Venlafaxine Hydrochloride (venlafaxine hydrochloride 75 mg) Dailymed

• Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicide risk ( 5.1).
• Serotonin Syndrome: Risk increases with concomitant use of other serotonergic drugs. Discontinue venlafaxine hydrochloride extended-release capsules and initiate supportive treatment if serotonin syndrome occurs ( 4.2, 5.2, 7.3).
• Elevations in Blood Pressure: Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment ( 5.3).
• Abnormal Bleeding: Venlafaxine hydrochloride extended-release capsules may increase risk of bleeding events. Caution patients about the risk of bleeding associated with the concomitant use of venlafaxine hydrochloride extended-release capsules and NSAIDs, aspirin, or other drugs that affect coagulation ( 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: Use cautiously in patients with bipolar disorder. Caution patients about the risk of activation of mania/hypomania ( 5.6).
• Sexual Dysfunction: venlafaxine hydrochloride extended-release capsules may cause symptoms of sexual dysfunction ( 5.13).

5.1Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled studies in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.

Table 1: Difference in the Number of Cases of Suicidality per 1,000 Patients Treated versus Placebo

Age Range	Increases Compared to Placebo
< 18	14 additional cases
18 to 24	5 additional cases
	Decreases Compared to Placebo
25 to 64	1 fewer case
≥ 65	6 fewer cases

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD, as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions ( 5.7) and Dosage and Administration ( 2.8)] .

Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for venlafaxine hydrochloride extended-release capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that venlafaxine hydrochloride extended-release capsules are not approved for use in treating bipolar depression.

5.2 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including venlafaxine hydrochloride extended-release capsules alone, but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s wort) and with drugs that impair metabolism of serotonin in particular, MAOIs, both those intended to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma) autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, flushing, and dizziness), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination); seizures and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of venlafaxine hydrochloride extended-release capsules with MAOIs (intended to treat psychiatric disorders) is contraindicated. Venlafaxine hydrochloride extended-release capsules should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking venlafaxine hydrochloride extended-release capsules. Venlafaxine hydrochloride extended-release capsules should be discontinued before initiating treatment with the MAOI [see Contraindications ( 4.2), Dosage and Administration ( 2.6), and Drug Interactions ( 7.3)].

If concomitant use of venlafaxine hydrochloride extended-release capsules with other serotonergic drugs (e.g., triptans, tricyclic antidepressants, mirtazapine, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, or St. John's wort) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions ( 7.3)] . Patients should be made aware of the potential risk of serotonin syndrome. Treatment with venlafaxine hydrochloride extended-release capsules and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated.

5.3 Elevations in 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 ( 6.2)] .

Monitor blood pressure before initiating treatment with venlafaxine hydrochloride extended-release capsules and regularly during treatment. Control preexisting hypertension before initiating treatment with venlafaxine hydrochloride extended-release capsules. Use caution in treating patients with preexisting 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 tablets, 1.4% of patients in the venlafaxine hydrochloride extended-release capsule 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 capsule 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 Table 10 in Adverse Reactions ( 6.2)] . Venlafaxine hydrochloride extended-release capsule treatment was associated with sustained hypertension (defined as treatment-emergent SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for three consecutive on-therapy visits [see Table 11 in Adverse Reactions ( 6.2)] . An insufficient number of patients received mean doses of venlafaxine hydrochloride 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 Abnormal Bleeding

SSRIs and SNRIs, 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. Caution patients about the risk of bleeding associated with the concomitant use of venlafaxine hydrochloride extended-release capsules and NSAIDs, aspirin, or other drugs that affect coagulation.

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.

5.6 Activation ofMania/Hypomania

Mania or hypomania was reported in venlafaxine hydrochloride extended-release capsule treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat MDD. Venlafaxine hydrochloride extended-release capsules should be used cautiously in patients with a history of mania or hypomania.

Table 2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine Hydrochloride Extended-release Capsule Treated 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 spontaneous reports of other 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 [see Dosage and Administration ( 2.8)] .

