(Venlafaxine Hydrochloride) Extended Release Capsules (37.5, 75, 150 mg)

ANTIDEPRESSANT/ANXIOLYTIC

(c)WYETH CANADA MONTREAL, CANADA

Date of Revision: June 16, 2008 Submission Control No: 110459

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 18 DRUG INTERACTIONS 44 DOSAGE AND ADMINISTRATION 50 OVERDOSAGE 53 ACTION AND CLINICAL PHARMACOLOGY 55 STORAGE AND STABILITY 58 SPECIAL HANDLING INSTRUCTIONS 58 DOSAGE FORMS, COMPOSITION AND PACKAGING 59

PART II: SCIENTIFIC INFORMATION 60

PHARMACEUTICAL INFORMATION 60 CLINICAL TRIALS 61 DETAILED PHARMACOLOGY 64 TOXICOLOGY 64 REFERENCES 67

PART III: CONSUMER INFORMATION. 70

EFFEXOR XR

Venlafaxine Hydrochloride Extended Release Capsules PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Hypersensitivity:

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.

Monoamine Oxidase Inhibitors (MAOIs)

:

EFFEXOR XR should not be used in combination with MAOIs or within two weeks of terminating treatment with MAOIs. Treatment with MAOIs should not be started until 2 weeks after discontinuation of EFFEXOR XR therapy. Adverse reactions, some serious, have been reported when EFFEXOR XR therapy is initiated soon after discontinuing an MAOI and when an MAOI is initiated soon after discontinuation of EFFEXOR XR. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hypothermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI.

WARNINGS AND PRECAUTIONS

POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.

Pediatrics: Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer anti-depressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among the drugs in the class.

Adults and Pediatrics: Additional data

There are clinical trial and post-marketing reports with SSRIs and other newer anti-depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation- type emotional and behavioural changes.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behaviour, worsening of depression, and suicidal ideation, especially when initiating therapy or during any change in dose or dosage regimen. The risk of suicide attempt must be considered, especially in depressed patients (see OVERDOSAGE).

Discontinuation Symptoms

Patients currently taking EFFEXOR XR should NOT be discontinued abruptly, due to risk of discontinuation symptoms (See WARNINGS and PRECAUTIONS, Discontinuation Symptoms). At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose, rather than an abrupt cessation, is recommended.

General

Allergic Reactions

Patients should be advised to notify their physician if they develop a rash, hives or a related allergic phenomenon.

Hypertension General

Dose-related increases in blood pressure have been reported in some patients treated with venlafaxine. Also, rare cases of hypertensive crisis and malignant hypertension have been reported in normotensive and treated-hypertensive patients in post-marketing experience (see Acute Severe Hypertension below). Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure.

Acute Severe Hypertension:

Cases of severe elevated blood pressure requiring immediate treatment have been reported in postmarketing experience, including reports of hypertensive crisis and malignant hypertension. The reports included normotensives and treated-hypertensive patients as well. Pre-existing hypertension should be controlled before treatment with venlafaxine. All patients should have their blood pressure evaluated before starting venlafaxine and monitored regularly during treatment. Patients should be told to consult their doctors if they have symptoms associated with acute severe hypertension, such as headache (particularly in the back of head/neck when waking up), stronger heart beat and possibly more rapid, palpitations, dizziness, easy fatigability, blurred vision, chest pain.

Sustained Hypertension: Venlafaxine treatment has been associated with sustained hypertension (see Table 1). Sustained increases in blood pressure could have adverse consequences. Therefore, it is recommended that patients have their blood pressure monitored before starting venlafaxine and then regularly during treatment. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered after a benefit-risk assessment is made.

Venlafaxine Immediate Release Tablets

Treatment with immediate release venlafaxine HCl tablets was associated with modest but sustained increases in blood pressure during premarketing studies. Sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) $ 90 mm Hg and $ 10 mm Hg above baseline for 3 consecutive visits, showed the following incidence and dose- relationship:

TABLE 1: PROBABILITY OF SUSTAINED ELEVATION IN SDBP

* Not evaluable

An analysis of the blood pressure increases in patients with sustained hypertension and in the 19 patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) showed that most of the blood pressure increases were in the range of 10 to 15 mm Hg, SDBP.

