VENLAFAXINE Drug Interactions: What You Need to Know

Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.

Cimetidine

Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (C max ) of the drug were increased by about 60%. However, co-administration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.

Diazepam

Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.

Haloperidol

Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol C max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t 1/2 ) was unchanged. The mechanism explaining this finding is unknown.

Lithium

The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs , below).

Drugs Highly

Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine hydrochloride to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding 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. Patients receiving warfarin therapy should be carefully monitored when venlafaxine hydrochloride is initiated or discontinued. Drugs that Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor. Ketoconazole A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O–desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine C max increased by 26% in EM subjects and 48% in PM subjects. C max values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs -38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMS and 53% in PMs (range in PMs 4% to 134%). Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. CYP3A4 Inhibitors In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small. The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient's therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems.

Drugs

Metabolized by Cytochrome P450 Isoenzymes CYP2D6 In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan. Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, C max , and C min increased by about 35% in the presence of venlafaxine.

The

2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown. Metoprolol—Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30 to 40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol. Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving venlafaxine hydrochloride have regular monitoring of blood pressure (see WARNINGS ). Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine co-administration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). CYP3A4 Venlafaxine did not inhibit CYP3A4 in vitro . This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine. Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C max . Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. CYP1A2 Venlafaxine did not inhibit CYP1A2 in vitro . This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate. CYP2C9 Venlafaxine did not inhibit CYP2C9 in vitro . In vivo , venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide. CYP2C19 Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above).

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS . CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required (see CONTRAINDICATIONS and WARNINGS ).

Serotonergic Drugs

Based on the mechanism of action of SNRIs and SSRIs, including venlafaxine hydrochloride, and the potential for serotonin syndrome, caution is advised when venlafaxine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, amphetamines, or St. John’s Wort (see WARNINGS : Serotonin Syndrome ). If concomitant treatment of venlafaxine hydrochloride with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome ). The concomitant use of venlafaxine hydrochloride with tryptophan supplements is not recommended (see CONTRAINDICATIONS and WARNINGS, Serotonin Syndrome ).

Triptans

There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of venlafaxine hydrochloride with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome ). Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/ mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

Electroconvulsive Therapy

There are no clinical data establishing the benefit of electroconvulsive therapy combined with venlafaxine hydrochloride treatment.

Postmarketing Spontaneous Drug Interaction Reports

See ADVERSE REACTIONS, Postmarketing Reports .

CONTRAINDICATIONS

4.1 Hypersensitivity Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs (intended to treat psychiatric disorders) concomitantly with venlafaxine hydrochloride extended-release capsules or within 7 days of discontinuing treatment with venlafaxine hydrochloride extended-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine hydrochloride extended-release capsules within 14 days of discontinuing treatment with an MAOI (intended to treat psychiatric disorders) is also contraindicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]</span>. Starting venlafaxine hydrochloride extended-release capsules in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is also contraindicated, because of an increased risk of serotonin syndrome <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3)]</span>.

• Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in the venlafaxine hydrochloride extended-release capsules formulation (4.1).
• Do not use with an MAOI or within 14 days of stopping an MAOI.

Allow

7 days after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI, because of the risk of serotonin syndrome (4.2, 5.2, 7.3).

4.1 Hypersensitivity Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs (intended to treat psychiatric disorders) concomitantly with venlafaxine hydrochloride extended-release capsules or within 7 days of discontinuing treatment with venlafaxine hydrochloride extended-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine hydrochloride extended-release capsules within 14 days of discontinuing treatment with an MAOI (intended to treat psychiatric disorders) is also contraindicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]</span>. Starting venlafaxine hydrochloride extended-release capsules in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is also contraindicated, because of an increased risk of serotonin syndrome <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3)]</span>.