5.8 Seizures

Seizures have occurred with venlafaxine therapy. Venlafaxine hydrochloride extended-release capsules, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures. [Must mitigate the risk: Risk factors, concomitant meds that lower the seizure threshold.]

5.9 Hyponatremia

Hyponatremia can occur as a result of treatment with SSRIs and 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 SSRIs and SNRIs [see Use in Specific Populations ( 8.5)] . Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk. 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 HeightChanges 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 in Double-blind, Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-release Capsules

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 Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-release Capsules

Indication (Duration)	Venlafaxine Hydrochloride Extended-release Capsules	Placebo
MDD and GAD (4 pooled studies, 8 weeks)	18 a (n = 333)	3.6 (n = 333)
SAD (16 weeks)	47 a (n = 137)	14 (n = 148)
a p < 0.001 versus placebo

Weight loss was not limited to patients with treatment-emergent 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).

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 twelve.

Table 5: Average Height Increases (cm) in Pediatric Patients in Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-release Capsules

Indication (Duration)	Venlafaxine Hydrochloride Extended-release Capsules	Placebo
MDD (8 weeks)	0.8 (n = 146)	0.7 (n = 147)
GAD (8 weeks)	0.3 a (n = 122)	1.0 (n = 132)
SAD (16 weeks)	1.0 (n = 109)	1.0 (n = 112)
a p = 0.041

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 (< 12 years old) than for adolescents (≥ 12 years old).

5.11Appetite Changes in Pediatric Patients

Decreased appetite (reported as treatment-emergent anorexia) was more commonly observed in venlafaxine hydrochloride extended-release capsule treated patients versus placebo-treated patients in the premarketing evaluation of venlafaxine hydrochloride extended-release capsules for MDD, GAD, and SAD (see Table 6).

Table 6: Incidence (%) of Decreased Appetite and Associated Discontinuation Rates ^a (%) in Pediatric Patients in Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-release Capsules

Indication (Duration)	Venlafaxine Hydrochloride Extended-release Capsules Incidence	Discontinuation	Placebo Incidence	Discontinuation
MDD and GAD (pooled, 8 weeks)	10	0.0	3	-
SAD (16 weeks)	22	0.7	3	0.0
a The discontinuation rates for weight loss were 0.7% for patients receiving either venlafaxine hydrochloride extended-release capsules or placebo.

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 adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered.

5.13Sexual Dysfunction

Use of SNRIs, including venlafaxine hydrochloride extended-release capsules, 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 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.

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label:

• Hypersensitivity [see Contraindications ( 4.1)]
• Suicidal Thoughts and Behaviors in Children, Adolescents, and Adults [see Warnings and Precautions ( 5.1)]
• Serotonin Syndrome [see Warnings and Precautions ( 5.2)]
• Elevations in Blood Pressure [see Warnings and Precautions ( 5.3)]
• Abnormal Bleeding [see Warnings and Precautions ( 5.4)]
• Angle Closure Glaucoma [see Warnings and Precautions ( 5.5)]
• Activation of Mania/Hypomania [see Warnings and Precautions ( 5.6)]
• Discontinuation Syndrome [see Warnings and Precautions (5.7)]
• Seizure [see Warnings and Precautions ( 5.8)]
• Hyponatremia [see Warnings and Precautions ( 5.9)]
• Weight and Height changes in Pediatric Patients [see Warnings and Precautions ( 5.10)]
• Appetite Changes in Pediatric Patients [see Warnings and Precautions ( 5.11)]
• Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions ( 5.12)]
• Sexual Dysfunction [see Warnings and Precautions ( 5.13)]

Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): nausea, somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, erectile dysfunction, and libido decreased ( 6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872  or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Most Common Adverse Reactions

The most commonly observed adverse reactions in the clinical study database in venlafaxine hydrochloride extended-release capsule treated patients in MDD, GAD, SAD, and PD (incidence ≥ 5% and at least twice the rate of placebo) were: nausea (30.0%), somnolence (15.3%), dry mouth (14.8%), sweating (11.4%), abnormal ejaculation (9.9%), anorexia (9.8%), constipation (9.3%), impotence (5.3%) and decreased libido (5.1%).

