VORTIOXETINE HYDROBROMIDE Drug Interactions: What You Need to Know

INTERACTIONS

• Strong inhibitors of CYP2D6: Reduce TRINTELLIX dose by half when coadministered ( 2.5 , 7.1 ).
• Strong CYP Inducers: Consider dose increase of TRINTELLIX dose when coadministered for more than 14 days. The maximum recommended dose should not exceed 3 times the original dose ( 2.6 , 7.1 ).

7.1 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 (2.4) , Contraindications (4) , Warnings and Precautions (5.2) ] 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 (5.2) ] .

Examples

Other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, 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 (2.5) ] . 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 (2.6) ]. 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 (5.3) , Drug Interactions (7.2) ] . 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 (7.2) ] .

Examples

Warfarin

7.2 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 (12.3) ] . Patients receiving other drugs that interfere with hemostasis should be carefully monitored when TRINTELLIX is initiated or discontinued [see Warnings and Precautions (5.3) , Drug Interactions (7.1) ] .

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 (7.1) , Clinical Pharmacology (12.3) ] .

7.3 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.

4 CONTRAINDICATIONS

• Hypersensitivity to vortioxetine or any component of the formulation. Hypersensitivity reactions including anaphylaxis, angioedema, and urticaria have been reported in patients treated with TRINTELLIX [see Adverse Reactions (6.2) ] .
• The use of MAOIs intended to treat psychiatric disorders with TRINTELLIX or within 21 days of stopping treatment with TRINTELLIX is contraindicated because of an increased risk of serotonin syndrome. The use of TRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.4) , Warnings and Precautions (5.2) ] . Starting TRINTELLIX 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 Warnings and Precautions (5.2) ] .
• Hypersensitivity to vortioxetine or any components of the TRINTELLIX formulation ( 4 ).
• Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with TRINTELLIX or within 21 days of stopping treatment with TRINTELLIX. Do not use TRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start TRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue ( 4 ).

AND PRECAUTIONS

• Serotonin Syndrome : Increased risk when coadministered with other serotonergic agents, but also when taken alone. If it occurs, discontinue TRINTELLIX and serotonergic agents and initiate supportive measures ( 5.2 ).
• Increased Risk of Bleeding : Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, or other drugs that affect coagulation may increase risk ( 5.3 ).
• Activation of Mania/Hypomania : 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 ( 5.6 ).
• Hyponatremia : Can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) ( 5.7 ).
• Sexual Dysfunction: TRINTELLIX may cause symptoms of sexual dysfunction ( 5.8 ).

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1 .

Table

1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric TRINTELLIX is not approved for use in pediatric patients. and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in adolescents and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that the use of antidepressants can delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for all approved populations for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing TRINTELLIX, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts and behaviors.

5.2 Serotonin Syndrome Serotonergic antidepressants, including TRINTELLIX, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, meperidine, methadone, buspirone, amphetamines, and St. John&apos;s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs <span class="opacity-50 text-xs">[see Contraindications (4) , Drug Interactions (7.1) ]</span> . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of TRINTELLIX with MAOIs is contraindicated. In addition, do not initiate TRINTELLIX in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking TRINTELLIX, discontinue TRINTELLIX before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4) , Drug Interactions (7.1) ]</span> . Monitor all patients taking TRINTELLIX for the emergence of serotonin syndrome. Discontinue treatment with TRINTELLIX and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of TRINTELLIX with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

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. Based on data from the published observational studies, exposure to SSRIs or SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span> .

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 &lt;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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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.