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warnings and cautions
5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue Venlafaxine Extended-Release Tablets and serotonergic agents and initiate supportive treatment ( 4 , 5.2 , 7.1 ). Elevated Blood Pressure: Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment ( 5.3 ). Increased Risk of Bleeding: Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase risk ( 5.4 ). Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.5 ). Activation of Mania/Hypomania: Screen patients for bipolar disorder ( 2.4 , 5.6 ). Discontinuation Syndrome: Taper dose and monitor for discontinuation symptoms ( 5.7 ). Seizure: Can occur. Use with caution in patients with seizure disorder ( 5.8 ). Hyponatremia: Can occur in association with SIADH ( 5.9 ). Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur ( 5.12 ). Sexual Dysfunction: Venlafaxine Extended-Release Tablets may cause symptoms of sexual dysfunction ( 5.13 ). 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* and Adult Patients *Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo < 18 years old 14 additional patients 18–24 years old 5 additional patients Decreases Compared to Placebo 25–64 years old 1 fewer patient ≥ 65 years old 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 trials 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 any indication 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 Venlafaxine Extended-Release Tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Venlafaxine Extended-Release 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, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] . 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, 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 Venlafaxine Extended-Release Tablets with MAOIs is contraindicated. In addition, do not initiate Venlafaxine Extended-Release 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 Venlafaxine Extended-Release Tablets, discontinue Venlafaxine Extended-Release Tablets before initiating treatment with the MAOI [see Dosage and Administration ( 2.9 ), Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Monitor all patients taking Venlafaxine Extended-Release Tablets for the emergence of serotonin syndrome. Discontinue treatment with Venlafaxine Extended-Release Tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Venlafaxine Extended-Release Tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Elevated Blood Pressure In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension [see Adverse Reactions ( 6.1 )] . Monitor blood pressure before initiating treatment with Venlafaxine Extended-Release Tablets and regularly during treatment. Control pre-existing hypertension before initiating treatment with Venlafaxine Extended-Release Tablets. Use caution in treating patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of elevated blood pressure requiring immediate treatment have been reported with venlafaxine extended-release capsules. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure. Across all clinical studies with venlafaxine, 1.4% of patients in the venlafaxine extended-release capsules treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure (SDBP) ≥ 105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine extended-release capsules treated groups experienced a ≥ 20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥ 180 mm Hg, compared to 0.3% of patients in the placebo groups [see Adverse Reactions ( 6.1 )] . Treatment with venlafaxine extended-release capsules was associated with sustained hypertension (defined as SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for three consecutive on-therapy visits) [see Adverse Reactions (6.1)] . An insufficient number of patients received mean doses of venlafaxine extended-release capsules over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses. 5.4 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including Venlafaxine Extended-Release Tablets, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti-coagulants or other drugs known to affect platelet function 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 SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1 )] . Inform patients about the increased risk of bleeding associated with the concomitant use of Venlafaxine Extended-Release Tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Venlafaxine Extended-Release Tablets. 5.5 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including Venlafaxine Extended-Release 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 Venlafaxine Extended-Release Tablets, in patients with untreated anatomically narrow angles. 5.6 Activation of Mania/Hypomania In patients with bipolar disorder, treating a depressive episode with Venlafaxine Extended-Release Tablets or another antidepressant may precipitate a mixed/manic episode. Mania or hypomania was reported in venlafaxine extended-release capsules treated patients in the premarketing studies in MDD (see Table 2). Prior to initiating treatment with Venlafaxine Extended-Release Tablets, screen for any personal or family history of bipolar, mania, or hypomania. Table 2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine Extended-Release Capsules Treated Patients in the Premarketing Studies Indication Venlafaxine Extended-Release Capsules Placebo MDD 0.3 0.0 GAD 0.0 0.2 5.7 Discontinuation Syndrome Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting. There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe. Completed suicide, suicidal thoughts, aggression and violent behavior have been observed in patients during reduction in venlafaxine extended-release capsules dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of venlafaxine extended-release capsules. During marketing of venlafaxine extended-release capsules, other SNRIs, and SSRIs, there have been reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: irritability, lethargy, emotional lability, tinnitus, and seizures. Patients should be monitored for these symptoms when discontinuing treatment with Venlafaxine Extended-Release Tablets. A gradual reduction in the dose, rather than abrupt cessation, is recommended. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months [see Dosage and Administration ( 2.8 )] . Given that dosage strengths of Venlafaxine Extended-Release Tablets are not available below 112.5 mg, use another venlafaxine extended-release product for discontinuation [see Dosage and Administration ( 2.1 )] . 5.8 Seizures Cases of seizures have been reported with venlafaxine therapy. Venlafaxine Extended-Release Tablets has not been systematically evaluated in patients with seizure disorder. Venlafaxine Extended-Release Tablets should be prescribed with caution in patients with a history of seizures and should be discontinued in any patient who develops seizures. 5.9 Hyponatremia Hyponatremia can occur as a result of treatment with SNRIs, including Venlafaxine Extended-Release Tablets In many cases, the hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk [see Use in Specific Populations ( 8.5 ) and Clinical Pharmacology ( 12.3 )] . Consider discontinuation of Venlafaxine Extended-Release Tablets in patients with symptomatic hyponatremia, and institute appropriate medical intervention. 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. 5.10 Weight and Height Changes in Pediatric Patients Weight Changes The average change in body weight and incidence of weight loss (percentage of patients who lost 3.5% or more) in the placebo-controlled pediatric studies in MDD and GAD with venlafaxine extended-release capsules are shown in Tables 3 and 4. Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients [see Use in Specific Populations ( 8.4 )] . Table 3: Average Change in Body Weight (kg) From Beginning of Treatment in Pediatric Patients a in Double-blind, Placebo-controlled Studies of Venlafaxine Extended-Release Capsules Indication (Study Duration) Venlafaxine Extended-Release Capsules Placebo a Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. MDD and GAD (4 pooled studies, 8 weeks) -0.45 (n = 333) +0.77 (n = 333) Table 4: Incidence (%) of Pediatric Patients a Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Venlafaxine Extended-Release Capsules Indication (Study Duration) Venlafaxine Extended-Release Capsules Placebo a Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. b p < 0.001 versus placebo MDD and GAD (4 pooled studies, 8 weeks) 18 b (n = 333) 3.6 (n = 333) Weight loss was not limited to patients with anorexia [see Warnings and Precautions ( 5.11 )] . The risks associated with longer term use of venlafaxine extended-release capsules were assessed in an open-label MDD study of pediatric patients 6 years to 17 years old who received venlafaxine extended-release capsules for up to six months. The pediatric patients 6 years to 17 years old in the study had increases in weight that were less than expected, based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for pediatric patients 6 years to < 12 years old than for pediatric patients ≥ 12 years old. Height Changes Table 5 shows the average height increase in pediatric patients in the short-term, placebo-controlled MDD and GAD studies with venlafaxine extended-release capsules. The differences in height increases in GAD and MDD studies were most notable in patients younger than twelve. Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients [see Use in Specific Populations ( 8.4 )] . Table 5: Average Height Increases (cm) in Pediatric Patients a in Placebo-controlled Studies of Venlafaxine Extended-Release Capsules a Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. b p = 0.041 Indication (Study Duration) Venlafaxine Extended-Release Capsules Placebo MDD (8 weeks) 0.8 (n = 146) 0.7 (n = 147) GAD (8 weeks) 0.3 b (n = 122) 1.0 (n = 132) In the six-month, open-label MDD study with venlafaxine extended-release capsules, pediatric patients 6 years to 17 years old had height increases that were less than expected, based on data from age- and sex-matched peers. The difference between observed and expected growth rates was larger for pediatric patients 6 years to < 12 years old than for pediatric patients ≥ 12 years old [see Use in Specific Populations ( 8.4 )] . 5.11 Appetite Changes in Pediatric Patients Decreased appetite (reported as anorexia) was more commonly observed in venlafaxine extended-release capsule-treated pediatric patients 6 years to 17 years old versus placebo-treated patients in the premarketing evaluation of venlafaxine extended-release capsules for MDD and GAD (see Table 6). Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients [see Use in Specific Populations ( 8.4 )] . Table 6: Incidence (%) of Decreased Appetite and Associated Discontinuation Rates a (%) in Pediatric Patients b in Placebo-controlled Studies of Venlafaxine Extended-Release Capsules Indication (Study Duration) Venlafaxine Extended-Release Capsules Incidence Discontinuation Placebo Incidence a The discontinuation rates for weight loss were 0.7% for patients receiving either venlafaxine extended-release capsules or placebo. b Venlafaxine Extended-Release Tablets are not approved for use in pediatric patients. MDD and GAD (pooled, 8 weeks) 10 0.0 3 5.12 Interstitial Lung Disease and Eosinophilic Pneumonia Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these events should be considered in Venlafaxine Extended-Release Tablets patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of Venlafaxine Extended-Release Tablets should be considered. 5.13 Sexual Dysfunction Use of SNRIs, including Venlafaxine Extended-Release Tablets, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 )] . In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI 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 Venlafaxine Extended-Release 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.