EFFEXOR XR Capsules

Depression: In placebo-controlled premarketing depression studies with EFFEXOR XR, a final on-therapy mean increase in supine diastolic pressure (SDBP) of < 1.2 mm Hg was observed for EFFEXOR XR-treated patients compared with a mean decrease of 0.2 mm Hg for placebo- treated patients. Less than 3% of EFFEXOR XR patients treated with doses of 75 to 300 mg/day had sustained elevations in blood pressure (defined as treatment-emergent SDBP $90 mm Hg and $10 mm Hg above baseline for 3 consecutive on-therapy visits). An insufficient number of patients received doses of EFFEXOR XR >300 mg/day to evaluate systematically sustained blood pressure increases. Less than 1% of EFFEXOR XR-treated patients in double- blind, placebo-controlled premarketing depression studies discontinued treatment because of elevated blood pressure compared with 0.4% of placebo-treated patients.

Generalized Anxiety Disorder (GAD):

In placebo-controlled premarketing anxiety studies with EFFEXOR XR 37.5-225 mg/day, a final on-drug mean increase in SDBP of 0.4 mm Hg was observed for EFFEXOR XR treated patients compared with a mean decrease of 0.8 mm Hg for placebo treated patients.

Social Anxiety Disorder (Social Phobia)

: In 4 placebo-controlled premarketing Social Anxiety Disorder studies with EFFEXOR XR 75-225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 0.9 mm Hg was observed for EFFEXOR XR-treated patients compared with

a mean decrease of 1.6 mm Hg for placebo-treated patients. In one placebo-controlled premarketing Social Anxiety Disorder study with EFFEXOR XR up to 6 months, a final on-drug mean decrease in SDBP of 0.2 mm Hg was observed for EFFEXOR XR-treated patients who received fixed doses of 75 mg/day and a mean increase of 1.5 mm Hg was observed for EFFEXOR XR-treated patients who received flexible doses of 150 to 225 mg/day, compared with a mean decrease of 0.6 mm Hg for placebo-treated patients. Among patients treated with 75-225 mg per day of EFFEXOR XR in all premarketing Social Anxiety Disorder studies, 0.6% (5/771) experienced sustained hypertension. In all premarketing Social Anxiety Disorder studies with patients treated with 75-225 mg per day, 0.6% (5/771) of the EFFEXOR XR-treated patients discontinued treatment because of elevated blood pressure.

Panic Disorder

: In placebo-controlled premarketing Panic Disorder studies with EFFEXOR XR 75-225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 0.3 mm Hg was observed for EFFEXOR XR-treated patients compared with a mean decrease of 1.1 mm Hg for placebo-treated patients.

Among patients treated with 75 to 225 mg/day of Effexor XR in premarketing Panic Disorder studies up to 12 weeks, 0.9% (9/973) experienced sustained hypertension. In premarketing Panic Disorder studies up to 12 weeks, 0.5% (5/1001) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure.

Serotonin Syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter systems (please see Serotonin Syndrome/Neuroleptic Malignant Syndrome, and DRUG INTERACTIONS, Serotonergic Drugs).

Discontinuation Symptoms

Discontinuation symptoms have been assessed both in patients with depression and those with anxiety. Abrupt discontinuation, dose reduction, or tapering 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. If venlafaxine is used until or shortly before birth, discontinuation effects in the newborn should be considered. Reported symptoms include aggression, agitation, anorexia, anxiety, asthenia, confusion, convulsions, coordination impaired, diarrhoea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headache, hypomania, insomnia, nausea, nightmares, nervousness, paresthesia, electric shock sensations, sensory disturbances (including shock like electrical sensations), sleep disturbances, somnolence, sweating, tinnitus, vertigo, and vomiting. Where such symptoms occurred they were usually self-limiting but in a few patients continued for several weeks. Discontinuation effects are well known to occur with antidepressants, and, therefore, it is recommended that the dosage be tapered gradually and the patient monitored. Time to event onset after dose reduction or discontinuation can vary in individual patients and range from the same day to several weeks. (See also ADVERSE REACTIONS, Discontinuation Symptoms; DOSAGE AND ADMINISTRATION, Discontinuing Venlafaxine.)

