vilazodone hydrochloride Dailymed

Warning: Suicidal Thoughts And Behaviors

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 )] .


WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

• Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients (5.1).
• Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors (5.1).
• Vilazodone hydrochloride tablets is not approved for use in pediatric patients (8.4).

Recent Major Changes Section

Warnings and Precautions (5.2, 5.3) 8/2023

1 Indications And Usage

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


Vilazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults (1).

2 Dosage And Administration

• 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)

2.1 Dosage for Treatment of Major Depressive Disorder

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.

2.2 Screen for Bipolar Disorder Prior to Starting Vilazodone Hydrochloride Tablets

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)].  

2.3 Switching to or from a Monoamine Oxidase Inhibitor Antidepressant

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)].

2.4 Dosage Adjustments with CYP3A4 Inhibitors or Inducers

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)].

Patients receiving concomitant CYP3A4 inducers:

Based on clinical response, consider increasing the dosage of vilazodone hydrochloride by 2-fold, up to a maximum 80 mg once daily, over 1 to 2 weeks in patients taking strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin) for greater than 14 days. If CYP3A4 inducers are discontinued, gradually reduce the vilazodone hydrochloride dosage to its original level over 1 to 2 weeks [see Drug Interactions (7)].

2.5 Discontinuing Treatment with Vilazodone Hydrochloride Tablets

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.

• 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)

5.1 Suicidal Thoughts and Behavior in Adolescents and Young Adults

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.

Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age Range (years)	Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1,000 Patients Treated
	Increases Compared to Placebo
<18	14 additional patients
18-24	5 additional patients
	Decreases Compared to Placebo
25-64	1 fewer patient
≥65	6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing vilazodone hydrochloride, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome

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.

5.3 Increased Risk of Bleeding

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. 

5.4 Activation of Mania or Hypomania

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)].

5.5 Discontinuation Syndrome

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)].

5.6 Seizures

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.

5.7 Angle-Closure Glaucoma

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.

5.8 Hyponatremia

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)].

5.9 Sexual Dysfunction

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.

6 Adverse Reactions

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)].

Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): diarrhea, nausea, vomiting, and insomnia (6).

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience

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.

Patient Exposure

The safety of vilazodone hydrochloride was evaluated in 3,007 patients (18 to 70 years of age) diagnosed with MDD who participated in clinical studies, representing 676 patient-years of exposure. In an open-label 52 week study at 40 mg daily, 599 patients were exposed to vilazodone hydrochloride for a total of 348 patient-years.

The adverse reaction information presented below was derived from studies of vilazodone hydrochloride 20 mg and 40 mg daily in patients with MDD including:

• Four placebo-controlled 8 to 10-week studies in 2,233 patients, including 1,266 vilazodone hydrochloride-treated patients; and
• An open-label 52-week study of 599 vilazodone hydrochloride-treated patients.

These studies included a titration period of 10 mg daily for 7 days, followed by 20 mg daily for 7 days or to 40 mg daily over 2 weeks. In these clinical trials, vilazodone hydrochloride was administered with food.

Adverse reactions reported as reasons for discontinuation of treatment

In these studies, 7.3% of the vilazodone hydrochloride-treated patients discontinued treatment due to an adverse reaction, compared with 3.5% of placebo-treated patients. The most common adverse reaction leading to discontinuation in at least 1% of the vilazodone hydrochloride-treated patients in the placebo-controlled studies was nausea (1.4%).

Common adverse reactions in placebo-controlled MDD studies

Table 2 shows the incidence of common adverse reactions occurring in ≥ 2% of vilazodone hydrochloride-treated patients and greater than the rate of placebo-treated patients in MDD Studies. There were no dose-related adverse reactions between 20 mg and 40 mg reported.

Table 2: Common Adverse Reactions Occurring in ≥ 2% of Vilazodone Hydrochloride-treated Patients and Greater than the Rate of Placebo-Treated Patients

System Organ Class Preferred Term	Placebo N=967	Vilazodone Hydrochloride 20 mg/day N=288	Vilazodone Hydrochloride 40 mg/day N=978
1 Includes abdominal discomfort, abdominal pain upper, and abdominal pain.
2 Includes headache and tension headache
3 Includes restlessness, akathisia, and restless legs syndrome
Sexual adverse reactions are presented in Table 3
Gastrointestinal disorders
Diarrhea	10%	26%	29%
Nausea	7%	22%	24%
Dry mouth	5%	8%	7%
Vomiting	2%	4%	5%
Abdominal pain1	3%	7%	4%
Dyspepsia	2%	2%	3%
Flatulence	1%	3%	3%
Gastroenteritis	1%	1%	2%
Abdominal distension	1%	2%	1%
Nervous system disorders
Headache2	14%	15%	14%
Dizziness	5%	6%	8%
Somnolence	2%	4%	5%
Paresthesia	1%	1%	2%
Psychiatric disorders
Insomnia	2%	7%	6%
Abnormal dreams	2%	2%	3%
Restlessness3	1%	2%	3%
General disorders
Fatigue	3%	4%	3%
Cardiac disorders
Palpitations	<1%	1%	2%
Metabolism and nutrition disorders
Increased appetite	1%	1%	3%
Musculoskeletal and connective tissue disorders
Arthralgia	1%	2%	1%
Investigations
Increased weight	1%	1%	2%

Sexual adverse reactions

Table 3 displays the most common sexual adverse reactions in the placebo-controlled MDD studies.

Table 3: Common Sexual Adverse Reactions Occurring in ≥ 2% of Vilazodone Hydrochloride-treated Patients and Greater than the Rate of Placebo-Treated Patients

− Not applicable*Includes abnormal orgasm and anorgasmia
Preferred Term	Males			Females
	Placebo N=416	Vilazodone Hydrochloride 20 mg/day N=122	Vilazodone Hydrochloride 40 mg/day N=417	Placebo N=551	Vilazodone Hydrochloride 20 mg/day N=166	Vilazodone Hydrochloride 40 mg/day N=561
Abnormal Orgasm*	<1%	2%	2%	0%	1%	1%
Erectile dysfunction	1%	0%	3%	-	-	-
Libido decreased	<1%	3%	4%	<1%	2%	2%
Ejaculation disorder	0%	1%	2%	-	-	-

Other adverse reactions observed in clinical studies

The following ul does not include reactions: 1) already uled in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients:

Cardiac disorders: infrequent: ventricular extrasystoles

Eye disorders: infrequent: dry eye, vision blurred, rare: cataracts

Nervous System: frequent: sedation, tremor; infrequent: migraine  

Psychiatric disorders: infrequent: panic attack  

Skin and subcutaneous tissue disorders: infrequent: hyperhidrosis, night sweats

6.2 Postmarketing Experience

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 uled 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