Trintellix

Before taking vortioxetine,

• tell your doctor and pharmacist if you are allergic to vortioxetine, any other medications, or any of the ingredients in vortioxetine tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• tell your doctor if you are taking monoamine oxidase (MAO) inhibitors, including isocarboxazid (Marplan), linezolid (Zyvox), methylene blue, phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate) or if you have stopped taking them within the past 2 weeks. Your doctor may tell you not to take vortioxetine. If you stop taking vortioxetine, you should wait at least 21 days before you start to take an MAO inhibitor.
• tell your doctor and pharmacist what other prescription and nonprescription medications, and vitamins, nutritional supplements you are taking or plan to take. Be sure to mention any of the following: anticoagulants ('blood thinners') such as warfarin (Coumadin, Jantoven); antidepressants ('mood elevators') such as amitriptyline, amoxapine, clomipramine (Anafranil), desipramine (Norpramin), doxepin (Silenor), imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil); bupropion (Aplenzin, Forfivo, Wellbutrin, Zyban); aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn); buspirone; carbamazepine (Carbatrol, Equetro, Tegretol); diuretics ('water pills'); fentanyl (Actiq, Duragesic, Fentora, Lazanda, others); lithium (Lithobid); medications for mental illness; medications for migraine headaches such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig); phenytoin (Dilantin, Phenytek); quinidine (in Nuedexta); rifampin (Rifadin, Rimactane); other selective serotonin-reuptake inhibitors such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), fluvoxamine (Luvox), paroxetine (Brisdelle, Prozac, Pexeva), and sertraline (Zoloft); serotonin and norepinephrine reuptake inhibitors such as duloxetine (Cymbalta), desvenlafaxine (Khedezla, Pristiq), and venlafaxine (Effexor); and tramadol (Conzip, Ulltram). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor what herbal products and nutritional supplements you are taking, especially St. John's wort and tryptophan.
• tell your doctor if you have a low level of sodium in your blood, if you drink or have ever drunk large amounts of alcohol, and if you have or have ever had seizures, bleeding problems, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking vortioxetine, call your doctor. Vortioxetine may cause problems in newborns following delivery if it is taken during the last few months of pregnancy.
• if you are having surgery, including dental surgery, or a medical test that involves dyes, tell the doctor or dentist that you are taking vortioxetine.
• you should know that vortioxetine may affect your judgment, thinking, and movements. Do not drive a car or operate machinery until you know how this medication affects you.
• ask your doctor about the safe use of alcoholic beverages while you are taking vortioxetine.
• you should know that vortioxetine may cause angle-closure glaucoma (a condition where the fluid is suddenly blocked and unable to flow out of the eye causing a quick, severe increase in eye pressure which may lead to a loss of vision). Talk to your doctor about having an eye examination before you start taking this medication. If you have nausea, eye pain, changes in vision, such as seeing colored rings around lights, and swelling or redness in or around the eye, call your doctor or get emergency medical treatment right away.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Dosage Forms & Strengths

tablet, immediate-release

• 5mg
• 10mg
• 20mg
• NOTE: Former brand name Brintellix

Major Depressive Disorder

10 mg PO qDay initially; gradually increase to 20 mg/day as tolerated (higher doses demonstrated better treatment effects in clinical trials)

Not to exceed 20 mg/day

Dosage Modifications

Consider decreasing dose to 5 mg/day if higher doses not tolerated

CYP2D6 poor metabolizers: Not to exceed 10 mg/day

Coadministration with CYP2D6 inhibitors: Decrease vortioxetine dose by 50%; increase dose to original level when CYP2D6 inhibitor discontinued

Coadministration with strong CYP inducers: Consider increasing the vortioxetine dose when strong CYP inducers is coadministered for >14 days; not to exceed 3 times original dose; decrease dose to original level within 14 days when the inducer is discontinued

Dosing Considerations

Former brand name Brintellix changed to Trintellix in June 2016 because of confusion with antiplatelet Brilinta (ticagrelor)

Acute episodes of major depression should be followed by several months or longer of sustained pharmacologic therapy; a maintenance study of vortioxetine demonstrated a decreased risk of recurrence of depressive episodes

Safety and efficacy not established

>10%

Nausea (21-32%)

1-10%

Diarrhea (7-10%)

Dizziness (6-9%)

Dry mouth (6-8%)

Constipation (3-6%)

Vomiting (3-6%)

Flatulence (1-3%)

Pruritus (1-3%)

Abnormal dreams (<1-3%)

Postmarketing Reports

Weight gain

Acute pancreatitis

Angle closure glaucoma

Seizure

Rash, generalized rash

• Takeda Pharmaceuticals America, Inc.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Trintellix, there are no specific foods that you must exclude from your diet when receiving this medication.