Venlafaxine Treatment during Pregnancy-Effects on Newborns

Post-marketing reports indicate that some neonates exposed to venlafaxine, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer anti-depressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. When treating a pregnant woman with EFFEXOR XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Woman; DOSAGE AND ADMINISTRATION, Special Patient Populations-Treatment of Pregnant Women During the Third Trimester.

Psychomotor Impairment

In healthy volunteers receiving an immediate release venlafaxine formulation at a stable regimen of 150 mg/day, some impairment of psychomotor performance was observed. Patients should be cautioned about operating hazardous machinery, including automobiles, or engaging in tasks requiring alertness until they have been able to assess the drug's effect on their own psychomotor performance.

The following additional precautions are listed alphabetically. Carcinogenesis and Mutagenesis

For animal data see TOXICOLOGY.

Cardiovascular

Hypertension

See WARNINGS AND PRECAUTIONS, General, Hypertension

Cardiac Disease

Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's clinical trials. Therefore it should be used with caution in these patients. Evaluation of the electrocardiograms for 769 patients who received venlafaxine immediate release tablets in 4- to 6-week double-blind trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The electrocardiograms for 357 patients who received EFFEXOR XR and 285 patients who received placebo in 8 to 12 week double-blind, placebo-controlled trials in depression were analyzed. The mean change from baseline in corrected QT interval (QTc) for EFFEXOR XR- treated patients in depression studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for EFFEXOR XR and decrease of 1.9 msec for placebo). The clinical significance of this change is unknown. Three of 705 EFFEXOR XR-treated patients in phase III studies experienced QTc prolongation to 500 msec during treatment. Baseline QTc was >450 msec for all 3 patients. Electrocardiograms are available for 815 patients who received EFFEXOR XR and 379 patients who received placebo in up to 6-month, double-blind, placebo-controlled trials in Generalized Anxiety Disorder. The mean change from baseline in the corrected QT interval (QTc) for EFFEXOR XR-treated patients in the GAD studies did not differ significantly from that with placebo. One of the 815 EFFEXOR XR-treated patients experienced QTc prolongation to 593 msec. Baseline QTc was 460 msec for this one patient. Electrocardiograms were evaluated for 401 patients who received EFFEXOR XR and 444 patients who received placebo in four 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline in QTc for EFFEXOR XR-treated patients in the 12-week Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 4.1 msec for EFFEXOR XR and decrease of 1.4 msec for placebo). Electrocardiograms were evaluated for 101 patients who received EFFEXOR XR 75 mg/day, 96 patients who received 150-225 mg/day, and 90 patients who received placebo in one 6-month double-blind, placebo-controlled trial in Social Anxiety Disorder. A mean decrease from baseline in QTc of 0.05 ms was observed for patients treated with EFFEXOR XR 75 mg/day, a mean increase from baseline in QTc of 3.4 ms was observed for patients treated with EFFEXOR XR 150-225 mg/day, and a mean increase from baseline in QTc of 0.5 ms was observed for patients treated with placebo in the 6-month Social Anxiety Disorder study. Electrocardiograms were evaluated for 661 patients who received EFFEXOR XR and 395 patients who received placebo in three 10- to 12-week double-blind, placebo-controlled trials in Panic Disorder. The mean change from baseline in QTc for EFFEXOR XR-treated patients in the Panic Disorder studies was increased relative to that for placebo-treated patients (increase of 1.5 msec for EFFEXOR XR and decrease of 0.7 msec for placebo). No case of sudden unexplained death or serious ventricular arrhythmia, which are possible clinical sequelae of QTc prolongation, was reported in EFFEXOR XR pre-marketing studies. The mean heart rate was increased by about 3-4 beats per minute during treatment with venlafaxine in clinical trials of depression and GAD. The mean change from baseline in heart rate for EFFEXOR XR-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for EFFEXOR XR and no change for placebo). The mean change from baseline in heart rate for EFFEXOR XR-treated patients in the Panic Disorder studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for EFFEXOR XR and a mean decrease of less than 1 beat per minute for placebo). Increases in heart rate can occur, particularly with higher doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.

