1.1 Major Depressive Disorder

Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of major depressive disorder (MDD). Efficacy was established in three short-term

(4, 8, and 12 weeks) and two long-term, maintenance trials.

1.2 Generalized Anxiety Disorder

Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of Generalized Anxiety Disorder (GAD). Efficacy was established in two 8-week and

two 26-week placebo-controlled trials.

1.3 Social Anxiety Disorder

Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of Social Anxiety Disorder (SAD), also known as social phobia. Efficacy was

established in four 12-week and one 26- week, placebo-controlled trials.

1.4 Panic Disorder

Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of Panic Disorder (PD), with or without agoraphobia. Efficacy was established in

two 12-week placebo-controlled trials.

2.1 Major Depressive Disorder

For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release capsules 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, since steady-state plasma levels of venlafaxine and its major metabolites are

achieved in most patients by day 4 [see Clinical Pharmacology (12.3)]. In the clinical studies establishing efficacy, upward titration was permitted at intervals of 2

weeks or more.

It should be noted that, while the maximum recommended dose for moderately depressed outpatients is also 225 mg per day for venlafaxine tablets

(immediate-release), more severely depressed inpatients in one study of the development program for that product responded to a mean dose of 350 mg per day

(range of 150 to 375 mg per day). Whether or not higher doses of venlafaxine hydrochloride extended- release capsules are needed for more severely depressed

patients is unknown; however, the experience with venlafaxine hydrochloride extended-release capsules doses higher than 225 mg per day is very limited.

2.2 Generalized Anxiety Disorder

For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release capsules 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, since steady-state plasma levels of venlafaxine and its major metabolites are

achieved in most patients by day 4 [see Clinical Pharmacology (12.3)].

2.3 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.

2.4 Panic Disorder

The recommended starting dose is 37.5 mg per day of venlafaxine hydrochloride extended-release capsules 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.

2.5 Switching Patients from Venlafaxine Tablets

Depressed patients who are currently being treated at a therapeutic dose with venlafaxine tablets (immediate release) may be switched to venlafaxine hydrochloride

extended-release capsules at the nearest equivalent dose (mg per day), e.g., 37.5 mg venlafaxine twice a day to 75 mg venlafaxine hydrochloride extended-release

capsules once daily. However, individual dosage adjustments may be necessary.

2.6 Specific Populations

Patients with Hepatic Impairment

The total daily dose should be reduced by 50% in patients with mild (Child-Pugh = 5 to 6) to moderate (Child-Pugh = 7 to 9) hepatic impairment. In patients with

severe hepatic impairment (Child-Pugh = 10 to 15) or hepatic cirrhosis, it may be necessary to reduce the dose by 50% or more [see Use in Specific Populations (8.7)].

Patients with Renal Impairment

The total daily dose should be reduced by 25% to 50% in patients with mild (CLcr = 60 to 89 mL/min) or moderate (CLcr = 30 to 59 mL/min) renal impairment. In

patients undergoing hemodialysis or with severe renal impairment (CLcr < 30 mL/min), the total daily dose should be reduced by 50% or more. Because there was

much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients [see Use in Specific

Populations (8.7)].

2.7 Maintenance Treatment

There is no body of evidence available from controlled studies to indicate how long patients with MDD, GAD, SAD, or PD should be treated with venlafaxine

hydrochloride extended-release capsules.

It is generally agreed that acute episodes of MDD require several months or longer of sustained pharmacological therapy beyond response to the acute episode.

Venlafaxine hydrochloride extended- release capsules/venlafaxine tablets have demonstrated continuation of response in clinical studies up to 52 weeks, at the same

dose at which patients responded during the initial treatment [see Clinical Studies (14.1)]. It is not known whether or not the dose of venlafaxine hydrochloride

extended-release capsules needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to

determine the need for maintenance treatment and the appropriate dose for such treatment.

In patients with GAD and SAD, venlafaxine hydrochloride extended-release capsules have been shown to be effective in 6-month clinical studies. The need for continuing

medication in patients with GAD and SAD who improve with venlafaxine hydrochloride extended-release capsule treatment should be periodically reassessed.

