Effexor (venlafaxine hydrochloride 75 mg) Dailymed

Indication	Starting Dose	Target Dose	Maximum Dose
MDD (2.2)	37.5 –75 mg/day	75 mg/day	225 mg/day
GAD (2.3)	37.5 –75 mg/day	75 mg/day	225 mg/day
SAD (2.4)	75 mg/day	75 mg/day	75 mg/day
PD (2.5)	37.5 mg/day	75 mg/day	225 mg/day

• •Take once daily with food. Capsules should be taken whole; do not divide, crush, chew, or dissolve (2.1).
• •When discontinuing treatment, reduce the dose gradually (2.10, 5.7).
• •Renal impairment: reduce the total daily dose by 25% to 50% in patients with renal impairment. Reduce the total daily dose by 50% or more in patients undergoing dialysis or with severe renal impairment (2.9).
• •Hepatic impairment: reduce the daily dose by 50% in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment or hepatic cirrhosis, it may be necessary to reduce the dose by more than 50% (2.8).

2.1 General Administration Information

Administer Effexor XR as a single dose with food, either in the morning or in the evening at approximately the same time each day [see Clinical Pharmacology (12.3)]. Swallow capsules whole with fluid. Do not divide, crush, chew, or place in water.

The capsule may also be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets (spheroids).

2.2 Major Depressive Disorder

For most patients, the recommended starting dose for Effexor XR is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 4 days. In the clinical studies establishing efficacy, upward titration was permitted at intervals of 2 weeks or more.

2.3 Generalized Anxiety Disorder

For most patients, the recommended starting dose for Effexor XR is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to 75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 4 days.

2.4 Social Anxiety Disorder (Social Phobia)

The recommended dose is 75 mg per day, administered in a single dose. There was no evidence that higher doses confer any additional benefit.

2.5 Panic Disorder

The recommended starting dose is 37.5 mg per day of Effexor XR for 7 days. Patients not responding to 75 mg per day may benefit from dose increases to a maximum of approximately 225 mg per day. Dose increases should be in increments of up to 75 mg per day, as needed, and should be made at intervals of not less than 7 days.

2.6 Screen for Bipolar Disorder Prior to Starting Effexor XR

Prior to initiating treatment with Effexor XR, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6) ].

2.7 Switching Patients from Effexor Tablets

Patients with depression who are currently being treated with Effexor may be switched to Effexor XR at the nearest equivalent dose (mg per day), e.g., 37.5 mg venlafaxine twice a day to 75 mg Effexor XR once daily. However, individual dosage adjustments may be necessary.

2.8 Dosage Recommendations for Patients with Hepatic Impairment

Reduce the Effexor XR total daily dose by 50% in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. Reduce the total daily dose by 50% or more in patients with severe hepatic impairment (Child-Pugh Class C) or hepatic cirrhosis [see Use in Specific Populations (8.6) ] .

2.9 Dosage Recommendations for Patients with Renal Impairment

Reduce the Effexor XR total daily dose by 25% to 50% in patients with mild (CLcr 60–89 mL/min) or moderate (CLcr 30–59 mL/min) renal impairment. Reduce the total daily dose by 50% or more in patients undergoing hemodialysis or with severe renal impairment (CLcr <30 mL/min). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage is recommended in some patients [see Use in Specific Populations (8.7) ] .

2.10 Discontinuing Treatment with Effexor XR

A gradual reduction in the dose, rather than abrupt cessation, is recommended when discontinuing therapy with Effexor XR. In clinical studies with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at one-week intervals. Individualization of tapering may be necessary. In some patients, discontinuation may need to occur over a period of several months [see Warnings and Precautions (5.7) ] .

2.11 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days must elapse between discontinuation of an MAOI antidepressant and initiation of Effexor XR. In addition, at least 7 days must elapse after stopping Effexor XR before starting an MAOI antidepressant [see Contraindications (4) , Warnings and Precautions (5.2) , and Drug Interactions (7.1) ] .