Concomitant Illness

Clinical experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering venlafaxine to patients with diseases or conditions that could affect hemodynamic responses or metabolism (see also WARNINGS AND PRECAUTIONS, General, Hypertension. Patients should be questioned about any prescription or "over the counter drugs, herbal or natural products or dietary supplements" that they are taking, or planning to take, since there is a potential for interactions.

Dependence/Tolerance

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behaviour in the clinical trials. 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 behaviour).

Endocrine and Metabolism

Serum Cholesterol Elevation

Clinically relevant increases in total serum cholesterol were recorded in 5.3% of venlafaxine- treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo- controlled trials in Major Depressive Disorders. (See Monitoring Laboratory Changes, Serum

Cholesterol Elevation). Consistent with the above findings, elevations of High Density Lipoprotein Cholesterol (HDL), Low Density Lipoprotein Cholesterol (LDL) and the overall ratio of Total Cholesterol/HDL have been observed in placebo controlled clinical trials for Social Anxiety Disorder (SAD) and Panic Disorder. Measurement of serum cholesterol levels (including a complete lipid profile/fractionation and an assessment of the patient's individual risk factors) should be considered especially during long- term treatment.

Changes in Appetite and Weight

Treatment-emergent anorexia and weight loss were more commonly reported for venlafaxine- treated patients than for placebo-treated patients in depression and GAD, Social Anxiety Disorder and Panic Disorder trials. Significant weight loss, especially in underweight depressed/GAD patients, may be an undesirable result of treatment. Venlafaxine is not recommended for weight loss alone or in combination with other products such as phentermine or sibutramine. Based on the known mechanisms of action, the potential harm of co- administration includes the possibility of serotonin syndrome. (See DRUG INTERACTIONS,

Serotonergic Drugs.)

Gastrointestinal

Results of testing in healthy volunteers demonstrated differences in the gastrointestinal tolerability of different formulations of venlafaxine. Data from healthy volunteers showed reduced incidence and severity of nausea with EFFEXOR XR capsules, compared with immediate release tablets. In a 12-week study comparing immediate release tablets with EFFEXOR XR capsules, once daily, EFFEXOR XR was significantly more effective at weeks 8 and 12, compared with immediate release tablets given twice daily for treating major depression. Analysis of safety data from this trial showed that the incidence of treatment-emergent nausea and nausea severity over time were lower with EFFEXOR XR than with immediate release tablets. Additionally, the incidence of vomiting was lower with EFFEXOR XR than with immediate release tablets.

Genitourinary

Hyponatremia

As with some other antidepressants, several cases of hyponatremia have been reported with venlafaxine, usually in volume-depleted or dehydrated patients including those taking diuretics. The hyponatremia appeared to be reversible when venlafaxine was discontinued. The majority of these occurrences have been in the elderly individuals.

Inappropriate Antidiuretic Hormone Secretion

Rare events of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion have been reported, usually in volume-depleted or dehydrated patients including elderly patients and patients taking diuretics, treated with venlafaxine. Although the reported events occurred coincident with treatment with venlafaxine, the relationship to treatment is unknown.

Hematologic

Abnormal Bleeding

There have been reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences. Skin and other mucous membrane bleedings have been reported following treatment with venlafaxine. Venlafaxine should therefore be used with caution in patients concomitantly treated with drugs that give an increased risk for bleeding (e.g. anticoagulants, nonsteroidal anti- inflammatories and ASA) and in patients with a known tendency for bleeding or those with predisposing conditions.

Hepatic/Biliary/Pancreatic

Dosage adjustment is necessary in these patients Recommended Dose, Patients with Hepatic Impairment, Patients with Renal Impairment

In patients with hepatic impairment, the pharmacokinetic disposition of both venlafaxine and ODV are significantly altered.

(See

).

Immune

Venlafaxine and O-desmethylvenlafaxine produced only limited effects in immunological studies which were generally at doses greater than those required to produce antidepressant effects in animals.