4.1 Hypersensitivity Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs (intended to treat psychiatric disorders) concomitantly with venlafaxine hydrochloride extended-release capsules or within 7 days of discontinuing treatment with venlafaxine hydrochloride extended-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine hydrochloride extended-release capsules within 14 days of discontinuing treatment with an MAOI (intended to treat psychiatric disorders) is also contraindicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)]</span>. Starting venlafaxine hydrochloride extended-release capsules in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is also contraindicated, because of an increased risk of serotonin syndrome <span class="opacity-50 text-xs">[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.3)]</span>.

AND PRECAUTIONS .

Serotonin

Syndrome : Increased risk when co-administered with other serotonergic agents but also when taken alone. If it occurs, discontinue Venlafaxine hydrochloride extended-release capsules 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 /or Hypomania : Screen patients for bipolar disorder ( 5.6 ).

Discontinuation

Syndrome: Taper dose and monitor for discontinuation symptoms ( 5.7 ). Seizures : Can occur. Use cautiously 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 hydrochloride extended-release capsules 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 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 * Venlafaxine hydrochloride extended-release capsules is not approved in pediatric 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 hydrochloride extended-release capsules, 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 hydrochloride extended-release capsules, 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 <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, 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 hydrochloride extended-release capsules with MAOIs is contraindicated. In addition, do not initiate Venlafaxine hydrochloride extended-release capsules 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 hydrochloride extended-release capsules, discontinue Venlafaxine hydrochloride extended-release capsules before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7.1)]</span>. Monitor all patients taking Venlafaxine hydrochloride extended-release capsules for the emergence of serotonin syndrome. Discontinue treatment with Venlafaxine hydrochloride extended-release capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Venlafaxine hydrochloride extended-release capsules 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Monitor blood pressure before initiating treatment with Venlafaxine hydrochloride extended-release capsules and regularly during treatment. Control pre-existing hypertension before initiating treatment with Venlafaxine hydrochloride extended-release capsules. 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 hydrochloride 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 hydrochloride tablets, 1.4% of patients in the Venlafaxine hydrochloride 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 hydrochloride 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 in Adverse Reactions (6.1) ]. Treatment with venlafaxine hydrochloride 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsule 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 hydrochloride extended-release capsules, 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1)]</span>. Inform patients about the increased risk of bleeding associated with the concomitant use of Venlafaxine hydrochloride extended-release capsules and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Venlafaxine hydrochloride extended-release capsules.

5.5 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Venlafaxine hydrochloride extended-release capsules 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 hydrochloride extended-release capsules, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with Venlafaxine hydrochloride extended-release capsules or another antidepressant may precipitate a mixed/maniac episode. Mania or hypomania was reported in Venlafaxine hydrochloride extended-release capsules treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Prior to initiating treatment with Venlafaxine hydrochloride extended-release capsules, screen for any personal or family history of bipolar disorder, mania, or hypomania.

Table

2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine hydrochloride extended-release capsulesTreated Patients in the Premarketing Studies Indication Venlafaxine hydrochloride extended-release capsules Placebo MDD 0.3

0.0 GAD 0.0

0.2 SAD 0.2

0.0 PD 0.1 0.0

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 and SAD. 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 hydrochloride 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 hydrochloride extended-release capsules. During marketing of Venlafaxine hydrochloride 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 hydrochloride extended-release capsules. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.10)]</span>.

5.8 Seizures Cases of seizure have been reported with venlafaxine therapy. Venlafaxine hydrochloride extended-release capsules has not been systematically evaluated in patients with seizure disorder. Venlafaxine hydrochloride extended-release capsules should be prescribed with caution in patients with a seizure disorder.

