Vilazodone Hydrochloride: Package Insert and Label Information (Page 3 of 6)

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 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

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Vilazodone Hydrochloride

Table 4: Clinically Important Drug Interactions with Vilazodone Hydrochloride

Concomitant Drug Name or Drug Class

Clinical Rationale

Clinical Recommendation

Monoamine Oxidase Inhibitors (MAOIs)

The concomitant use of MAOIs and serotonergic drugs including vilazodone hydrochloride increases the risk of serotonin syndrome.

Vilazodone hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)].

Other Serotonergic Drugs

The concomitant use of serotonergic drugs including vilazodone hydrochloride and other serotonergic drugs increases the risk of serotonin syndrome.

Monitor patients for signs and symptoms of serotonin syndrome, particularly during vilazodone hydrochloride initiation. If serotonin syndrome occurs, consider discontinuation of vilazodone hydrochloride and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].

Antiplatelet Agents and Anticoagulants

Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with vilazodone hydrochloride may potentiate the risk of bleeding.

Inform patients of the increased risk of bleeding with the concomitant use of vilazodone hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating, titrating, or discontinuing vilazodone hydrochloride [see Warnings and Precautions (5.3)].

Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole)

The concomitant use of vilazodone hydrochloride and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of vilazodone hydrochloride alone [see Clinical Pharmacology (12.3)].

The vilazodone hydrochloride dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Strong CYP3A4

Inducers (e.g., carbamazepine, phenytoin, rifampin)

The concomitant use of vilazodone hydrochloride and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of vilazodone hydrochloride alone [see Clinical Pharmacology (12.3)].

Based on clinical response, consider increasing the dosage of vilazodone hydrochloride, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Digoxin

Digoxin is a narrow therapeutic index drug. Concomitant use of vilazodone hydrochloride increased digoxin concentrations [see Clinical Pharmacology (12.3)].

Measure serum digoxin concentrations before initiating concomitant use of vilazodone hydrochloride. Continue monitoring and reduce digoxin dose as necessary.

7.2 Drugs Having No Clinically Important Interactions with Vilazodone Hydrochloride

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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.

Risk Summary

There are no adequate and well-controlled studies of vilazodone hydrochloride in pregnant women. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. In animal reproduction studies, oral administration of vilazodone during the period of organogenesis at doses up to 48 and 17 times the maximum recommended human dose (MRHD) in rats and rabbits, respectively, resulted in decreased fetal body weight gain and delayed skeletal ossification but no teratogenic effects were observed. Decreased fetal body weight and delayed skeletal ossification were not observed at doses up to 10 and 4 times the MRHD in rats and rabbits, respectively [see Data].

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Fetal/Neonatal adverse reactions

Exposure to SSRIs and SNRIs, including vilazodone hydrochloride, in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). Monitor neonates who were exposed to vilazodone hydrochloride in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [see Data].

Data

Human Data

Third Trimester Exposure

Neonates exposed to SSRIs or SNRIs late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on postmarketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome [see Warnings and Precautions (5.2)].

Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997 to 2005 found a PPHN risk ratio of 2.4 (95% CI 1.2 to 4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and a PPHN risk ratio of 3.6 (95% CI 1.2 to 8.3) associated with a combination of patient-reported maternal use of SSRIs “in early pregnancy” and an antenatal SSRI prescription “in later pregnancy.”

Animal Data

No teratogenic effects were observed when vilazodone was given to pregnant rats or rabbits during the period of organogenesis at oral doses up to 200 mg/kg/day and 36 mg/kg/day, respectively. These doses are 48 and 17 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 40 mg on a mg/m2 basis. Fetal body weight gain was reduced, and skeletal ossification was delayed in both rats and rabbits at these doses; these effects were not observed at doses up to 10 times the MRHD in rats or 4 times the MRHD in rabbits.

When vilazodone was administered to pregnant rats at an oral dose of 30 times the MRHD during the period of organogenesis and throughout pregnancy and lactation, the number of live born pups was decreased. There was an increase in early postnatal pup mortality, and among surviving pups there was decreased body weight, delayed maturation, and decreased fertility in adulthood. There was some maternal toxicity at this dose. These effects were not seen at 6 times the MRHD.

8.2 Lactation

Risk Summary

There are no data on the presence of vilazodone in human milk, the effects of vilazodone on the breastfed infant, or the effects of the drug on milk production. However, vilazodone is excreted in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for vilazodone hydrochloride and any potential adverse effects on the breastfed child from vilazodone hydrochloride or from the underlying maternal condition.

Data

Animal Data

Administration of vilazodone to lactating rats at an oral dose of 30 times the maximum recommended human dose (MRHD), resulted in early postnatal pup mortality, and among surviving pups there was decreased body weight and delayed maturation.

8.4 Pediatric Use

The safety and effectiveness of vilazodone hydrochloride have not been established in pediatric patients for the treatment of MDD.

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 vilazadone (10 mg/kg/day, 50 mg/kg/day, 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. 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. 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.

Pediatric information describing a clinical study in which efficacy was not demonstrated is approved for Allergan’s Viibryd (vilazodone hydrochloride) tablets. However, due to Allergan’s marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use

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.

8.6 Use in Other Patient Populations

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)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Vilazodone hydrochloride is not a controlled substance.

9.2 Abuse and Dependence

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.

10 OVERDOSAGE

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 mg 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.

11 DESCRIPTION

Vilazodone hydrochloride tablets for oral administration contain polymorph Form IV vilazodone hydrochloride (HCl), a selective serotonin reuptake inhibitor and a 5HT1A receptor partial agonist.

Vilazodone HCl is 2-benzofurancarboxamide, 5-[4-[4-(5-cyano-1H -indol-3-yl)butyl]-1-piperazinyl]-, hydrochloride (1:1). It has a molecular formula C26 H27 N5 O2 . HCl and its molecular weight is 477.99. The structural formula is:

formula
(click image for full-size original)

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, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3350, polyvinyl alcohol – part hydrolyzed, talc and titanium dioxide. Additionally, the 10 mg tablets contain iron oxide red, the 20 mg tablets contain iron oxide red and iron oxide yellow, and the 40 mg tablets contain FD&C Blue #2/indigo carmine aluminum lake.

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