Neurologic

Seizures

EFFEXOR XR should be used cautiously in patients with a history of seizures, and should be promptly discontinued in any patient who develops seizures. Seizures have also been reported as a discontinuation symptom (see also WARNINGS AND PRECAUTIONS, Discontinuation Symptoms; ADVERSE RECTIONS, Discontinuation Symptoms; DOSAGE AND ADMINISTRATION, Discontinuing Venlafaxine). During premarketing testing, seizures were reported in 8 out of 3,082 immediate release tablet- treated patients (0.3%). In 5 of the 8 cases with immediate release tablets, patients were receiving doses of 150 mg/day or less. During premarketing depression studies no seizures were seen in 705 EFFEXOR XR Capsule-treated patients. Premarketing, no seizures occurred among 1381 EFFEXOR XR-treated patients in Generalized Anxiety Disorder studies or among 277 EFFEXOR XR-treated patients in Social Anxiety Disorder Studies. In Panic Disorder studies, 1 seizure occurred among 1001 Effexor XR-treated patients (0.1%). However, patients with a history of convulsive disorders were excluded from most of these studies. EFFEXOR XR should be used cautiously in patients with a history of seizures, and should be promptly discontinued in any patient who develops seizures.

Serotonin Syndrome/Neuroleptic Malignant Syndrome

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment with SSRIs, including venlafaxine, particularly when given in combination with other serotonergic and/or neuroleptic/antipsychotic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with venlafaxine should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma and supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome venlafaxine should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (triptans, lithium, tramadol, St. John's Wort, most tricyclic antidepressants) or neuroleptics/antipsychotics (see CONTRAINDICATIONS and DRUG INTERACTIONS, Serotonergic Drugs).

Ophthalmologic

Mydriasis

Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intra-ocular pressure or patients at risk for acute narrow-angle glaucoma (angle closure glaucoma) be closely monitored.

Psychiatric

Suicide

The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist until significant remission occurs. Close supervision of patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization of high risk patients. In order to reduce the risk of overdose, prescriptions for EFFEXOR XR (venlafaxine HCl) Capsules should be written for the smallest quantity of capsules consistent with good patient management.

WARNINGS AND PRECAUTIONS:

.) EMOTIONAL CHANGES, INCLUDING SELF-HARM POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND

The same precautions observed when treating patients with depression should be observed when treating patients with GAD or Social Anxiety Disorder. (See

Insomnia and Nervousness

Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with venlafaxine than with placebo (see ADVERSE REACTIONS) in depression, GAD, Social Anxiety Disorder and Panic disorder studies, as shown in Table 2.

Table 2

Incidence of Insomnia and Nervousness in Placebo-Controlled Depression, GAD, Social Anxiety Disorder, and Panic Disorder Trials

Social Anxiety

Depression GAD Disorder Panic Disorder

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with EFFEXOR XR in depression studies. In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with EFFEXOR XR up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with EFFEXOR XR up to 6 months. In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in 2% and 1%, respectively, of the patients treated with EFFEXOR XR up to 12 weeks and 2% and 3%, respectively, of the patients treated with EFFEXOR XR up to 6 months. In Panic Disorder trials, insomnia and nervousness led to drug discontinuation in 1% and 0.1%, respectively, of the patients treated with Effexor XR up to 12 weeks.

Activation of Mania/Hypomania

During Phase II and III trials, mania or hypomania occurred in 0.5% of venlafaxine immediate release tablet-treated patients and in 0.3% and 0% of EFFEXOR XR Capsule-treated patients in depression and anxiety studies respectively. In premarketing Social Anxiety Disorder studies, 0.2% of EFFEXOR XR-treated patients and no placebo-treated patients experienced mania or hypomania. In premarketing Panic Disorder studies, 0.1% of Effexor XR-treated patients and 0.0% placebo-treated patients experienced mania or hypomania. Mania or hypomania occurred in 0.4% of all venlafaxine-treated patients. Mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, EFFEXOR XR should be used cautiously in patients with a history or family history of bipolar disorder. A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.