3 Dosage Forms And Strengths

Effexor XR^® is available in the following strengths:

• •37.5 mg extended-release capsule: grey cap and peach body with "W" and "Effexor XR" on the cap and "37.5" on the body
• •75 mg extended-release capsule: peach cap and body with "W" and "Effexor XR" on the cap and "75" on the body
• •150 mg extended-release capsule: dark orange cap and body with "W" and "Effexor XR" on the cap and "150" on the body

• •Ÿ Extended-release capsules: 37.5 mg, 75 mg, and 150 mg ( 3 ).

4 Contraindications

Effexor XR is contraindicated in patients:

• •with known hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation [see Adverse Reactions (6.2)].
• •taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of the risk of serotonin syndrome [see Dosage and Administration (2.11), Warnings and Precautions (5.2), and Drug Interactions (7.1)].

• •ŸHypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in the Effexor XR formulation (4).
• • Concomitant use of monoaminoxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI ( 4 , 5.2 , 7.1 ).

5 Warnings And Precautions

• •Ÿ Serotonin Syndrome : Increased risk when co-administered with other serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also when taken alone. If it occurs, discontinue Effexor XR and initiate supportive treatment ( 4 , 5.2 , 7.1 ).
• •ŸElevated 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).
• •ŸDiscontinuation Syndrome: Taper dose and monitor for discontinuation symptoms (5.7).
• • Ÿ Seizures: Can occur. Use cautiously in patients with seizure disorder (5.8).
• •ŸHyponatremia: Can occur in association with SIADH (5.9).
• • Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur (5.12).
• • Sexual Dysfunction: Effexor XR 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 PediatricEffexor XR is not approved in pediatric patients. 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

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 Effexor XR, 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 Effexor XR, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7.1) ] . Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of Effexor XR with MAOIs is contraindicated. In addition, do not initiate Effexor XR 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 Effexor XR, discontinue Effexor XR before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7.1) ] .

Monitor all patients taking Effexor XR for the emergence of serotonin syndrome. Discontinue treatment with Effexor XR and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Effexor XR with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Elevated Blood Pressure

In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension [see Adverse Reactions (6.1)].

Monitor blood pressure before initiating treatment with Effexor XR and regularly during treatment. Control pre-existing hypertension before initiating treatment with Effexor XR. 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 Effexor XR. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure.

Across all clinical studies with Effexor, 1.4% of patients in the Effexor XR 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 Effexor XR treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups [see Adverse Reactions (6.1)]. Treatment with Effexor XR was associated with sustained hypertension defined as SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits [see Adverse Reactions (6.1)]. An insufficient number of patients received mean doses of Effexor XR 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 Effexor XR, 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.

Inform patients about the risk of bleeding associated with the concomitant use of Effexor XR 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 Effexor XR.

5.5 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including Effexor XR 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 Effexor XR, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with Effexor XR or another antidepressant may precipitate a mixed/manic episode. Mania or hypomania was reported in Effexor XR treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2 ). Prior to initiating treatment with Effexor XR, screen for any personal or family history of bipolar disorder, mania, or hypomania.

Table 2: Incidence (%) of Mania or Hypomania Reported in Effexor XR Treated Patients in the Premarketing Studies

Indication	Effexor XR	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 Effexor XR 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 Effexor XR.

During marketing of Effexor XR, 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 Effexor XR. 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 (2.10)].

5.8 Seizures

Cases of seizure have been reported with venlafaxine therapy. Effexor XR has not been systematically evaluated in patients with seizure disorder. Effexor XR 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 Effexor XR. 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 [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Consider discontinuation of Effexor XR 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 PatientsEffexor XR is not approved for use in pediatric patients. in Double-blind, Placebo-controlled Studies of Effexor XR

Indication   (Duration)	Effexor XR	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 PatientsEffexor XR is not approved for use in pediatric patients. Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Effexor XR

Indication   (Duration)	Effexor XR	Placebo
MDD and GAD   (4 pooled studies, 8 weeks)	18p <0.001 versus placebo(n = 333)	3.6 (n = 333)
SAD  (16 weeks)	47(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 Effexor XR use were assessed in an open-label MDD study of children and adolescents who received Effexor XR 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).