In a clinical study for PD, patients continuing venlafaxine hydrochloride extended-release capsules at the same dose at which they responded during the initial 12

weeks of treatment experienced a statistically significantly longer time to relapse than patients randomized to placebo [see Clinical Studies (14.4)]. The need for

continuing medication in patients with PD who improve with venlafaxine hydrochloride extended-release capsule treatment should be periodically reassessed.

2.8 Discontinuing Venlafaxine Hydrochloride Extended-release Capsules

A gradual reduction in the dose, rather than abrupt cessation, is recommended whenever possible. In clinical studies with venlafaxine hydrochloride extended-release

capsules, tapering was achieved by reducing the daily dose by 75 mg at one-week intervals. Individualization of tapering may be necessary [see Warnings and

Precautions (5.7)].

2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI (intended to treat psychiatric disorders) and initiation of therapy with venlafaxine hydrochloride

extended-release capsules. In addition, at least 7 days should be allowed after stopping venlafaxine hydrochloride extended-release capsules before starting an MAOI

intended to treat psychiatric disorders [see Contraindications (4.2), Warnings and Precautions (5.2), and Drug Interactions (7.2)].

Use of Venlafaxine Hydrochloride Extended-release Capsules with other MAOIs such as Linezolid or Intravenous Methylene Blue

Do not start venlafaxine hydrochloride extended-release capsules in a patient who is being treated with linezolid or intravenous methylene blue, because there is an

increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization should

be considered [see Contraindications (4.2)].

In some cases, a patient already receiving venlafaxine hydrochloride extended-release capsule therapy may require urgent treatment with linezolid or intravenous

methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue are not available and the potential benefits of linezolid or intravenous methylene

blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, venlafaxine hydrochloride extended-release capsules should be stopped

promptly, and linezolid or intravenous methylene blue can be administered. Monitor the patient for symptoms of serotonin syndrome for 7 days or until 24 hours after

the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with venlafaxine hydrochloride extended-release capsules can be resumed 24

hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg

concomitantly with venlafaxine hydrochloride extended-release capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent

symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].

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 [see

Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)].

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 [see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions

(7.3)].

7.1 Central Nervous System (CNS)-Active Drugs

The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when venlafaxine

hydrochloride extended-release capsules are taken in combination with other CNS-active drugs.

7.2 Monoamine Oxidase Inhibitors

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from an MAOI and started on antidepressants with

pharmacological properties similar to venlafaxine hydrochloride extended-release capsules (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy

discontinued prior to initiation of an MAOI [see Dosage and Administration (2.9), Contraindications (4.2), and Warnings and Precautions (5.2)].

7.3 Serotonergic Drugs

Based on the mechanism of action of venlafaxine hydrochloride extended-release capsules and the potential for serotonin syndrome, caution is advised when

venlafaxine hydrochloride extended-release capsules are coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans,

SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s wort. If concomitant treatment with venlafaxine

hydrochloride extended-release capsules and these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation

and dose increases. The concomitant use of venlafaxine hydrochloride extended-release capsules with tryptophan supplements is not recommended [see Dosage and

Administration (2.9), Contraindications (4.2), and Warnings and Precautions (5.2)].

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. The use of psychotropic drugs that interfere with serotonin reuptake is associated with the

occurrence of upper gastrointestinal bleeding and concurrent use of an NSAID or aspirin may potentiate this risk of bleeding [see Warnings and Precautions (5.4)].

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 extended-release capsules are initiated or discontinued.

7.5 Weight Loss Agents

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration of

venlafaxine hydrochloride extended-release capsules and weight loss agents is not recommended. Venlafaxine hydrochloride extended-release capsules are not

indicated for weight loss alone or in combination with other products.

7.6 Effects of Other Drugs on Venlafaxine Hydrochloride Extended-release Capsules

Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; Cmax, peak plasma concentrations; EM’s, extensive metabolizers; PM’s, poor metabolizers

* No dose adjustment on coadministration with CYP2D6 inhibitors (Fig 3 and Metabolism Section 12.3)

7.7 Effects of Venlafaxine Hydrochloride Extended-release Capsules on Other Drugs

Abbreviations: AUC, area under the curve; Cmax, peak plasma concentrations; OH, hydroxyl

* Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for Cmax and AUC of 2-OH desipramine were 6.6 (5.5, 7.9) and 4.4 (3.8,

5.0), respectively.

Note:

*: 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.