Renal

In patients with renal impairment (GFR=10-70 mL/min), the pharmacokinetic disposition of both venlafaxine and ODV are significantly altered. Dosage adjustment is necessary in these patients (See DOSAGE AND ADMINISTRATION, Patients with Renal Impairment and Recommended Dose, Patients with Renal Impairment).

Sexual Function/Reproduction

See ADVERSE REACTIONS and PART II: SCIENTIFIC INFORMATION,

TOXICOLOGY, Reproductive Toxicity.

Special Populations

Pregnant Women:

There are no adequate and well controlled studies with venlafaxine in pregnant women. Therefore, venlafaxine should only be used during pregnancy if clearly needed. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Post-marketing reports indicate that some neonates exposed to venlafaxine, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants 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 other newer antidepressants, 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, Serotonin Syndrome/Neuroleptic Malignant Syndrome). When treating a pregnant woman with EFFEXOR XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. (See DOSAGE AND ADMINISTRATION, Treatment of Pregnant Women During the Third Trimester).

Nursing Women:

Because venlafaxine and its active metabolite, O-desmethylvenlafaxine, have been reported to be excreted in human milk, lactating women should not nurse their infants while receiving venlafaxine. If the mother is taking EFFEXOR XR while nursing, the potential for discontinuation effects in the infant upon cessation of nursing should be considered.

Pediatrics (<18 years of age)EFFEXOR XR (venlafaxine) is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association With Behavioral and Emotional Changes, Including Self-Harm).

:

Geriatrics (> 65 years of age)

: Of the 2,897 patients in Phase II and III trials with venlafaxine immediate release tablets, 357 (12%) were 65 years of age or older. Forty three (4%) of the patients in premarketing depression and 77 (6%) in GAD trials respectively, with EFFEXOR XR Capsules, were 65 years of age or older. Ten (1%) patients in placebo-controlled Social Anxiety Disorder studies were 65 years or older. Sixteen (2%) patients in placebo-controlled Panic Disorder studies were 65 years or older. No overall differences in effectiveness and safety were observed between these geriatric patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

Monitoring and Laboratory Tests

Self-Harm

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes (See WARNINGS AND PRECAUTIONS, POTENTIAL

ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

Sustained Hypertension and Acute Severe Hypertension

Venlafaxine treatment has been associated with sustained hypertension. Also, cases of severe elevated blood pressure requiring immediate treatment have been reported in postmarketing experience, including hypertensive crisis and malignant hypertension. The reports included normotensives and treated-hypertensive patients as well. It is recommended that patients receiving venlafaxine have their blood pressure evaluated before starting venlafaxine and monitored regularly during treatment.

WARNINGS and PRECAUTIONS, General, Hypertension.

For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered after a benefit-risk assessment is made. Patients should be told to consult their doctors if they have symptoms associated with acute severe hypertension such as headache (particularly in the back of head/neck when waking up), stronger heart beat and possibly more rapid, palpitations, dizziness, easy fatigability, blurred vision, chest pain. (See also

)

Serum Cholesterol Elevation

Clinically relevant increases in total serum cholesterol were recorded in 5.3% of venlafaxine- treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-

controlled trials in Major Depressive Disorder. (See ADVERSE REACTIONS, Laboratory Changes-Cholesterol). Consistent with the above findings, elevations of High Density Lipoprotein Cholesterol (HDL), Low Density Lipoprotein Cholesterol (LDL) and the overall ratio of Total Cholesterol/HDL have been observed in placebo controlled clinical trials for Social Anxiety Disorder (SAD) and Panic Disorder. Measurement of serum cholesterol levels (including a complete lipid profile/fractionation and an assessment of the patient's individual risk factors) should be considered especially during long- term treatment.

DRUG INTERACTIONS

Serious Drug Interactions

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS

Overview

Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Drug-Drug Interactions

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION, Switching Patients to or from a Monoamine Oxidase Inhibitor.

Other CNS-Active Drugs

The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required.