Adverse Reactions Reported as Reasons for Discontinuation of Treatment

Combined across short-term, placebo-controlled premarketing studies for all indications, 12% of the 3,558 patients who received venlafaxine hydrochloride extended-release capsules (37.5 mg to 225 mg) discontinued treatment due to an adverse experience, compared with 4% of the 2,197 placebo-treated patients in those studies.

The most common adverse reactions leading to discontinuation in ≥ 1% of the venlafaxine hydrochloride extended-release capsule treated patients in the short-term studies (up to 12 weeks) across indications are shown in Table 7.

Table 7: Incidence (%) of Patients Reporting Adverse Reactions Leading to Discontinuation in Placebo-controlled Clinical Studies (up to 12 Weeks Duration)

Body System Adverse Reaction	Venlafaxine Hydrochloride Extended-release Capsules n = 3,558	Placebo n = 2,197
Body as a whole
Asthenia	1.7	0.5
Headache	1.5	0.8
Digestive system
Nausea	4.3	0.4
Nervous system
Dizziness	2.2	0.8
Insomnia	2.1	0.6
Somnolence	1.7	0.3
Skin and appendages	1.5	0.6
Sweating	1.0	0.2

Common Adverse Reactions in Placebo-controlled Studies

The number of patients receiving multiple doses of venlafaxine hydrochloride extended-release capsules during the premarketing assessment for each approved indication is shown in Table 8. The conditions and duration of exposure to venlafaxine in all development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine tablets only) and outpatient studies, fixed-dose, and titration studies.

Table 8: Patients Receiving Venlafaxine Hydrochloride Extended-release Capsules in Premarketing Clinical Studies

Indication	Venlafaxine Hydrochloride Extended-release Capsules
MDD	705 a
GAD	1,381
SAD	819
PD	1,314
a In addition, in the premarketing assessment of venlafaxine tablets, multiple doses were administered to 2,897 patients in studies for MDD.

The incidences of common adverse reactions (those that occurred in ≥ 2% of venlafaxine hydrochloride extended-release capsule treated patients [357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and more frequently than placebo) in venlafaxine hydrochloride extended-release capsule treated patients in short-term, placebo-controlled, fixed- and flexible-dose clinical studies (doses 37.5 mg to 225 mg per day) are shown in Table 9.

The adverse reaction profile did not differ substantially between the different patient populations.

Table 9: Common Adverse Reactions: Percentage of Patients Reporting Adverse Reactions (≥ 2% and > placebo) in Placebo-controlled Studies (up to 12 Weeks Duration) across All Indications

Body System	Venlafaxine Hydrochloride Extended-release Capsules	Placebo
Adverse Reaction	n = 3,558	n = 2,197
Body as a whole
Asthenia	12.6	7.8
Cardiovascular system
Hypertension	3.4	2.6
Palpitation	2.2	2.0
Vasodilatation	3.7	1.9
Digestive system
Anorexia	9.8	2.6
Constipation	9.3	3.4
Diarrhea	7.7	7.2
Dry mouth	14.8	5.3
Nausea	30.0	11.8
Vomiting	4.3	2.7
Nervous system
Abnormal dreams	2.9	1.4
Dizziness	15.8	9.5
Insomnia	17.8	9.5
Libido decreased	5.1	1.6
Nervousness	7.1	5.0
Paresthesia	2.4	1.4
Somnolence	15.3	7.5
Tremor	4.7	1.6
Respiratory system
Yawn	3.7	0.2
Skin and appendages
Sweating (including night sweats)	11.4	2.9
Special senses
Abnormal vision	4.2	1.6
Urogenital system
Abnormal ejaculation/orgasm (men) a	9.9	0.5
Anorgasmia (men) a	3.6	0.1
Anorgasmia (women) b	2.0	0.2
Impotence (men) a	5.3	1.0
a Percentages based on the number of men (venlafaxine hydrochloride extended-release capsules, n = 1,440; placebo, n = 923) b Percentages based on the number of women (venlafaxine hydrochloride extended-release capsules, n = 2,118; placebo, n = 1,274)