7.8 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.

5.1 Suicidal 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.

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 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

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder

1.2 Generalized Anxiety Disorder

1.3 Social Anxiety Disorder

1.4 Panic Disorder

2 DOSAGE AND ADMINISTRATION

2.1 Major Depressive Disorder

2.2 Generalized Anxiety Disorder

2.3 Social Anxiety Disorder (Social Phobia)

2.4 Panic Disorder

2.5 Switching Patients from Venlafaxine Tablets

2.6 Specific Populations

2.7 Maintenance Treatment

2.8 Discontinuing Venlafaxine Hydrochloride Extended-release Capsules

2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs)

5 WARNINGS AND PRECAUTIONS

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

5.2 Serotonin Syndrome

5.3 Elevations in Blood Pressure

5.4 Abnormal Bleeding

5.5 Angle-Closure Glaucoma

5.6 Activation of Mania/Hypomania

5.7 Discontinuation Syndrome

5.8 Seizures

5.9 Hyponatremia

5.10 Weight and Height Changes in Pediatric Patients

5.11 Appetite Changes in Pediatric Patients

5.12 Interstitial Lung Disease and Eosinophilic Pneumonia

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Vital Sign Changes

6.3 Laboratory Changes

6.4 Pediatric Patients

6.5 Adverse Reactions Identified During Postapproval Use

7 DRUG INTERACTIONS

7.1 Central Nervous System (CNS)-Active Drugs

7.2 Monoamine Oxidase Inhibitors

7.3 Serotonergic Drugs

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

7.5 Weight Loss Agents

7.6 Effects of Other Drugs on Venlafaxine Hydrochloride Extended-release Capsules

7.7 Effects of Venlafaxine Hydrochloride Extended-release Capsules on Other Drugs

7.8 Drug-Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Age and Gender

8.7 Use in Patient Subgroups

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

10.1 Human Experience

10.2 Management of Overdosage

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

14.2 Generalized Anxiety Disorder

14.3 Social Anxiety Disorder (also known as Social Phobia)

14.4 Panic Disorder

14.5 Pediatric Patients

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

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 of Mania / 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.

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.

During marketing of venlafaxine hydrochloride extended-release capsules, other SNRIs, and SSRIs, there have been spontaneous reports of adverse events occurring

upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g.,

paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these

events are generally self-limiting, there have been reports of serious discontinuation symptoms.

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 whenever possible. 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 physician may continue decreasing the dose, but at a more gradual rate

[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 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.

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.

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).

5.11 Appetite 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).

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.

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 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.

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.

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 to 225 mg per day) are shown in Table 9.

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

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.

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.

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)].

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).

Venlafaxine hydrochloride extended-release capsule 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 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).

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)]

To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or

www.fda.gov/medwatch.

8.1 Pregnancy

Teratogenic Effects – Pregnancy Category C

Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily

dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of

lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the

maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. In reproductive developmental studies in rats

and rabbits with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, evidence of teratogenicity was not observed at exposure margins of 13 in

rats and 0.3 in rabbits. There are no adequate and well-controlled studies in pregnant women. Venlafaxine hydrochloride extended-release capsules should be used

during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because animal reproduction studies are not always predictive of human response,

this drug should be used during pregnancy only if clearly needed.

Non-teratogenic Effects

Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring

prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included

respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor,

jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs, or possibly a drug discontinuation

syndrome. It should be noted, that in some cases the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions

(7.3)]. When treating a pregnant woman with venlafaxine hydrochloride extended-release capsules during the third trimester, the physician should carefully consider

the potential risks and benefits of treatment.

8.2 Labor and Delivery

The effect of venlafaxine on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from venlafaxine

hydrochloride extended-release capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of

the drug to the mother.

8.4 Pediatric Use

Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with

venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support a claim for use in pediatric patients.

Anyone considering the use of venlafaxine hydrochloride extended-release capsules in a child or adolescent must balance the potential risks with the clinical need [see

Boxed Warning, Warnings and Precautions (5.1, 5.10, 5.11) and Adverse Reactions (6.4)].

Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-release capsules’s impact on the growth, development, and maturation

of children and adolescents, the studies that have been done suggest that venlafaxine hydrochloride extended-release capsules may adversely affect weight and height

[see Warnings and Precautions (5.10)]. Should the decision be made to treat a pediatric patient with venlafaxine hydrochloride extended-release capsules, regular

monitoring of weight and height is recommended during treatment, particularly if treatment is to be continued long-term [see Warnings and Precautions (5.10, 5.11)].

The safety of venlafaxine hydrochloride extended-release capsule treatment for pediatric patients has not been systematically assessed for chronic treatment longer

than six months in duration. In the studies conducted in pediatric patients (ages 6 to 17), the occurrence of blood pressure and cholesterol increases considered to be

clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients [see Warnings

and Precautions (5.3, 6.3)].

8.5 Geriatric Use

The percentage of patients in clinical studies for venlafaxine hydrochloride extended-release capsules for MDD, GAD, SAD, and PD who were 65 years of age or older

are shown in Table 15.

* In addition, in the premarketing assessment of venlafaxine tablets (immediate release), 12% (357/2,897) of patients were   65 years of age.

No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not

identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and

SNRIs, including venlafaxine hydrochloride extended-release capsules, have been associated with cases of clinically significant hyponatremia in elderly patients, who

may be at greater risk for this adverse event [see Warnings and Precautions (5.9)].

The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly [see Clinical Pharmacology (12.3)] (see Figure 3). No dose adjustment is

recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or

hepatic impairment, may warrant a dose reduction [see Dosage and Administration (2.6)].

8.6 Age and Gender

A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both twice daily and three times daily regimens showed that

dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a

patient is generally not necessary [see Dosage and Administration (2.6)] (see Table 15).

8.7 Use in Patient Subgroups

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; Cmax, peak plasma concentrations;

* Similar effect is expected with strong CYP2D6 inhibitors

9.1 Controlled Substance

Venlafaxine hydrochloride extended-release capsules are not a controlled substance.

9.2 Abuse

While venlafaxine has not been systematically studied in clinical studies for its potential for abuse, there was no indication of drug-seeking behavior in the clinical

studies. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS-active drug will be misused, diverted, and/or abused

once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of

misuse or abuse of venlafaxine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

9.3 Dependence

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.

Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant

or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine [see Dosage and Administration (2.8)].

Human Experience

During the premarketing evaluations of venlafaxine hydrochloride extended-release capsules (for MDD, GAD, SAD, and PD) and venlafaxine tablets (for MDD), there

were twenty reports of acute overdosage with venlafaxine tablets (6 and 14 reports in venlafaxine hydrochloride extended-release capsules and venlafaxine tablet

patients, respectively), either alone or in combination with other drugs and/or alcohol.

Somnolence was the most commonly reported symptom. Among the other reported symptoms were paresthesia of all four limbs, moderate dizziness, nausea, numb

hands and feet, and hot-cold spells 5 days after the overdose. In most cases, no signs or symptoms were associated with overdose. The majority of the reports involved

ingestion in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. One patient who ingested

2.75 g of venlafaxine was observed to have two generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus

tachycardia was reported in two of the other patients.

Actions taken to treat the overdose included no treatment, hospitalization and symptomatic treatment, and hospitalization plus treatment with activated charcoal. All

patients recovered.

In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported

events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram

changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver

necrosis, serotonin syndrome, and death have been reported.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI

antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher

preexisting burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the

toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. 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.

Management of Overdosage

Consult a Certified Poison Control Center for up-to-date guidance and advice (1-800-222-1222 or www.poison.org). In case of an overdose, provide supportive care,

including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug.

Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Provide supportive

and symptomatic measures.

12.1 Mechanism of Action

The exact mechanism of the antidepressant action of venlafaxine in humans is unknown, but is thought to be related to the potentiation of serotonin and

norepinephrine in the central nervous system, through inhibition of their reuptake. Non- clinical studies have demonstrated that venlafaxine and its active metabolite,

ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

12.2 Pharmacodynamics

Venlafaxine and ODV have no significant affinity for muscarinic-cholinergic, H1-histaminergic, or  1 adrenergic receptors in vitro. Pharmacologic activity at these

receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV

do not possess monoamine oxidase (MAO) inhibitory activity.

Cardiac Electrophysiology

The effect of venlafaxine on the QT interval was evaluated in a randomized, double-blind, placebo-and positive-controlled three-period crossover thorough QT study in

54 healthy adult subjects. No significant QT prolongation effect of venlafaxine 450 mg was detected.