Serotonergic Drugs

Serotonin Syndrome

Based on the known mechanism of action of venlafaxine and the potential for serotonin syndrome, the concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended. As with other serotonergic agents, serotonin syndrome, a potentially life threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter systems (such as triptans, selective serotonin reuptake inhibitors, other serotonin and norepinephrine reuptake inhibitors, linezolid, sibutramine, tramadol, St. John's Wort or lithium), with drugs which impair metabolism of serotonin (including MAOIs; see CONTRAINDICATIONS), or with serotonin precursors (such as tryptophan supplements). Rare postmarketing reports describe patients with symptoms suggestive of, or diagnostic of, serotonin syndrome, following the combined use of a selective serotonin reuptake inhibitor (SSRI) with 5HT1-agonists (triptans) or lithium. If concomitant treatment with EFFEXOR XR and a triptan (e.g., almotriptan, sumatriptan, rizatriptan, naratriptan, zolmitriptan), tricyclic antidepressants, or other drugs or agents with serotonergic activity (including but not limited to St. John's Wort) is clinically warranted, appropriate

observation of the patient for acute and long-term adverse events is advised. (See also WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Changes in Appetite and Weight; and WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome.)

Alcohol

The possibility of additive psychomotor impairment should be considered if venlafaxine is used in combination with alcohol. Patients should be advised to avoid alcohol while taking venlafaxine.

Lithium

The steady-state pharmacokinetics of venlafaxine 150 mg administered as 50 mg every 8 hours was not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV was also unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium. (Also see Other CNS-Active Drugs.)

Diazepam

The steady-state pharmacokinetics of venlafaxine 150 mg administered as 50 mg every 8 hours was not affected when a single 10 mg oral dose of diazepam was administered to 18 healthy male subjects. ODV was also unaffected. Venlafaxine had no effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam. Additionally, venlafaxine administration did not affect the psychomotor and psychometric effects induced by diazepam.

Cimetidine

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

Haloperidol

Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown.

Drugs Highly Bound to Plasma Proteins

Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

Drugs that Inhibit Cytochrome P450 Isoenzymes

CYP2D6-Inhibitors:

In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6 mediated metabolism and venlafaxine. Drug interactions that reduce the metabolism of venlafaxine to ODV (see Imipramine below) potentially increase the plasma concentrations of venlafaxine and lower the concentrations of the active metabolite. However, the pharmacokinetic profile of venlafaxine in subjects concomitantly receiving a CYP2D6-inhibitor would not be substantially different than the pharmacokinetic profile in subjects who are CYP2D6 poor metabolizers, and no dosage adjustment is required.

CYP3A3/4 Inhibitors:

Because the two primary metabolic pathways for venlafaxine are through CYP2D6 and, to a lesser extent, CYP3A3/4, concomitant intake of inhibitors of both of these isoenzymes is not recommended during treatment with venlafaxine. Interactions between concomitant intake of inhibitors of both CYP2D6 and CYP3A3/4 with venlafaxine have not been studied. In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A3/4. However, a study showed that the use of ketoconazole (a CYP3A4 inhibitor) resulted in the increase of the plasma levels of venlafaxine and ODV (see DRUG INTERACTIONS, Drug-Drug Interactions, Drugs that Inhibit Cytochrome P450 Isozymes, CYP3A3/4 Inhibitors, Ketoconazole). Therefore, concomitant use of CYP3A4 inhibitors (such as ketoconazole) and venlafaxine may increase levels of venlafaxine and ODV. Caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.

Ketoconazole

A pharmacokinetic study with ketoconazole in extensive (EM) and poor metabolizers (PM) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects. AUC values for ODV increased by 23% and 33% in EM and PM subjects, respectively.

Drugs Metabolized by Cytochrome P450 Isoenzymes

CYP2D6

In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in vivo by a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.

Imipramine

Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH- imipramine. However, AUC, Cmax and Cmin of desipramine (the active metabolite of imipramine) increased by approximately 35% in the presence of venlafaxine. The 2- OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). The clinical significance of elevated 2-OH-desipramine levels is unknown. Imipramine partially inhibited the CYP2D6-mediated formation of ODV. However, the total concentration of active compounds (venlafaxine plus ODV) was not affected by coadministration with imipramine, and no dosage adjustment is required.

