborn (8.1).

Drugs that interfere with serotonin reuptake inhibition, including vilazodone hydrochloride, 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 vilazodone hydrochloride and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing vilazodone hydrochloride. 

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.

The most commonly observed adverse reactions in vilazodone hydrochloride-treated patients with major depressive disorder (MDD) in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were diarrhea, nausea, vomiting, and insomnia.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

Dosage and Administration

Instruct patients to take vilazodone hydrochloride with food and to follow prescribed dosage instructions [see Dosage and Administration (2.1, 2.3, 2.4, 2.5)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of vilazodone hydrochloride with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7)].

Increased Risk of Bleeding

Inform patients about the concomitant use of vilazodone hydrochloride tablets with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use of drugs that interfere with serotonin reuptake (e.g., vilazodone hydrochloride) and these medications has been associated with an increased risk of bleeding. Advise them to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.3)].  

Activation of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.4)].

Discontinuation Syndrome

Advise patients not to abruptly discontinue vilazodone hydrochloride tablets and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when vilazodone hydrochloride tablets are discontinued [see Warnings and Precautions (5.5)].

Seizures

Caution patients about using vilazodone hydrochloride if they have a history of a seizure disorder [see Warnings and Precautions (5.6)].

Sexual Dysfunction

Advise patients that use of vilazodone hydrochloride may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.9)].

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see Adverse Reactions (6.2)].

Concomitant Medications

Advise patients to inform their health care providers if they are taking, or plan to take any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions (7.1)].

Pregnancy

• Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with vilazodone hydrochloride tablets [see Use in Specific Populations (8.1)].
• Advise patients that vilazodone hydrochloride tablets use late in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) [see Use in Specific Populations (8.1)].
• Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to vilazodone hydrochloride tablets during pregnancy [see Use in Specific Populations (8.1)].

Vilazodone hydrochloride tablets are supplied in the following configurations:  

10 mg: Pink colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “14” on other side, free from physical defects

60505-4372-3: 30-count bottles

20 mg: Orange colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “15” on other side, free from physical defects

60505-4373-3: 30-count bottles

40 mg: Blue colored, ellipse shaped, biconvex, film coated tablets, debossed with “MV” on one side and “16” on other side, free from physical defects

60505-4374-3: 30-count bottles

Blister Package:

10 mg: 100 (10 x 10) Unit-dose tablets NDC 60505-4372-0

20 mg: 100 (10 x 10) Unit-dose tablets NDC 60505-4373-0

40 mg: 100 (10 x 10) Unit-dose tablets NDC 60505-4374-0

Vilazodone hydrochloride tablets should be stored at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

In patients with bipolar disorder, treating a depressive episode with vilazodone hydrochloride 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 vilazodone hydrochloride. Prior to initiating treatment with vilazodone hydrochloride, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration (2.2)].

No dosage adjustment of vilazodone hydrochloride is necessary on the basis of gender, renal function (mild to severe renal impairment, glomerular filtration rate: 15 to 90 mL/minute), or hepatic function (mild to severe hepatic impairment, Child-Pugh score: 5 to 15 [see Clinical Pharmacology (12.3)].

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and  young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)] . Vilazodone hydrochloride tablets is not approved for use in pediatric patients [see Use in Specific Populations (8.4 )] .

The recommended target dosage for vilazodone hydrochloride 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 vilazodone hydrochloride 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.

Adverse reactions may occur upon discontinuation of vilazodone hydrochloride [see Warnings and Precautions (5.5)]. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible. Vilazodone hydrochloride should be down tapered from the 40 mg once daily dose to 20 mg once daily for 4 days, followed by 10 mg once daily for 3 days. Patients taking vilazodone hydrochloride 20 mg once daily should be tapered to 10 mg once daily for 7 days.

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 1,000 patients treated are provided in Table 1.

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 vilazodone hydrochloride, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of vilazodone hydrochloride. In addition, at least 14 days must elapse after stopping vilazodone hydrochloride before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)].

Prior to initiating treatment with vilazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.4)].  

Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and/or P-glycoprotein (except narrow therapeutic index drugs, e.g., digoxin), when vilazodone hydrochloride is administered concomitantly [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].