12.3 Pharmacokinetics

Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics

over the dose range of 75 to 450 mg per day. Mean   SD steady-state plasma clearance of venlafaxine and ODV is 1.3   0.6 and 0.4   0.2 L/h/kg, respectively;

apparent elimination half-life is 5   2 and 11   2 hours, respectively; and apparent (steady state) volume of distribution is 7.5   3.7 and 5.7   1.8 L/kg, respectively.

Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively).

Absorption and Distribution

Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the major active metabolite. On the basis of mass balance studies, at least 92% of a single

oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is approximately 45%.

Administration of venlafaxine hydrochloride extended-release capsules (150 mg once daily) generally resulted in lower Cmax and later Tmax values than for venlafaxine

tablets (immediate release) administered twice daily (Table 16). When equal daily doses of venlafaxine were administered as either an immediate-release tablet or the

extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower

with the venlafaxine hydrochloride extended-release capsule. Therefore, venlafaxine hydrochloride extended-release capsules provide a slower rate of absorption, but

the same extent of absorption compared with the immediate-release tablet.

Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM versus PM) did not affect the pharmacokinetics of

venlafaxine and ODV from the 75 mg venlafaxine hydrochloride extended-release capsule.

Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine hydrochloride extended-release capsules to a patient taking another drug

that is highly protein-bound should not cause increased free concentrations of the other drug.

Metabolism and Elimination

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine,

N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a

clinical study showing that patients with low CYP2D6 levels (poor metabolizers) had increased levels of venlafaxine and reduced levels of ODV compared to people with

normal CYP2D6 levels (extensive metabolizers) [see Use in Specific Populations (8.7)].

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%),

or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.

14.1 Major Depressive Disorder

The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Major Depressive Disorder (MDD) was established in two placebo-controlled, short-term

(8 weeks for study 1; 12 weeks for study 2), flexible-dose studies, with doses starting at 75 mg per day and ranging to 225 mg per day in adult outpatients meeting

DSM-III-R or DSM-IV criteria for MDD. In moderately depressed outpatients, the initial dose of venlafaxine was 75 mg per day. In both studies, venlafaxine hydrochloride

extended-release capsules demonstrated superiority over placebo on the primary efficacy measure defined as change from baseline in the HAM-D-21 total score to the

endpoint visit, venlafaxine hydrochloride extended-release capsules also demonstrated superiority over placebo on the key secondary efficacy endpoint, the Clinical Global

Impressions (CGI) Severity of Illness scale. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizing venlafaxine tablets in a range of 150 to 375 mg per day (divided in a

three-times-a-day schedule) demonstrated superiority of venlafaxine hydrochloride tablets over placebo based on the HAM-D-21 total score. The mean dose in

completers was 350 mg per day (study 3).

In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label study on venlafaxine hydrochloride extended-release capsules (75,

150, or 225 mg, once daily every morning) were randomized to continuation of their same venlafaxine hydrochloride extended-release capsule dose or to placebo, for

up to 26 weeks of observation for relapse. Response during the open-label phase was defined as a CGI Severity of Illness item score of   3 and a HAM-D-21 total score

of   10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV

criteria and a CGI Severity of Illness item score of   4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of   4, or (3) a final CGI Severity of Illness

item score of   4 for any patient who withdrew from the study for any reason. Patients receiving continued venlafaxine hydrochloride extended-release capsule

treatment experienced statistically significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo (study 4).

In a second longer term trial, adult outpatients with MDD, recurrent type, who had responded (HAM-D-21 total score   12 at the day 56 evaluation) and continued to

be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score   20; (2) no more than 2 HAM-D-21 total scores > 10,

and (3) no single CGI Severity of Illness item score   4 (moderately ill)] during an initial 26 weeks of treatment on venlafaxine tablets [100 to 200 mg per day, on a

twice daily schedule] were randomized to continuation of their same venlafaxine tablet dose or to placebo. The follow-up period to observe patients for relapse, defined

as a CGI Severity of Illness item score   4, was for up to 52 weeks. Patients receiving continued venlafaxine tablet treatment experienced statistically significantly

lower relapse rates over the subsequent 52 weeks compared with those receiving placebo (study 5).

