Chemical formula: C₂₆H₂₇N₅O₂ Molecular mass: 441.525 g/mol PubChem compound: 6918314
There are no adequate and well-controlled studies of vilazodone 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 2-4% and of miscarriage is 15-20% 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].
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.
Exposure to SSRIs and SNRIs, including vilazodone, 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 in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [see 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 post-marketing 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.
Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 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 1997-2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient-reported maternal use of SSRIs “in early pregnancy” and an antenatal SSRI prescription "in later pregnancy."
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 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.
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 and any potential adverse effects on the breastfed child from vilazodone or from the underlying maternal condition.
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.
Carcinogenicity studies were conducted in which B6C3F1mice and Wistar rats were given oral doses of vilazodone up to 135 and 150 mg/kg/day, respectively, for 2 years. These doses are approximately 16.5 and 36 times the maximum recommended human dose (MRHD) of 40 mg, respectively, on a mg/m2 basis.
In mice, the incidence of hepatocellular carcinomas was increased in males at 16.5 times the MRHD; this finding was not observed at 5.5 times the MRHD. The incidence of malignant mammary gland tumors was numerically increased in females at 5.5 and 16.5 times the MRHD, with statistical significance at 16.5 the MRHD; this finding was not observed at 1.8 times the MRHD. Elevated prolactin levels were observed in a 2-week study of vilazodone administered at 5.5 and 33 times the MRHD. Increases in prolactin levels are known to cause mammary tumors in rodents.
In the rat study, vilazodone was not carcinogenic in either sex at doses up to 36 times the MRHD.
Vilazodone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test). Vilazodone was negative in the in vitro V79/HGRPT mammalian cell forward mutation assay. Vilazodone was clastogenic in two in vitro mammalian cell chromosome aberration assays. However, vilazodone was negative for clastogenic activity in both an in vivo rat bone marrow chromosome aberration assay and a micronucleus test. Vilazodone was also negative in an in vivo/in vitro unscheduled DNA synthesis assay in rats.
Treatment of rats with vilazodone at a dose of 125 mg/kg, which is 30 times the MRHD of 40 mg on a mg/m2 basis, caused impairment of male fertility with no effect on female fertility. Impaired male fertility was not observed at 6 times the MRHD.
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-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.
The safety of vilazodone was evaluated in 3,007 patients (18-70 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 for a total of 348 patient-years.
The adverse reaction information presented below was derived from studies of vilazodone 20 mg and 40 mg daily in patients with MDD including:
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 was administered with food.
In these studies, 7.3% of the vilazodone-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-treated patients in the placebo-controlled studies was nausea (1.4%).
Table 1 shows the incidence of common adverse reactions occurring in ≥2% of vilazodone-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 1. Common Adverse Reactions Occurring in ≥2% of Vilazodone-treated Patients and Greater than the Rate of Placebo-Treated Patients:
| System Organ Class Preferred Term | Placebo N=967 | Vilazodone 20 mg/day N=288 | Vilazodone 40 mg/day N=978 |
|---|---|---|---|
| Gastrointestinal disorders | |||
| Diarrhea | 10% | 26% | 29% |
| Nausea | 7% | 22% | 24% |
| Dry mouth | 5% | 8% | 7% |
| Vomiting | 2% | 4% | 5% |
| Abdominal pain 1 | 3% | 7% | 4% |
| Dyspepsia | 2% | 2% | 3% |
| Flatulence | 1% | 3% | 3% |
| Gastroenteritis | 1% | 1% | 2% |
| Abdominal distension | 1% | 2% | 1% |
| Nervous system disorders | |||
| Headache 2 | 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% |
| Restlessness 3 | 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% |
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 2.
Table 2 displays the most common sexual adverse reactions in the placebo-controlled MDD studies.
Table 2. Common Sexual Adverse Reactions Occurring in ≥2% of Vilazodone-treated Patients and Greater than the Rate of Placebo-Treated Patients:
| Preferred Term | Males | Females | ||||
|---|---|---|---|---|---|---|
| Placebo N=416 | Vilazodone 20 mg/day N=122 | Vilazodone 40 mg/day N=417 | Placebo N=551 | Vilazodone 20 mg/day N=166 | Vilazodone 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% | − | − | − |
− Not applicable
* Includes abnormal orgasm and anorgasmia
The following list does not include reactions: 1) already listed 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 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 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:
in frequent: hyperhidrosis, night sweats
The following adverse reactions have been identified during post-approval use of vilazodone. 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 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
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