Do not use this medicine if you have used an MAO inhibitor in the past 14 days, such as isocarboxazid, methylene blue injection, phenelzine, rasagiline, selegiline, or tranylcypromine. After you stop taking vortioxetine you must wait at least 21 days before you start taking an MAO inhibitor.

Some young people have thoughts about suicide when first taking an antidepressant. Stay alert to changes in your mood or symptoms. Report any new or worsening symptoms to your doctor.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

You may take this medicine with or without food. Take this medicine at the same time each day.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For depression:
    • Adults—At first, 10 milligrams (mg) once per day. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 20 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• Tell all of your health care providers that you take Trintellix. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• Do not stop taking Trintellix all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop this medicine, you will want to slowly stop it as ordered by your doctor.
• Avoid drinking alcohol while taking Trintellix.
• Talk with your doctor before you use other drugs and natural products that slow your actions.
• In depression, sleep and appetite may get better soon after starting this medicine. Other low mood signs may take up to 4 weeks to get better.
• This medicine may raise the chance of bleeding. Sometimes, bleeding can be life-threatening. Talk with the doctor.
• Some people may have a higher chance of eye problems with Trintellix. Your doctor may want you to have an eye exam to see if you have a higher chance of these eye problems. Call your doctor right away if you have eye pain, change in eyesight, or swelling or redness in or around the eye.
• Low blood sodium levels may happen with this medicine. In very bad cases, this can be deadly. Talk with the doctor.
• If you are on a low-salt or salt-free diet, talk with your doctor.
• Some drugs may look the same as Trintellix (vortioxetine) or may have names that sound like this medicine. Always check to make sure you have the right product. If you see any change in the way Trintellix looks like shape, color, size, or wording, check with your pharmacist.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Trintellix while you are pregnant.
• Taking this medicine late in pregnancy may raise the chance of breathing or feeding problems, low body temperature, or withdrawal symptoms in the newborn. Talk with the doctor.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Trintellix is available as immediate-release, film-coated tablets in the following strengths:

• 5 mg: pink, almond shaped biconvex film coated tablet, debossed with "5" on one side and "TL" on the other side
• 10 mg: yellow, almond shaped biconvex film coated tablet, debossed with "10" on one side and "TL" on the other side
• 20 mg: red, almond shaped biconvex film coated tablet, debossed with "20" on one side and "TL" on the other side

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)]
• Angle Closure Glaucoma [see Warnings and Precautions (5.5)]
• Hyponatremia [see Warnings and Precautions (5.6)]

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, 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 the rates observed in clinical practice.

Patient Exposure

Trintellix 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 Trintellix 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 Trintellix in a 24 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 Trintellix in open-label studies, 1727 were exposed to Trintellix 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 Trintellix 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 Trintellix 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 Trintellix dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebo-controlled studies.

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 two weeks. Nausea was more common in females than males. Nausea most commonly occurred in the first week of Trintellix treatment with 15 to 20% of patients experiencing nausea after one to two days of treatment. Approximately 10% of patients taking Trintellix 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 Trintellix, 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 Trintellix 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 Trintellix 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 Trintellix or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects.

Adverse Reactions Following Abrupt Discontinuation of Trintellix Treatment

Discontinuation symptoms have been prospectively evaluated in patients taking Trintellix 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 Trintellix 15 mg/day and 20 mg/day.

Laboratory Tests

Trintellix 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 Trintellix [see Warnings and Precautions (5.6)]. In the six month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Trintellix during the initial 12 week, open-label phase, there were no clinically important changes in lab test parameters between Trintellix and placebo-treated patients.

Weight

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

Vital Signs

Trintellix 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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Trintellix. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Metabolic disorders weight gain

Nervous system disorders seizure

Skin and subcutaneous tissue disorders rash, generalized rash

Gastrointestinal System acute pancreatitis

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 (5.2)].

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 (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)].

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 (12.3)].

Figure 3. Impact of Intrinsic Factors on Vortioxetine PK