Other Adverse Reactions Observed in Clinical Studies

Body as a whole – Photosensitivity reaction, chills

Cardiovascular system – Postural hypotension, syncope, hypotension, tachycardia

Digestive system – Gastrointestinal hemorrhage [see Warnings and Precautions ( 5.4)] , bruxism

Hemic/Lymphatic system – Ecchymosis [see Warnings and Precautions ( 5.4)]

Metabolic/Nutritional – Hypercholesterolemia, weight gain [see Warnings and Precautions ( 5.10)] , weight loss [see Warnings and Precautions ( 5.10)]

Nervous system – Seizures [see Warnings and Precautions ( 5.8)] , manic reaction [see Warnings and Precautions ( 5.6)] , agitation, confusion, akathisia, hallucinations, hypertonia, myoclonus, depersonalization, apathy

Skin and appendages – Urticaria, pruritus, rash, alopecia

Special senses – Mydriasis, abnormality of accommodation, tinnitus, taste perversion

Urogenital system – Urinary retention, urination impaired, urinary incontinence, urinary frequency increased, menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g., menorrhagia, metrorrhagia)

6.2 Vital Sign Changes

In placebo-controlled premarketing studies, there were increases in mean blood pressure (see Table 10). Across most indications, a dose-related increase in mean supine systolic and diastolic blood pressure was evident in patients treated with venlafaxine hydrochloride extended-release capsules. Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the venlafaxine hydrochloride extended-release capsules groups experienced an increase in SDBP of ≥ 15 mm Hg along with a blood pressure ≥ 105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine hydrochloride extended-release capsules groups experienced an increase in SSBP of ≥ 20 mm Hg with a blood pressure ≥ 180 mm Hg, compared to 0.3% of patients in the placebo groups.

Table 10: Final On-therapy Mean Changes From Baseline in Supine Systolic (SSBP) and Diastolic (SDBP) Blood Pressure (mm Hg) in Placebo-controlled Studies

Indication (Duration)	Venlafaxine Hydrochloride Extended-release Capsules				Placebo
	≤ 75 mg per day		> 75 mg per day
	SSBP	SDBP	SSBP	SDBP	SSBP	SDBP
MDD
(8 to 12 weeks)	-0.28	0.37	2.93	3.56	-1.08	-0.10
GAD
(8 weeks)	-0.28	0.02	2.40	1.68	-1.26	-0.92
(6 months)	1.27	-0.69	2.06	1.28	-1.29	-0.74
SAD
(12 weeks)	-0.29	-1.26	1.18	1.34	-1.96	-1.22
(6 months)	-0.98	-0.49	2.51	1.96	-1.84	-0.65
PD
(10 to 12 weeks)	-1.15	0.97	-0.36	0.16	-1.29	-0.99

Venlafaxine hydrochloride extended-release capsule treatment was associated with sustained hypertension (defined as treatment-emergent Supine Diastolic Blood Pressure [SDBP] ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for three consecutive on-therapy visits (see Table 11). An insufficient number of patients received mean doses of venlafaxine hydrochloride 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.

Table 11: Sustained Elevations in SDBP in Venlafaxine Hydrochloride Extended-release Capsules Premarketing Studies

Indication	Dose Range (mg per day)	Incidence (%)
MDD	75 to 375	19/705 (3)
GAD	37.5 to 225	5/1011 (0.5)
SAD	75 to 225	5/771 (0.6)
PD	75 to 225	9/973 (0.9)

Venlafaxine hydrochloride extended-release capsules were associated with mean increases in pulse rate compared with placebo in premarketing placebo-controlled studies (see Table 12) [see Warnings and Precautions ( 5.3, 5.4)].