Effexor XR is 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 PatientsEffexor XR is not approved for use in pediatric patients. in Placebo-controlled Studies of Effexor XR

Indication   (Duration)	Effexor XR	Placebo
MDD   (8 weeks)	0.8 (n = 146)	0.7 (n = 147)
GAD   (8 weeks)	0.3p = 0.041 (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 (<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 Effexor XR treated patients versus placebo-treated patients in the premarketing evaluation of Effexor XR for MDD, GAD, and SAD (see Table 6).

Effexor XR is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

Table 6: Incidence (%) of Decreased Appetite and Associated Discontinuation RatesThe discontinuation rates for weight loss were 0.7% for patients receiving either Effexor XR or placebo. (%) in Pediatric PatientsEffexor XR is not approved for use in pediatric patients. in Placebo-controlled Studies of Effexor XR

Indication   (Duration)	Effexor XR Incidence	Discontinuation	Placebo 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 Effexor XR-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of Effexor XR should be considered.

5.13Sexual Dysfunction

Use of SNRIs, including Effexor XR, 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 Effexor XR 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 more detail in other sections of the labeling:

• •Hypersensitivity [see Contraindications (4)]
• •Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1)]
• •Serotonin Syndrome [see Warnings and Precautions (5.2)]
• •Elevated Blood Pressure [see Warnings and Precautions (5.3)]
• •Increased Risk of 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, impotence (men), and libido decreased (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

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

Most Common Adverse Reactions

The most commonly observed adverse reactions in the clinical study database in Effexor XR 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 Effexor XR (37.5–225 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 Effexor XR 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	Effexor XR 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 Effexor XR 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 (Effexor only) and outpatient studies, fixed-dose, and titration studies.

Table 8: Patients Receiving Effexor XR in Premarketing Clinical Studies

Indication	Effexor XR
MDD	705In addition, in the premarketing assessment of Effexor, multiple doses were administered to 2,897 patients in studies for MDD.
GAD	1,381
SAD	819
PD	1,314

The incidences of common adverse reactions (those that occurred in ≥2% of Effexor XR treated patients [357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and more frequently than placebo) in Effexor XR treated patients in short-term, placebo-controlled, fixed- and flexible-dose clinical studies (doses 37.5 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 Adverse Reaction	Effexor XR n = 3,558	Placebo 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)Percentages based on the number of men (Effexor XR, n = 1,440; placebo, n = 923)	9.9	0.5
  Anorgasmia (men)	3.6	0.1
  Anorgasmia (women)Percentages based on the number of women (Effexor XR, n = 2,118; placebo, n = 1,274)	2.0	0.2
  Impotence (men)	5.3	1.0

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)

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 Effexor XRs. Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the Effexor XR 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 Effexor XR 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

	Effexor XR				Placebo
Indication	≤75 mg per day		>75 mg per day
  (Duration)	SSBP	SDBP	SSBP	SDBP	SSBP	SDBP
MDD
  (8–12 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
  (10–12 weeks)	-1.15	0.97	-0.36	0.16	-1.29	-0.99

Effexor XR treatment was associated with sustained hypertension (defined as 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 Effexor XR 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 Effexor XR Premarketing Studies

Indication	Dose Range (mg per day)	Incidence (%)
MDD	75–375Maximum recommended dosage for Effexor XR is 225 mg once daily.	19/705 (3)
GAD	37.5–225	5/1011 (0.5)
SAD	75–225	5/771 (0.6)
PD	75–225	9/973 (0.9)

Effexor XR was 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 Effexor XR Premarketing Placebo-controlled Studies (up to 12 Weeks Duration)

Indication   (Duration)	Effexor XR	Placebo
MDD  (12 weeks)	2	1
GAD  (8 weeks)	2	< 1
SAD  (12 weeks)	3	1
PD  (12 weeks)	1	< 1

Laboratory Changes

Serum Cholesterol

Effexor XR was 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 Effexor XR Premarketing Studies

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

Effexor XR (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. Effexor XR 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. Effexor XR 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 and 4.2 mg/dL, respectively, for placebo. Effexor XR 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 Effexor (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

Effexor XR was 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 Effexor XR Premarketing Studies

Indication   (Duration)	Effexor XR	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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Effexor XR. 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)]