5.9 Hyponatremia Hyponatremia can occur as a result of treatment with SNRIs, including Venlafaxine hydrochloride extended-release capsules. 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 SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ]</span> . Consider discontinuation of Venlafaxine hydrochloride extended-release capsules 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, GAD, and SAD are shown in Tables 3 and 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 hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) -0.45 (n=333) +0.77 (n=333) SAD (16 weeks) -0.75 (n=137) +0.76 (n=148)

Table

4: Incidence (%) of Pediatric Patients a Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p < 0.001 versus placebo Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) 18 b (n = 333) 3.6 (n = 333) SAD (16 weeks) 47 b (n = 137) 14 (n = 148) Weight loss was not limited to patients with anorexia [ see Warnings and Precautions (5.11) ]. The risks associated with longer term Venlafaxine hydrochloride extended-release capsules use were assessed in an open-label MDD study of children and adolescents who received Venlafaxine hydrochloride extended-release capsules for up to six months. The children and adolescents 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 children (<12 years old) than for adolescents (≥12 years old). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients [ Use in Specific Populations (8.4) ] .

Height Changes Table

5 shows the average height increase in pediatric patients in the short-term, placebo-controlled MDD, GAD, and SAD studies. The differences in height increases in GAD and MDD studies were most notable in patients younger than 12 years old.

Table

5: Average Height Increases (cm) in Pediatric Patients a in Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p =

0.041 Indication (Duration) Venlafaxine hydrochloride 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) SAD (16 weeks) 1.0 (n = 109) 1.0 (n = 112) In the six-month, open-label MDD study, children and adolescents 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 children (&lt;12 years old) than for adolescents (≥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 hydrochloride extended-release capsules treated patients versus placebo-treated patients in the premarketing evaluation of Venlafaxine hydrochloride extended-release capsules for MDD, GAD, and SAD (see Table 6). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> .

Table

6: Incidence (%) of Decreased Appetite and Associated Discontinuation Rates a (%) in Pediatric Patients b in Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a The discontinuation rates for weight loss were 0.7% for patients receiving either Venlafaxine hydrochloride extended-release capsules or placebo. b Venlafaxine hydrochloride extended-release capsules is not approved for use in pediatric patients. - Venlafaxine hydrochloride extended-release capsules Placebo (Duration)

Incidence Discontinuation Incidence

Discontinuation MDD and GAD (pooled, 8 weeks) 10 0.0 3 - SAD (16 weeks) 22 0.7 3 0.0

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 hydrochloride extended-release capsules-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine hydrochloride extended-release should be considered.

5.13 Sexual Dysfunction Use of SNRIs, including Venlafaxine hydrochloride extended-release capsules, may cause symptoms of sexual dysfunction <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. 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 hydrochloride extended-release capsules 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.

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 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 * Venlafaxine hydrochloride extended-release capsules is not approved in pediatric 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 hydrochloride extended-release capsules, 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 hydrochloride extended-release capsules, 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 <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, 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 hydrochloride extended-release capsules with MAOIs is contraindicated. In addition, do not initiate Venlafaxine hydrochloride extended-release capsules 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 hydrochloride extended-release capsules, discontinue Venlafaxine hydrochloride extended-release capsules before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7.1)]</span>. Monitor all patients taking Venlafaxine hydrochloride extended-release capsules for the emergence of serotonin syndrome. Discontinue treatment with Venlafaxine hydrochloride extended-release capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Venlafaxine hydrochloride extended-release capsules 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Monitor blood pressure before initiating treatment with Venlafaxine hydrochloride extended-release capsules and regularly during treatment. Control pre-existing hypertension before initiating treatment with Venlafaxine hydrochloride extended-release capsules. 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 hydrochloride 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 hydrochloride tablets, 1.4% of patients in the Venlafaxine hydrochloride 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 hydrochloride 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 in Adverse Reactions (6.1) ]. Treatment with venlafaxine hydrochloride 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsule 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 hydrochloride extended-release capsules, 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1)]</span>. Inform patients about the increased risk of bleeding associated with the concomitant use of Venlafaxine hydrochloride extended-release capsules and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Venlafaxine hydrochloride extended-release capsules.

5.5 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Venlafaxine hydrochloride extended-release capsules 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 hydrochloride extended-release capsules, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with Venlafaxine hydrochloride extended-release capsules or another antidepressant may precipitate a mixed/maniac episode. Mania or hypomania was reported in Venlafaxine hydrochloride extended-release capsules treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Prior to initiating treatment with Venlafaxine hydrochloride extended-release capsules, screen for any personal or family history of bipolar disorder, mania, or hypomania.

