Included as part of the PRECAUTIONS section.
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 to 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 trend toward 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 nine
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 two 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.
Table 1: Drug-Placebo Difference in Number of Cases of
Suicidality per 1000 Patients Treated
|Increases Compared to Placebo
| < 18
||14 additional cases
||5 additional cases
|Decreases Compared to Placebo
||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 MDD 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.
Families and caregivers of
patients being treated with antidepressants for MDD 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.
Screening Patients for Bipolar
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 BRINTELLIX is not approved for use in
treating bipolar depression.
The development of a potentially life-threatening
serotonin syndrome has been reported with serotonergic antidepressants
including BRINTELLIX, when used alone but more often when used concomitantly
with 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 BRINTELLIX with MAOIs intended to
treat psychiatric disorders is contraindicated. BRINTELLIX 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 a MAOI such as linezolid or intravenous methylene
blue in a patient taking BRINTELLIX. BRINTELLIX should be discontinued before
initiating treatment with the MAOI [see CONTRAINDICATIONS and DOSAGE
If concomitant use of BRINTELLIX 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 BRINTELLIX and any concomitant
serotonergic agents should be discontinued immediately if the above events
occur and supportive symptomatic treatment should be initiated.
The use of drugs that interfere with serotonin reuptake
inhibition, including BRINTELLIX, 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 drugs that
inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis,
and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the increased risk of
bleeding when BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs
that affect coagulation or bleeding [see DRUG INTERACTIONS].
Activation Of Mania/Hypomania
Symptoms of mania/hypomania were reported in < 0.1% of
patients treated with BRINTELLIX in pre-marketing clinical studies. Activation
of mania/hypomania has been reported in a small proportion of patients with
major affective disorder who were treated with other antidepressants. As with
all antidepressants, use BRINTELLIX cautiously in patients with a history or
family history of bipolar disorder, mania, or hypomania.
Angle Closure Glaucoma
Angle Closure Glaucoma: The pupillary dilation that
occurs following use of many antidepressant drugs, including BRINTELLIX, may trigger
an angle closure attack in a patient with anatomically narrow angles who does
not have a patent iridectomy.
Hyponatremia has occurred as a result of treatment with
serotonergic drugs. In many cases, hyponatremia appears to be the result of the
syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with
serum sodium lower than 110 mmol/L was reported in a subject treated with
BRINTELLIX in a pre-marketing clinical study. Elderly patients may be at
greater risk of developing hyponatremia with a serotonergic antidepressant.
Also, patients taking diuretics or who are otherwise volume depleted can be at
greater risk. Discontinuation of BRINTELLIX 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.
More severe and/or acute cases have included hallucination, syncope, seizure,
coma, respiratory arrest, and death.
Patient Counseling Information
See FDA-approved patient
labeling (Medication Guide) Advise patients and their caregivers about the
benefits and risks associated with treatment with BRINTELLIX 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 suicidal ideation and behavior, especially early
during treatment and when the dose is adjusted up or down [see BOXED WARNING
and WARNINGS AND PRECAUTIONS].
Discontinuation of Treatment
Patients who are on BRINTELLIX
15 mg/day or 20 mg/day may experience headache, muscle tension, mood swings,
sudden outburst of anger, dizziness and runny nose if they abruptly stop their
medicine. Advise patients not stopping BRINTELLIX without talking to their
healthcare provider [see ADVERSE REACTIONS].
Advise patients to inform their
physicians if they are taking, or plan to take, any prescription or
over-the-counter medications because of a potential for interactions. Instruct
patients not to take BRINTELLIX with an MAOI or within 14 days of stopping an
MAOI and to allow 21 days after stopping BRINTELLIX before starting an MAOI
[see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS
AND PRECAUTIONS, and DRUG INTERACTIONS].
Caution patients about the risk
of serotonin syndrome, particularly with the concomitant use of BRINTELLIX and
triptans, tricyclic antidepressants, fentanyl, Lithium, tramadol, tryptophan
supplements, and St. John's Wort supplements [see WARNINGS AND
PRECAUTIONS and DRUG INTERACTIONS].
Caution patients about the increased risk of abnormal
bleeding when BRINTELLIX is given with NSAIDs, aspirin, warfarin, or other
drugs that affect coagulation [see WARNINGS AND PRECAUTIONS].
Activation of Mania/Hypomania
Advise patients and their caregivers to look for signs of
activation of mania/hypomania [see WARNINGS AND PRECAUTIONS].
Angle Closure Glaucoma
Patients should be advised that taking BRINTELLIX can
cause mild pupillary dilation, which in susceptible individuals, can lead to an
episode of angle closure glaucoma. Pre-existing glaucoma is almost always
open-angle glaucoma because angle closure glaucoma, when diagnosed, can be
treated definitively with iridectomy. Open-angle glaucoma is not a risk factor
for angle closure glaucoma. Patients may wish to be examined to determine
whether they are susceptible to angle closure, and have a prophylactic
procedure (e.g., iridectomy), if they are susceptible [see WARNINGS AND
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 BRINTELLIX [see WARNINGS AND
Advise patients that nausea is the most common adverse reaction,
and is dose related. Nausea commonly occurs within the first week of treatment,
then decreases in frequency but can persist in some patients.
