Trintellix (Page 2 of 8)

5.2 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 (4), Drug Interactions (7.1)].

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.

5.3 Increased Risk of 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.

Inform patients about the increased risk of bleeding when TRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing TRINTELLIX [see Drug Interactions (7.1) ] .

5.4 Activation of Mania/Hypomania

In patients with bipolar disorder, treating a depressive episode with TRINTELLIX or another antidepressant may precipitate a mixed/manic episode. Symptoms of mania/hypomania were reported in <0.1% of patients treated with TRINTELLIX in premarketing clinical studies. Prior to initiating treatment with TRINTELLIX, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

5.5. Discontinuation Syndrome

Adverse reactions have been reported upon abrupt discontinuation of treatment with TRINTELLIX at doses of 15 mg/day and 20 mg/day [see Adverse Reactions (6.1) ] . A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.3) ].

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.

5.6 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.

5.7 Hyponatremia

Hyponatremia has occurred as a result of treatment with serotonergic drugs, including TRINTELLIX. 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 premarketing 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.

5.8 Sexual Dysfunction

Use of serotonergic antidepressants, including TRINTELLIX, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1) ] . In male patients, serotonergic antidepressant use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of TRINTELLIX and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

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)]
Discontinuation Syndrome [see Warnings and Precautions (5.5)]
Angle Closure Glaucoma [see Warnings and Precautions (5.6)]
Hyponatremia [see Warnings and Precautions (5.7)]

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 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 TRINTELLIX 10 mg/day TRINTELLIX 15 mg/day TRINTELLIX 20 mg/day Placebo
N=1013 % N=699 % N=449 % N=455 % N=1621 %
*
includes pruritus generalized

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

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 (14)].

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
*
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

Females

22%

23%

33%

34%

20%

Males

16%

20%

19%

29%

14%

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 (5.7)]. 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, 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

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