Table

2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine hydrochloride extended-release capsulesTreated Patients in the Premarketing Studies Indication Venlafaxine hydrochloride extended-release capsules Placebo MDD 0.3

0.0 GAD 0.0

0.2 SAD 0.2

0.0 PD 0.1 0.0

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 and SAD. 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 hydrochloride 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 hydrochloride extended-release capsules. During marketing of Venlafaxine hydrochloride 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 hydrochloride extended-release capsules. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.10)]</span>.

5.8 Seizures Cases of seizure have been reported with venlafaxine therapy. Venlafaxine hydrochloride extended-release capsules has not been systematically evaluated in patients with seizure disorder. Venlafaxine hydrochloride extended-release capsules should be prescribed with caution in patients with a seizure disorder.

5.9 Hyponatremia Hyponatremia can occur as a result of treatment with SNRIs, including Venlafaxine hydrochloride extended-release capsules. 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 SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ]</span> . Consider discontinuation of Venlafaxine hydrochloride extended-release capsules 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, GAD, and SAD are shown in Tables 3 and 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 hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) -0.45 (n=333) +0.77 (n=333) SAD (16 weeks) -0.75 (n=137) +0.76 (n=148)

Table

4: Incidence (%) of Pediatric Patients a Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p < 0.001 versus placebo Indication (Duration) Venlafaxine hydrochloride extended-release capsules Placebo MDD and GAD (4 pooled studies, 8 weeks) 18 b (n = 333) 3.6 (n = 333) SAD (16 weeks) 47 b (n = 137) 14 (n = 148) Weight loss was not limited to patients with anorexia [ see Warnings and Precautions (5.11) ]. The risks associated with longer term Venlafaxine hydrochloride extended-release capsules use were assessed in an open-label MDD study of children and adolescents who received Venlafaxine hydrochloride extended-release capsules for up to six months. The children and adolescents 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 children (<12 years old) than for adolescents (≥12 years old). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients [ Use in Specific Populations (8.4) ] .

Height Changes Table

5 shows the average height increase in pediatric patients in the short-term, placebo-controlled MDD, GAD, and SAD studies. The differences in height increases in GAD and MDD studies were most notable in patients younger than 12 years old.

Table

5: Average Height Increases (cm) in Pediatric Patients a in Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients. b p =

0.041 Indication (Duration) Venlafaxine hydrochloride 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) SAD (16 weeks) 1.0 (n = 109) 1.0 (n = 112) In the six-month, open-label MDD study, children and adolescents 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 children (&lt;12 years old) than for adolescents (≥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 hydrochloride extended-release capsules treated patients versus placebo-treated patients in the premarketing evaluation of Venlafaxine hydrochloride extended-release capsules for MDD, GAD, and SAD (see Table 6). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> .

Table

6: Incidence (%) of Decreased Appetite and Associated Discontinuation Rates a (%) in Pediatric Patients b in Placebo-controlled Studies of Venlafaxine hydrochloride extended-release capsules a The discontinuation rates for weight loss were 0.7% for patients receiving either Venlafaxine hydrochloride extended-release capsules or placebo. b Venlafaxine hydrochloride extended-release capsules is not approved for use in pediatric patients. - Venlafaxine hydrochloride extended-release capsules Placebo (Duration)

Incidence Discontinuation Incidence

Discontinuation MDD and GAD (pooled, 8 weeks) 10 0.0 3 - SAD (16 weeks) 22 0.7 3 0.0

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 hydrochloride extended-release capsules-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine hydrochloride extended-release should be considered.

5.13 Sexual Dysfunction Use of SNRIs, including Venlafaxine hydrochloride extended-release capsules, may cause symptoms of sexual dysfunction <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span>. 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 hydrochloride extended-release capsules 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.