A clinical study has shown that BRINTELLIX (single dose
of 20 or 40 mg/day) did not increase the impairment of mental and motor skills
caused by alcohol.
Advise patients to notify their healthcare provider if
they develop an allergic reaction such as rash, hives, swelling, or difficulty
Advise patients to notify their healthcare provider if
they become pregnant or intend to become pregnant during therapy with
BRINTELLIX [see Use In Specific Populations].
Advise patients to notify their healthcare provider if
they are breast-feeding an infant and would like to continue or start
BRINTELLIX [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies were conducted in which CD-1 mice
and Wistar rats were given oral doses of vortioxetine up to 50 and 100
mg/kg/day for male and female mice, respectively, and 40 and 80 mg/kg/day for
male and female rats, respectively, for 2 years. The doses in the two species
were approximately 12, 24, 20, and 39 times, respectively, the maximum
recommended human dose (MRHD) of 20 mg on a mg/m² basis.
In rats, the incidence of benign polypoid adenomas of the
rectum was statistically significantly increased in females at doses 39 times
the MRHD, but not at 15 times the MRHD. These were considered related to
inflammation and hyperplasia and possibly caused by an interaction with a
vehicle component of the formulation used for the study. The finding did not
occur in male rats at 20 times the MRHD.
In mice, vortioxetine was not carcinogenic in males or
females at doses up to 12 and 24 times, respectively, the MRHD.
Vortioxetine was not genotoxic in the in vitro bacterial
reverse mutation assay (Ames test), an in vitro chromosome aberration assay in cultured
human lymphocytes, and an in vivo rat bone marrow micronucleus assay.
Impairment of Fertility
Treatment of rats with vortioxetine at doses up to 120
mg/kg/day had no effect on male or female fertility, which is 58 times the
maximum recommended human dose (MRHD) of 20 mg on a mg/m² basis.
Use In Specific Populations
Pregnancy Category C
There are no adequate and
well-controlled studies of BRINTELLIX in pregnant women. Vortioxetine caused
developmental delays when administered during pregnancy to rats and rabbits at
doses 15 and 10 times the maximum recommended human dose (MRHD) of 20 mg,
respectively. Developmental delays were also seen after birth in rats at doses
20 times the MRHD of vortioxetine given during pregnancy and through lactation.
There were no teratogenic effects in rats or rabbits at doses up to 77 and 58
times, the MRHD of vortioxetine, respectively, given during organogenesis. The
incidence of malformations in human pregnancies has not been established for
BRINTELLIX. All human pregnancies, regardless of drug exposure, have a
background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy
loss. BRINTELLIX should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Neonates exposed to SSRIs or 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 these classes of drugs 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].
When treating a pregnant woman with BRINTELLIX during the third trimester, the
physician should carefully consider the potential risks and benefits of
Neonates exposed to SSRIs in pregnancy may have an
increased risk for persistent pulmonary hypertension of the newborn (PPHN).
PPHN occurs in one to two 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 in pregnancy and PPHN. Other studies do not show a significant statistical
A prospective longitudinal study was conducted 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 BRINTELLIX, the physician should carefully consider both the potential
risks of taking a serotonergic antidepressant, along with the established
benefits of treating depression with an antidepressant.
In pregnant rats and rabbits, no teratogenic effects were
seen when vortioxetine was given during the period of organogenesis at oral doses
up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times, in
rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 20
mg on a mg/m² basis. Developmental delay, seen as decreased fetal
body weight and delayed ossification, occurred in rats and rabbits at doses
equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD,
respectively) in the presence of maternal toxicity (decreased food consumption
and decreased body weight gain). When vortioxetine was administered to pregnant
rats at oral doses up to 120 mg/kg (58 times the MRHD) throughout pregnancy and
lactation, the number of live-born pups was decreased and early postnatal pup
mortality was increased at 40 and 120 mg/kg. Additionally, pup weights were decreased
at birth to weaning at 120 mg/kg and development (specifically eye opening) was
slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg
(5 times the MRHD).
It is not known whether vortioxetine is present in human
milk. Vortioxetine is present in the milk of lactating rats. Because many drugs
are present in human milk and because of the potential for serious adverse
reactions in nursing infants from BRINTELLIX, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Clinical studies on the use of BRINTELLIX in pediatric
patients have not been conducted; therefore, the safety and effectiveness of
BRINTELLIX in the pediatric population have not been established.
No dose adjustment is recommended on the basis of age
(Figure 3). Results from a single-dose pharmacokinetic study in elderly ( > 65
years old) vs. young (24 to 45 years old) subjects demonstrated that the
pharmacokinetics were generally similar between the two age groups.
Of the 2616 subjects in clinical studies of BRINTELLIX,
11% (286) were 65 and over, which included subjects from a placebo-controlled
study specifically in elderly patients [see Clinical Studies]. No
overall differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients.
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].
Use In Other Patient Populations
No dose adjustment of BRINTELLIX on the basis of race,
gender, ethnicity, or renal function (from mild renal impairment to end-stage
renal disease) is necessary. In addition, the same dose can be administered in
patients with mild to moderate hepatic impairment (Figure 3). BRINTELLIX has
not been studied in patients with severe hepatic impairment. Therefore,
BRINTELLIX is not recommended in patients with severe hepatic impairment.
Figure 3: Impact of Intrinsic Factors on Vortioxetine