VILAZODONE Drug Interactions: What You Need to Know

INTERACTIONS

• CYP3A4 Inhibitors: The vilazodone hydrochloride tablet dose should not exceed 20 mg once daily when co-administered with strong CYP3A4 inhibitors (2.4, 7)
• CYP3A4 Inducers: Consider increasing vilazodone hydrochloride tablets dosage by 2-fold, up to 80 mg once-daily over 1 to 2 weeks when used concomitantly with strong CYP3A4 inducers for greater than 14 days (2.4, 7)

7.1 Drugs Having Clinically Important Interactions With Vilazodone Hydrochloride Tablets Table 4: Clinically Important Drug Interactions with Vilazodone Hydrochloride Tablets Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of MAOIs and serotonergic drugs including vilazodone hydrochloride tablets increases the risk of serotonin syndrome. Vilazodone hydrochloride tablets are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue <span class="opacity-50 text-xs">[see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)]</span>.

Other Serotonergic Drugs

Concomitant use of vilazodone hydrochloride tablets with other serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during vilazodone hydrochloride tablets initiation. If serotonin syndrome occurs, consider discontinuation of vilazodone hydrochloride tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].

Antiplatelet

Agents and Anticoagulants Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with vilazodone hydrochloride tablets may potentiate the risk of bleeding. Inform patients of the increased risk of bleeding with the concomitant use of vilazodone hydrochloride tablets and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating, titrating, or discontinuing vilazodone hydrochloride tablets [see Warnings and Precautions (5.3)]. Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) The concomitant use of vilazodone hydrochloride tablets and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of vilazodone hydrochloride tablets alone [see Clinical Pharmacology (12.3)]. The vilazodone hydrochloride tablet dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin) The concomitant use of vilazodone hydrochloride tablets and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of vilazodone hydrochloride tablets alone [see Clinical Pharmacology (12.3)]. Based on clinical response, consider increasing the dosage of vilazodone hydrochloride tablets, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

Digoxin

Digoxin is a narrow therapeutic index drug. Concomitant use of vilazodone hydrochloride tablets increased digoxin concentrations [see Clinical Pharmacology (12.3)] . Measure serum digoxin concentrations before initiating concomitant use of vilazodone hydrochloride tablets. Continue monitoring and reduce digoxin dose as necessary.

7.2 Drugs Having No Clinically Important Interactions With Vilazodone Hydrochloride Tablets Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and/or P-glycoprotein (except narrow therapeutic index drugs, e.g., digoxin), when vilazodone hydrochloride tablets are administered concomitantly <span class="opacity-50 text-xs">[see Drug Interactions (7.1), Clinical Pharmacology (12.3)]</span> .

Vilazodone hydrochloride tablets are contraindicated in:

• Patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue, because of an increased risk of serotonin syndrome [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] .
• Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4 )

AND PRECAUTIONS

• Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue vilazodone hydrochloride tablets and serotonergic agents and initiate supportive treatment (5.2)
• Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk (5.3)
• Activation of Mania/Hypomania: Screen patients for bipolar disorder (5.4)
• Seizures: Can occur with treatment. Use with caution in patients with a seizure disorder (5.6)
• Angle Closure Glaucoma: Avoid use of antidepressants, including vilazodone hydrochloride tablets, in patients with untreated anatomically narrow angles (5.7)
• Sexual Dysfunction: Vilazodone hydrochloride tablets may cause symptoms of sexual dysfunction (5.9)

5.1 Suicidal Thoughts and Behavior 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 over 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater in antidepressant-treated patients 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 1000 patients treated are provided in Table 1.

Table

1: Risk Differences of the Number of Patients with Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range (years) Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18 to 24 5 additional patients Decreases Compared to Placebo 25 to 64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients 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 vilazodone hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome Serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitor (SSRIs), including vilazodone hydrochloride tablets, 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, meperidine, methadone, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs <span class="opacity-50 text-xs">[see Contraindications (4) and Drug Interactions (7)]</span> . Serotonin syndrome can also occur when these drugs are used alone. Symptoms of serotonin syndrome were noted in 0.1% of MDD patients treated with vilazodone hydrochloride tablets in premarketing clinical trials. 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 vilazodone hydrochloride tablets with MAOIs is contraindicated. In addition, do not initiate vilazodone hydrochloride tablets 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 vilazodone hydrochloride tablets, discontinue vilazodone hydrochloride tablets before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7.1)]</span>. Monitor all patients taking vilazodone hydrochloride tablets for the emergence of serotonin syndrome. Discontinue treatment with vilazodone hydrochloride tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of vilazodone hydrochloride tablets 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 Drugs that interfere with serotonin reuptake inhibition, including vilazodone hydrochloride tablets, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, 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, 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 interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of vilazodone hydrochloride tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing vilazodone hydrochloride tablets.

5.4 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with vilazodone hydrochloride tablets or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were excluded; however, symptoms of mania or hypomania were reported in 0.1% of undiagnosed patients treated with vilazodone hydrochloride tablets. Prior to initiating treatment with vilazodone hydrochloride tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania <span class="opacity-50 text-xs">[see Dosage and Administration (2.2)]</span> .

5.5 Discontinuation Syndrome 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. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible <span class="opacity-50 text-xs">[see Dosage and Administration (2.5)]</span> .

5.6 Seizures Vilazodone hydrochloride tablets have not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from clinical studies. Vilazodone hydrochloride tablets should be prescribed with caution in patients with a seizure disorder.

5.7 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including vilazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including vilazodone hydrochloride tablets, in patients with untreated anatomically narrow angles.

5.8 Hyponatremia Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including vilazodone hydrochloride tablets. Cases of serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue vilazodone hydrochloride tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5)]</span> .

5.9 Sexual Dysfunction Use of SSRIs, including vilazodone hydrochloride tablets, may cause symptoms of sexual dysfunction <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI 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 vilazodone hydrochloride tablets 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.