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Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
|Age Range||Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated|
|Increases Compared to Placebo|
|< 18||14 additional cases|
|18-24||5 additional cases|
|Decreases Compared to Placebo|
|25-64||1 fewer case|
|≥ 65||6 fewer cases|
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see DOSAGE AND ADMINISTRATION].
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for VIIBRYD should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose [see also PATIENT INFORMATION].
Screening patients for bipolar disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that VIIBRYD is not approved for use in treating bipolar depression.
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including VIIBRYD, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, 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 and intravenous methylene blue).
Serotonin syndrome 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/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of VIIBRYD with MAOIs intended to treat psychiatric disorders is contraindicated. VIIBRYD should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking VIIBRYD. VIIBRYD should be discontinued before initiating treatment with the MAOI [see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION].
If concomitant use of VIIBRYD with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases
Treatment with VIIBRYD and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
VIIBRYD has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Like other antidepressants, VIIBRYD should be prescribed with caution in patients with a seizure disorder.
The use of drugs that interfere with serotonin reuptake inhibition, including VIIBRYD, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), 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. Bleeding events related to SSRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of VIIBRYD and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
Activation of Mania/Hypomania
Symptoms of mania/hypomania were reported in 0.1% of patients treated with VIIBRYD in clinical studies. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use VIIBRYD cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.
Discontinuation of Treatment with VIIBRYD
There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Monitor patients for these symptoms when discontinuing VIIBRYD. Reduce the dose gradually whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, consider resuming the previously prescribed dose. Subsequently, the dose may be decreased, but at a more gradual rate [see DOSAGE AND ADMINISTRATION].
Although no cases of hyponatremia resulting from VIIBRYD treatment were reported in the clinical studies, hyponatremia has occurred as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of VIIBRYD in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Patient Counseling Information
See Medication Guide.
Information for Patients
Advise patients and their caregivers about the benefits and risks associated with treatment with VIIBRYD and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down [see BOX WARNING and WARNINGS AND PRECAUTIONS].
Dosing and Administration
Instruct patients to take VIIBRYD with food. When initiating treatment with VIIBRYD the dose should be titrated, starting with a dose of 10 mg once daily for 7 days, followed by 20 mg once daily for an additional 7 days, and then increased to 40 mg once daily.
Instruct patients not to take VIIBRYD with an MAOI or within 14 days of stopping an MAOI and to allow 14 days after stopping VIIBRYD before starting an MAOI [see CONTRAINDICATIONS].
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of VIIBRYD with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, 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) [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Caution patients about using VIIBRYD if they have a history of a seizure disorder [see WARNINGS AND PRECAUTIONS]. Patients with a history of seizures were excluded from clinical studies.
Caution patients about the concomitant use of VIIBRYD and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of abnormal bleeding [see WARNINGS AND PRECAUTIONS].
Activation of Mania/Hypomania
Advise patients and their caregivers to observe for signs of activation of mania/hypomania [see WARNINGS AND PRECAUTIONS].
Discontinuation of Treatment
Advise patients not to stop taking VIIBRYD without talking first with their healthcare provider. Patients should be aware that discontinuation effects may occur when suddenly stopping VIIBRYD [see WARNINGS AND PRECAUTIONS].
Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking VIIBRYD [see WARNINGS AND PRECAUTIONS].
Advise patients to avoid alcohol while taking VIIBRYD [see DRUG INTERACTIONS].
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with VIIBRYD [see Use In Specific Populations].
Advise patients to notify their healthcare provider if they are breastfeeding an infant and would like to continue or start VIIBRYD [see Use In Specific Populations].
Interference with Cognitive and Motor Performance
Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that VIIBRYD therapy does not adversely affect their ability to engage in such activities.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 MHRD; 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.
Impairment of Fertility
Treatment of rats with vilazodone at a dose of 125 mg/kg, which is 30 times the maximum recommended human dose (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.
Use In Specific Populations
Teratogenic Effects - Pregnancy Category C
Vilazodone caused some developmental toxicity in rats, but was not teratogenic in rats or rabbits. There are no adequate and well-controlled studies of VIIBRYD in pregnant women. When treating pregnant women with VIIBRYD, carefully consider whether the potential benefits outweigh the potential risks of treatment.
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.
Neonates exposed to VIIBRYD and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. 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. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see WARNINGS AND PRECAUTIONS].
Infants exposed to SSRIs in pregnancy 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. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including VIIBRYD) in pregnancy and PPHN. Other studies do not show a significant statistical association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with VIIBRYD, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis [see DOSAGE AND ADMINISTRATION].
Labor and Delivery
The effect of VIIBRYD on labor and delivery in humans is unknown. VIIBRYD should be used during labor and delivery only if the potential benefit outweighs the potential risk.
Vilazodone is excreted into the milk of lactating rats. The effect of VIIBRYD on lactation and nursing in humans is unknown. Breast feeding in women treated with VIIBRYD should be considered only if the potential benefit outweighs the potential risk to the child.
Clinical studies on the use of VIIBRYD in pediatric patients have not been conducted; therefore, the safety and effectiveness of VIIBRYD in the pediatric population have not been established. VIIBRYD is not approved for use in pediatric patients [see BOX WARNING and WARNINGS AND PRECAUTIONS].
No dose adjustment is recommended on the basis of age (see Figure 2). Results from a single-dose (20 mg) pharmacokinetic study in elderly ( > 65 years-old) vs. young (24-55 years-old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups.
Of the 2177 patients in clinical studies with VIIBRYD, 37 (1.7%) were 65 years of age or older, and 272 (12.5%) were 55 to 64 years of age.
Greater sensitivity of some older individuals cannot be ruled out [see DOSAGE AND ADMINISTRATION].
Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see WARNINGS AND PRECAUTIONS].
Vilazodone is eliminated primarily by hepatic metabolism. In mild and moderate hepatic impairment, no dose adjustment is necessary (see Figure 2). VIIBRYD has not been studied in patients with severe hepatic impairment [see DOSAGE AND ADMINISTRATION].
In mild, moderate, and severe renal impairment, no dose adjustment is necessary (see Figure 2 below) [see DOSAGE AND ADMINISTRATION].
After adjustment for body weight, the systemic exposures between males and females are similar (see Figure 2) [see DOSAGE AND ADMINISTRATION].
Figure 2: Impact of Intrinsic Factors on Vilazodone PK
Last reviewed on RxList: 1/10/2013
This monograph has been modified to include the generic and brand name in many instances.
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