WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)]. BRINTELLIX has not been evaluated for use in pediatric patients [see Use in Specific Populations (8.4)]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1). • Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1). • BRINTELLIX has not been evaluated for use in pediatric patients (8.4).
1 INDICATIONS AND USAGE BRINTELLIX is indicated for the treatment of major depressive disorder (MDD) (1, 14). 1.1 Major Depressive Disorder BRINTELLIX is indicated for the treatment of major depressive disorder (MDD). The efficacy of BRINTELLIX was established in six 6 to 8 week studies (including one study in the elderly) and one maintenance study in adults [see Clinical Studies (14)].
3 DOSAGE FORMS AND STRENGTHS BRINTELLIX 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 •15 mg: orange, almond shaped biconvex film coated tablet, debossed with “15” 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 BRINTELLIX is available as 5 mg, 10 mg, 15 mg, and 20 mg immediate release tablets (3).
4 CONTRAINDICATIONS •Hypersensitivity to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with BRINTELLIX. •The use of MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX is contraindicated because of an increased risk of serotonin syndrome. The use of BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. Starting BRINTELLIX in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.5) and Warnings and Precautions (5.2)]. •Hypersensitivity to vortioxetine or any components of the BRINTELLIX formulation (4). •Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with BRINTELLIX or within 21 days of stopping treatment with BRINTELLIX. Do not use BRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start BRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue (4).
5 WARNINGS AND PRECAUTIONS •Serotonin Syndrome has been reported with serotonergic antidepressants (SSRIs, SNRIs, and others), including with BRINTELLIX, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort). If such symptoms occur, discontinue BRINTELLIX and initiate supportive treatment. If concomitant use of BRINTELLIX with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.2). •Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding when BRINTELLIX is coadministered with nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation (5.3). •Activation of Mania/Hypomania can occur with antidepressant treatment. Screen patients for bipolar disorder (5.4). •Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.5). •Hyponatremia can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (5.6). 5.1 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 BRINTELLIX is not approved for use in treating bipolar depression. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including BRINTELLIX, 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 BRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. BRINTELLIX 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 BRINTELLIX. BRINTELLIX should be discontinued before initiating treatment with the MAOI [see Contraindications (4) and Dosage and Administration (2.4)]. If concomitant use of BRINTELLIX 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 BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.3 Abnormal Bleeding The use of drugs that interfere with serotonin reuptake inhibition, including BRINTELLIX, 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 BRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Drug Interactions (7.2)]. 5.4 Activation of Mania/Hypomania Symptoms of mania/hypomania were reported in <0.1% of patients treated with BRINTELLIX 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 BRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. 5.5 Angle Closure Glaucoma Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs, including BRINTELLIX, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.6 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 BRINTELLIX 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 BRINTELLIX 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.
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 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 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
7 DRUG INTERACTIONS •Strong inhibitors of CYP2D6: Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) is coadministered (2.6 and 7.3). •Strong CYP Inducers: Consider increasing BRINTELLIX dose when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for more than 14 days. The maximum recommended dose should not exceed 3 times the original dose (2.7 and 7.3). 7.1 CNS Active Agents Monoamine Oxidase Inhibitors Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI [see Dosage and Administration (2.4), Contraindications (4) and Warnings and Precautions (5.2)]. Serotonergic Drugs Based on the mechanism of action of BRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when BRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if BRINTELLIX is co-administered with other serotonergic drugs. Treatment with BRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs [see Warnings and Precautions (5.2)]. Other CNS Active Agents No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of BRINTELLIX. Multiple doses of BRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that BRINTELLIX (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). Details on the potential pharmacokinetic interactions between BRINTELLIX and bupropion can be found in Section 7.3. 7.2 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of BRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin [see Drug Interactions (7.4)]. Coadministration of aspirin 150 mg/day with multiple daily doses of BRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid [see Drug Interactions (7.4)]. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when BRINTELLIX is initiated or discontinued [see Warnings and Precautions (5.3)]. 7.3 Potential for Other Drugs to Affect BRINTELLIX Reduce BRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the BRINTELLIX dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose [see Dosage and Administration ( 2.5 and 2.6)] (Figure 1). Figure 1. Impact of Other Drugs on Vortioxetine PK Figure1.jpg 7.4 Potential for BRINTELLIX to Affect Other Drugs No dose adjustment for the comedications is needed when BRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinide), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary. Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of BRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of BRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2). Because vortioxetine is highly bound to plasma protein, coadministration of BRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of BRINTELLIX (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 (7.2)]. Figure 2. Impact of Vortioxetine on PK of Other Drugs Figure2.jpg
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