Trintellix Side Effects Center

SIDE EFFECTS

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

• Hypersensitivity [see CONTRAINDICATIONS]
• Clinical Worsening and Suicide Risk [see WARNINGS AND PRECAUTIONS]
• Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
• Abnormal Bleeding [see WARNINGS AND PRECAUTIONS]
• Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS]
• Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS]
• Angle Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
• Hyponatremia [see WARNINGS AND PRECAUTIONS]

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 5852 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre- and postmarketing 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; 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; and 429 patients were exposed to TRINTELLIX in a 32 week placebo-controlled maintenance study in the U.S. at doses of 5 mg, 10 mg, and 20 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 6 months and 885 were exposed for at least 1 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.

Table 2: Common Adverse Reactions Occurring in ≥2% of Patients Treated with Any TRINTELLIX Dose and at Least 2% Greater Than the Incidence in Placebo-Treated Patients

System Organ Class Preferred Term	TRINTELLIX 5 mg/day N=1013 %	TRINTELLIX 10 mg/day N=699 %	TRINTELLIX 15 mg/day N=449 %	TRINTELLIX 20 mg/day N=455 %	Placebo 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
Pruritus*	1	2	3	3	1
* includes pruritus generalized

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 or comorbid conditions, but they may also be consequences of pharmacologic treatment, including TRINTELLIX. In addition to the data from the MDD studies mentioned below, TRINTELLIX has been prospectively assessed for its effects in MDD patients with existing TESD induced by prior SSRI treatment and in healthy adults with normal sexual function at baseline [see Clinical Studies].

Voluntarily Reported Adverse Reactions Of Sexual Dysfunction

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.

Adverse Reactions Of Sexual Dysfunction In Patients With Normal Sexual Functioning At Baseline

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 self-reported 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 TESD when treated with TRINTELLIX 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*

	TRINTELLIX 5 mg/day N=65:67†	TRINTELLIX 10 mg/day N=94:86†	TRINTELLIX 15 mg/day N=57:67†	TRINTELLIX 20 mg/day N=67:59†	Placebo N=135:162†
Females	22%	23%	33%	34%	20%
Males	16%	20%	19%	29%	14%
* 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 † Sample size for each dose group is the number of patients (females:males) without sexual dysfunction at baseline

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]. In the 6-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, doubleblind, 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 postapproval 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.

Endocrine disorders - hyperprolactinemia

Gastrointestinal System - acute pancreatitis

Immune system disorders - hypersensitivity reactions (including anaphylaxis and urticaria)

Metabolic disorders - weight gain

Nervous system disorders - seizure, headache

Psychiatric disorders - aggression, agitation, anger, hostility, irritability

Skin and subcutaneous tissue disorders - rash, generalized rash, hyperhidrosis

DRUG INTERACTIONS

Drugs Having Clinically Important Interactions With TRINTELLIX

Table 4: Clinically Important Drug Interactions with TRINTELLIX

Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact	The concomitant use of SSRIs and SNRIs including TRINTELLIX with MAOIs increases the risk of serotonin syndrome.
Intervention	Concomitant use of TRINTELLIX is contraindicated: With an MAOI intended to treat psychiatric disorders or within 21 days of stopping treatment with TRINTELLIX. Within 14 days of stopping an MAOI intended to treat psychiatric disorders. In a patient who is being treated with linezolid or intravenous methylene blue. [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Examples	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Other Serotonergic Drugs
Clinical Impact	Concomitant use of TRINTELLIX with other serotonergic drugs increases the risk of serotonin syndrome.
Intervention	Monitor for symptoms of serotonin syndrome when TRINTELLIX is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of TRINTELLIX and/or concomitant serotonergic drugs [see WARNINGS AND PRECAUTIONS].
Examples	Other SNRIs, SSRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, and St. John's Wort
Strong Inhibitors of CYP2D6
Clinical Impact	Concomitant use of TRINTELLIX with strong CYP2D6 inhibitors increases plasma concentrations of vortioxetine.
Intervention	Reduce TRINTELLIX dose by half when a strong CYP2D6 inhibitor is coadministered [see DOSAGE AND ADMINISTRATION].
Examples	bupropion, fluoxetine, paroxetine, quinidine
Strong CYP Inducers
Clinical Impact	Concomitant use of TRINTELLIX with a strong CYP inducer decreases plasma concentrations of vortioxetine.
Intervention	Consider increasing the TRINTELLIX dose when a strong CYP inducer is coadministered. The maximum dose is not recommended to exceed three times the original dose [see DOSAGE AND ADMINISTRATION].
Examples	rifampin, carbamazepine, phenytoin
Drugs that Interfere with Hemostasis (antiplatelets agents and anticoagulants)
Clinical Impact	Concomitant use of TRINTELLIX with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding.
Intervention	Inform patients of the increased risk of bleeding associated with the concomitant use of TRINTELLIX and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see WARNINGS AND PRECAUTIONS), DRUG INTERACTIONS].
Examples	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact	TRINTELLIX is highly bound to plasma protein. The concomitant use of TRINTELLIX with another drug that is highly bound to plasma protein may increase free concentrations of TRINTELLIX or other tightly-bound drugs in plasma.
Intervention	Monitor for adverse reactions and reduce dosage of TRINTELLIX or other protein bound drugs as warranted [see DRUG INTERACTIONS].
Examples	Warfarin

Effect Of TRINTELLIX On Other Drugs

Other CNS Active Agents

No clinically relevant effect was observed on steady-state lithium exposure following coadministration with multiple daily doses of TRINTELLIX. Multiple doses of TRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam [see CLINICAL PHARMACOLOGY].

A clinical study has shown that TRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg) [see CLINICAL PHARMACOLOGY].

Drugs That Interfere With Hemostasis

Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of TRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin. Coadministration of aspirin 150 mg/day with multiple daily doses of TRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid [see CLINICAL PHARMACOLOGY]. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when TRINTELLIX is initiated or discontinued [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].

Highly Protein Bound Drugs

In a clinical study with coadministration of TRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein bound drug, no significant change in INR was observed [see DRUG INTERACTIONS, CLINICAL PHARMACOLOGY].

Interference With Urine Enzyme Immunoassays For Methadone

False positive results in urine enzyme immunoassays for methadone have been reported in patients who have taken vortioxetine. An alternative analytical technique (e.g., chromatographic methods) should be considered to confirm positive methadone urine drug screen results.

Read the entire FDA prescribing information for Trintellix (Vortioxetine Tablets)