6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label.

•Hypersensitivity [see Contraindications (4)] •Clinical Worsening and Suicide Risk [see Warnings and Precautions (5.1)] •Serotonin Syndrome [see Warnings and Precautions (5.2)] •Abnormal Bleeding [see Warnings and Precautions (5.3)] •Activation of Mania/Hypomania [see Warnings and Precautions (5.4)] •Hyponatremia [see Warnings and Precautions (5.6)] Most common adverse reactions (incidence?5 % and at least twice the rate of placebo) were: nausea, constipation and vomiting (6).

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Patient Exposure BRINTELLIX was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre-marketing clinical studies; 2616 of those patients were exposed to BRINTELLIX in 6 to 8 week, placebo-controlled studies at doses ranging from 5 mg to 20 mg once daily and 204 patients were exposed to BRINTELLIX in a 24 week to 64 week placebo-controlled maintenance study at doses of 5 mg to 10 mg once daily.

Patients from the 6 to 8 week studies continued into 12?month open-label studies.

A total of 2586 patients were exposed to at least one dose of BRINTELLIX in open-label studies, 1727 were exposed to BRINTELLIX for six months and 885 were exposed for at least one year.

Adverse Reactions Reported as Reasons for Discontinuation of Treatment In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5 %, 6 %, 8 % and 8 %, respectively, compared to 4 % of placebo-treated patients.

Nausea was the most common adverse reaction reported as a reason for discontinuation.

Common Adverse Reactions in Placebo-Controlled MDD Studies The most commonly observed adverse reactions in MDD patients treated with BRINTELLIX in 6 to 8 week placebo-controlled studies (incidence?5 % and at least twice the rate of placebo) were nausea, constipation and vomiting.

Table 2 shows the incidence of common adverse reactions that occurred in?2 % of MDD patients treated with any BRINTELLIX dose and at least 2 % more frequently than in placebo-treated patients in the 6 to 8 week placebo-controlled studies.

Table 2.

Common Adverse Reactions Occurring in?

2 % of Patients Treated with any BRINTELLIX Dose and at Least 2 % Greater than the Incidence in Placebo-treated Patients System Organ Class Preferred Term BRINTELLIX 5 mg/day BRINTELLIX 10 mg/day BRINTELLIX 15 mg/day BRINTELLIX 20 mg/day Placebo N=1013 % N=699 % N=449 % N=455 % N=1621 % Gastrointestinal disorders Nausea 21 26 32 32 9 Diarrhea 7 7 10 7 6 Dry mouth 7 7 6 8 6 Constipation 3 5 6 6 3 Vomiting 3 5 6 6 1 Flatulence 1 3 2 1 1 Nervous system disorders Dizziness 6 6 8 9 6 Psychiatric disorders Abnormal dreams <1 <1 2 3 1 Skin and subcutaneous tissue disorders PruritusIncludes pruritus generalized 1 2 3 3 1 Nausea Nausea was the most common adverse reaction and its frequency was dose-related (Table 2).

It was usually considered mild or moderate in intensity and the median duration was 2 weeks.

Nausea was more common in females than males.

Nausea most commonly occurred in the first week of BRINTELLIX treatment with 15 to 20 % of patients experiencing nausea after 1 to 2 days of treatment.

Approximately 10 % of patients taking BRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies.

Sexual Dysfunction Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment.

In the MDD 6 to 8 week controlled trials of BRINTELLIX, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms.

These event terms have been aggregated and the overall incidence was as follows.

In male patients the overall incidence was 3 %, 4 %, 4 %, 5 % in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2 % in placebo.

In female patients, the overall incidence was <1 %, 1 %, <1 %, 2 % in BRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1 % in placebo.

Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials.

The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction.

The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores.

For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed dose group.

Physicians should routinely inquire about possible sexual side effects.

Table 3.

ASEX Incidence of Treatment Emergent Sexual Dysfunction Incidence based on number of subjects with sexual dysfunction during the study/number of subjects without sexual dysfunction at baseline.

Sexual dysfunction was defined as a subject scoring any of the following on the ASEX scale at two consecutive visits during the study: 1) total score?19; 2) any single item?5; 3) three or more items each with a score?4 BRINTELLIX 5 mg/day N=65:67Sample size for each dose group is the number of patients (females:males) without sexual dysfunction at baseline BRINTELLIX 10 mg/day N=94:86 BRINTELLIX 15 mg/day N=57:67 BRINTELLIX 20 mg/day N=67:59 Placebo N=135:162 Females 22 % 23 % 33 % 34 % 20 % Males 16 % 20 % 19 % 29 % 14 % Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX Treatment Discontinuation symptoms have been prospectively evaluated in patients taking BRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in

clinical trials.

Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of

BRINTELLIX 15 mg/day and 20 mg/day.

Laboratory Tests BRINTELLIX has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (except sodium), hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies.

Hyponatremia has been reported with the treatment of BRINTELLIX [see Warnings and Precautions (5.6)].

In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there were no clinically important changes in lab test parameters between BRINTELLIX and placebo-treated patients.

Weight BRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies.

In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between BRINTELLIX and placebo-treated patients.

Vital Signs BRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.

Other Adverse Reactions Observed in Clinical Studies The following listing 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.

Ear and labyrinth disorders - vertigo Gastrointestinal disorders - dyspepsia Nervous system disorders - dysgeusia Vascular disorders - flushing

8 USE IN SPECIFIC POPULATIONS •Pregnancy: Based on animal data, BRINTELLIX may cause fetal harm (8.1).

•Nursing Mothers: Discontinue BRINTELLIX or nursing (8.3).

8.1 Pregnancy Pregnancy Category C Risk Summary 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.

Clinical Considerations 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 (5.2)].

When treating a pregnant woman with BRINTELLIX during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

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 association.

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.

Animal Data 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).

8.3 Nursing Mothers 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.

8.4 Pediatric Use 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.

8.5 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 BRINTELLIX, 11 % (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients [see Clinical Studies (14)].

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 (5.6)].

8.6 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 PK Figure3.jpg

8.3 Nursing Mothers 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.