Table 12: Approximate Mean Final On-therapy Increase in Pulse Rate (beats/min) in Venlafaxine Hydrochloride Extended-release Capsules Premarketing Placebo-controlled Studies (up to 12 Weeks Duration)

Indication (Duration)	Venlafaxine Hydrochloride Extended-release Capsules	Placebo
MDD (12 weeks)	2	1
GAD (8 weeks)	2	< 1
SAD (12 weeks)	3	1
PD (12 weeks)	1	< 1

6.3 Laboratory Changes

Serum Cholesterol

Venlafaxine hydrochloride extended-release capsules were associated with mean final increases in serum cholesterol concentrations compared with mean final decreases for placebo in premarketing MDD, GAD, SAD and PD clinical studies (Table 13).

Table 13: Mean Final On-therapy Changes in Cholesterol Concentrations (mg/dL) in Venlafaxine Hydrochloride Extended-release Capsules Premarketing Studies

Indication (Duration)	Venlafaxine Hydrochloride Extended-release Capsules	Placebo
MDD (12 weeks)	+1.5	-7.4
GAD (8 weeks) (6 months)	+1.0 +2.3	-4.9 -7.7
SAD (12 weeks) (6 months)	+7.9 +5.6	-2.9 -4.2
PD (12 weeks)	5.8	-3.7

Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Venlafaxine hydrochloride extended-release capsule treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Venlafaxine hydrochloride extended-release capsule treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 mg/dL and 4.2 mg/dL, respectively, for placebo. Venlafaxine hydrochloride extended-release capsule treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo.

Patients treated with venlafaxine tablets (immediate release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥ 50 mg/dL from baseline and to a value ≥ 261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥ 50 mg/dL from baseline and to a value ≥ 261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients.

Serum Triglycerides

Venlafaxine hydrochloride extended-release capsules were associated with mean final on-therapy increases in fasting serum triglycerides compared with placebo in premarketing clinical studies of SAD and PD up to 12 weeks (pooled data) and 6 months duration (Table 14).

Table 14: Mean Final On-therapy Increases in Triglyceride Concentrations (mg/dL) in Venlafaxine Hydrochloride Extended-release Capsules Premarketing Studies

Indication (Duration)	Venlafaxine Hydrochloride Extended-release Capsules	Placebo
SAD (12 weeks)	8.2	0.4
SAD (6 months)	11.8	1.8
PD (12 weeks)	5.9	0.9
PD (6 months)	9.3	0.3

6.4 Pediatric Patients

In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical studies) in children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed [see Warnings and Precautions ( 5.3, 5.10, 5.11) and Use in Specific Populations ( 8.4)] .

In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed.

Particularly, the following adverse reactions were observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

6.5 Adverse Reactions Identified During Postapproval Use

The following adverse reactions have been identified during postapproval use of venlafaxine hydrochloride extended-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Body as a whole – Anaphylaxis, angioedema

Cardiovascular system – QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathy

Digestive system – Pancreatitis

Hemic/Lymphatic system – Mucous membrane bleeding [see Warnings and Precautions ( 5.4)] , blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia

Metabolic/Nutritional – Hyponatremia [see Warnings and Precautions ( 5.9)] , Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [see Warnings and Precautions ( 5.9)] , abnormal liver function tests, hepatitis, prolactin increased

Musculoskeletal – Rhabdomyolysis

Nervous system – Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions ( 5.2)] , serotonergic syndrome [see Warnings and Precautions ( 5.2)] , delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia

Respiratory system – Dyspnea, interstitial lung disease, pulmonary eosinophilia [see Warnings and Precautions ( 5.12)]

Skin and appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Special senses – Angle-closure glaucoma [see Warnings and Precautions ( 5.5)]