14.2 Generalized Anxiety Disorder

The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week,

placebo-controlled, fixed-dose studies (75 to 225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one 6-month,

placebo-controlled, fixed-dose study (37.5, 75, and 150 mg per day) in adult outpatients meeting DSM-IV criteria for GAD.

In one 8-week study, venlafaxine hydrochloride extended-release capsules demonstrated superiority over placebo for the 75, 150, and 225 mg per day doses as

measured by the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale.

However, the 75 and 150 mg per day doses were not as consistently effective as the highest dose (study 1). A second 8-week study evaluating doses of 75 and 150 mg

per day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg per day dose was more

consistently effective than the 150 mg per day dose (study 2). A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg

per day dose range studied.

Two 6-month studies, one evaluating venlafaxine hydrochloride extended-release capsule doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluating

venlafaxine hydrochloride extended-release capsules doses of 75 to 225 mg per day (study 4), showed that daily doses of 75 mg or higher were more effective than

placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority

over placebo for the 37.5 mg per day dose, this dose was not as consistently effective as the higher doses.

Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

14.3 Social Anxiety Disorder (also known as Social Phobia)

The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Social Anxiety Disorder (SAD) was established in four double-blind,

parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies (studies 1 to 4) and one double-blind, parallel-group, 6-month, placebo-controlled,

fixed/flexible-dose study, which included doses in a range of 75 to 225 mg per day in adult outpatients meeting DSM-IV criteria for SAD (study 5).

In these five studies, venlafaxine hydrochloride extended-release capsules were statistically significantly more effective than placebo on change from baseline to

endpoint on the Liebowitz Social Anxiety Scale (LSAS) total score. There was no evidence for any greater effectiveness of the 150 to 225 mg per day group compared to

the 75 mg per day group in the 6-month study.

Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine

the effect of age or race on outcome in these studies.

14.4 Panic Disorder

The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Panic Disorder (PD) was established in two double-blind, 12-week, multicenter,

placebo-controlled studies in adult outpatients meeting DSM-IV criteria for PD, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg per day in

one study (study 1) and 75 or 225 mg per day in the other study (study 2).

Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety

Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders

(much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two studies, venlafaxine hydrochloride extended-release

capsules were statistically significantly more effective than placebo (for each fixed dose) on all three endpoints, but a dose-response relationship was not clearly

established.

Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine

the effect of age or race on outcome in these studies.

In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD who had responded during a 12-week open phase with venlafaxine hydrochloride

extended-release capsules (75 to 225 mg per day) were randomly assigned to continue the same venlafaxine hydrochloride extended-release capsules dose (75, 150,

or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as   1 full-symptom panic

attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the

double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as

determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the

randomized phase following the 12 week open-label period, patients receiving continued venlafaxine hydrochloride extended-release capsules experienced a

statistically significantly longer time to relapse.

14.5 Pediatric Patients

Two placebo-controlled studies in 766 pediatric patients with MDD and two placebo-controlled studies in 793 pediatric patients with GAD have been conducted with

venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support a claim for use in pediatric patients.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Tumors were not increased by venlafaxine treatment in mice or rats. Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day,

which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to

120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the

plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite (ODV) were lower in rats than in

patients receiving the maximum recommended dose.

O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, administered by oral gavage to mice and rats for 2 years did not increase the incidence of

tumors in either study. Mice received ODV at dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The exposure at the 300 mg/kg/day

dose is 9 times that of a human dose of 225 mg/day. Rats received ODV at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The exposure at the

highest dose is approximately 8 (males) or 11 (females) times that of a human dose of 225 mg/day.

Mutagenesis

Venlafaxine and the major human metabolite, ODV, were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster

ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation

assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not

clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay or in the in vivo chromosomal aberration assay in rats.

Impairment of Fertility

Reproduction and fertility studies of venlafaxine in rats showed no adverse effects of venlafaxine on male or female fertility at oral doses of up to 2 times the

maximum recommended human dose of 225 mg/day on a mg/m2 basis. However, reduced fertility was observed in a study in which male and female rats were

treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior to and during mating and gestation. This occurred at an ODV exposure

(AUC) approximately 2 to 3 times that associated with a human venlafaxine dose of 225 mg/day.