WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
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
Age Range |
|
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 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
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 TRINTELLIX is not approved for use in treating bipolar
depression.
Serotonin Syndrome
The development of a
potentially life-threatening serotonin syndrome has been reported with
serotonergic antidepressants including TRINTELLIX, 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 TRINTELLIX with MAOIs intended to
treat psychiatric disorders is contraindicated. TRINTELLIX 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 TRINTELLIX. TRINTELLIX should be discontinued before
initiating treatment with the MAOI [see CONTRAINDICATIONS and DOSAGE
AND ADMINISTRATION].
If concomitant use of TRINTELLIX 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 TRINTELLIX and any concomitant
serotonergic agents should be discontinued immediately if the above events
occur and supportive symptomatic treatment should be initiated.
Abnormal Bleeding
The use of drugs that interfere with serotonin reuptake
inhibition, including TRINTELLIX, 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 TRINTELLIX 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 TRINTELLIX 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 TRINTELLIX 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 TRINTELLIX, may
trigger an angle closure attack in a patient with anatomically narrow angles
who does not have a patent iridectomy.
Hyponatremia
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
TRINTELLIX 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 TRINTELLIX 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 TRINTELLIX 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.
Suicide Risk
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 TRINTELLIX 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 TRINTELLIX without talking to their healthcare provider [see ADVERSE
REACTIONS].
Concomitant Medication
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
TRINTELLIX with an MAOI or within 14 days of stopping an MAOI and to allow 21
days after stopping TRINTELLIX before starting an MAOI [see DOSAGE AND
ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS,
and DRUG INTERACTIONS].
Serotonin Syndrome
Caution patients about the risk of serotonin syndrome,
particularly with the concomitant use of TRINTELLIX and triptans, tricyclic
antidepressants, fentanyl, Lithium, tramadol, tryptophan supplements, and St.
John’s Wort supplements [see WARNINGS AND PRECAUTIONS and DRUG
INTERACTIONS].
Abnormal Bleeding
Caution patients about the increased risk of abnormal
bleeding when TRINTELLIX 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 TRINTELLIX 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
PRECAUTIONS].
Hyponatremia
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 TRINTELLIX [see WARNINGS AND
PRECAUTIONS].
Nausea
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.
Alcohol
A clinical study has shown that TRINTELLIX (single dose
of 20 or 40 mg/day) did not increase the impairment of mental and motor skills
caused by alcohol.
Allergic Reactions
Advise patients to notify their healthcare provider if
they develop an allergic reaction such as rash, hives, swelling, or difficulty
breathing.
Pregnancy
Advise a pregnant woman or a woman planning to become
pregnant that TRINTELLIX may cause withdrawal symptoms in the newborn or
persistent pulmonary hypertension of the newborn (PPHN) [see Use In Specific
Populations].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
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 two 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.
Mutagenicity
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
Risk Summary
There are limited human data on
TRINTELLIX use during pregnancy to inform any drug-associated risks. However,
there are clinical considerations regarding neonates exposed to SSRIs and
SNRIs, including TRINTELLIX, during the third trimester of pregnancy [see Clinical
Considerations]. Vortioxetine administered to pregnant rats and rabbits
during the period of organogenesis at doses ≥15 times and 10 times the
maximum recommended human dose (MRHD), respectively, resulted in decreased
fetal body weight and delayed ossification. No malformations were seen at doses
up to 77 times and 58 times the MRHD, respectively. Vortioxetine administered
to pregnant rats during gestation and lactation at oral doses ≥20 times
the MRHD resulted in a decrease in the number of live-born pups and an increase
in early postnatal pup mortality. Decreased pup weight at birth to weaning
occurred at 58 times the MRHD and delayed physical development occurred at
≥20 times the MRHD. These effects were not seen at 5 times the MRHD [see Data].
Advise a pregnant woman of the potential risk to a fetus.
The estimated background risk
of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss or other adverse
outcomes. In the U.S. general population, the estimated background risk of
major birth defects and miscarriage in clinically recognized pregnancies is
2-4% and 15-20%, respectively.
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 serotonergic
antidepressants, including TRINTELLIX, 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 TRINTELLIX 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 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 [see WARNINGS AND PRECAUTIONS].
Exposure during late pregnancy
to SSRIs 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.
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.”
Animal Data
In pregnant rats and rabbits, no malformations 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 the
maximum recommended human dose (MRHD) of 20 mg on a mg/m² basis, in rats and
rabbits, respectively. 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
of 40 and 120 mg/kg (20 and 58 times the MRHD, respectively) throughout
pregnancy and lactation, the number of live-born pups was decreased and early
postnatal pup mortality was increased. 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).
Lactation
Risk Summary
There is no information regarding the presence of
vortioxetine in human milk, the effects on the breastfed infant, or the effects
on milk production. Vortioxetine is present in rat milk [see Data]. The
developmental and health benefits of breastfeeding should be considered along
with the mother's clinical need for TRINTELLIX and any potential adverse
effects on the breastfed child from TRINTELLIX or from the underlying maternal
condition.
Data
Animal Data
Administration of [14C]-vortioxetine to
lactating rats at an oral dose of 20 times the maximum recommended human dose
(MRHD) of 20 mg on a mg/m² basis, resulted in drug-related material in milk
secretion. Milk to plasma ratio in lactating rats was 1, 1.2, 0.5, and 0.5 at
2, 6, 24, and 72 hours post dose.
Pediatric Use
Clinical studies on the use of TRINTELLIX in pediatric
patients have not been conducted; therefore, the safety and effectiveness of
TRINTELLIX in the pediatric population have not been established.
Geriatric Use
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 TRINTELLIX,
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 TRINTELLIX 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 severe hepatic impairment (Figure 3) [see CLINICAL
PHARMACOLOGY].
Figure 3: Impact of Intrinsic Factors on Vortioxetine PK