Metoprolol

Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to healthy volunteers in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, a-hydroxymetoprolol. Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in a study of healthy volunteers. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethyl venlafaxine. Caution should be exercised with co-administration of venlafaxine and metoprolol. (See also WARNINGS AND PRECAUTIONS, General, Hypertension).

Risperidone

Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine co- administration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).

CYP3A4

Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.

Indinavir

In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.

CYP1A2

Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.

CYP2C9

Venlafaxine did not inhibit CYP2C9 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of tolbutamide, a CYP2C9 substrate.

CYP2C19

Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above).

Postmarketing Reports of Drug-Drug Interactions

There have been reports of elevated clozapine levels that were temporally associated with adverse events including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.

Electroconvulsive Therapy

There are no clinical data on the use of electroconvulsive therapy combined with EFFEXOR XR treatment.

Drug-Food Interactions

Food has no significant effect on the absorption of venlafaxine or on the subsequent formation of ODV.

Drug-Herb Interactions

St. John's Wort

In common with SSRI's, pharmacodynamic interactions between EFFEXOR XR and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.

Drug-Lifestyle Interactions

Interference with Cognitive and Motor Performance

In healthy volunteers receiving an immediate release venlafaxine formulation at a stable regimen of 150 mg/day, some impairment of psychomotor performance was observed. Patients should be cautioned about operating hazardous machinery, including automobiles, or engaging in tasks requiring alertness until they have been able to assess the drug's effect on their own psychomotor performance.

Drug Abuse and Dependence

Physical and Psychological Dependence

In vitro

studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.

While venlafaxine has not been systematically studied in clinical trials for their potential for abuse, there was no indication of drug-seeking behaviour in the clinical trials. 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 behaviour).

DOSAGE AND ADMINISTRATION

Dosing Considerations

General

• EFFEXOR XR is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

• Discontinuing Venlafaxine When discontinuing venlafaxine after more than 1 week of therapy, it is generally recommended that the dose be tapered gradually to minimize the risk of discontinuation symptoms. Discontinuation symptoms have been assessed both in patients with depression and in those with GAD. Abrupt discontinuation, dose reduction, or tapering of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with higher dose levels and with longer duration of treatment. Reported symptoms include but are not limited to the following: aggression, agitation, anorexia, anxiety, asthenia, confusion, convulsions, coordination impaired, diarrhoea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headache, hypomania, insomnia, nausea, nightmares, nervousness, paresthesia, electric shock sensations, sensory disturbances (including shock like electrical sensations), sleep disturbances, somnolence, sweating, tinnitus, vertigo, and vomiting. Where such symptoms occurred they were usually self-limiting but in a few patients continued for several weeks. It is therefore recommended that the dosage of EFFEXOR XR be tapered gradually and the patient monitored. The period required for tapering may depend on the dose, duration of therapy and the individual patient. If venlafaxine has been used for more than 6 weeks, tapering over at least a two week period is recommended (see WARNINGS AND PRECAUTIONS, POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM, and also Discontinuation Symptoms; ADVERSE REACTIONS, Discontinuation Symptoms).

Patients With Hepatic or Renal Impairment:

Dosage adjustments are required (see DOSAGE AND ADMINISTRATION, Special Patient Populations below).

Switching Patients to or from a Monoamine Oxidase Inhibitor:

At least 14 days should elapse between discontinuation of an MAOI and initiation of

therapy with EFFEXOR XR. In addition, at least 14 days should be allowed after stopping EFFEXOR XR before starting an MAOI (see CONTRAINDICATIONS).

Switching Patients from Immediate Release Tablets:

Depressed patients who are currently being treated at a therapeutic dose with immediate

release tablets may be switched to EFFEXOR XR at the nearest equivalent dose

(mg/day), e.g., 37.5 mg immediate release two-times-a-day to 75 mg EFFEXOR XR once daily. However, individual dosage adjustments may be necessary.

Recommended Dose and Dosage Adjustment

ADULTS:

Patients with Major Depressive Disorder

The recommended dose for EFFEXOR XR is 75 mg/day, administered once daily with food, either in the morning or in the evening. For some patients, it may be desirable to start at 37.5 mg/day for 4-7 days to allow new patients to adjust to the medication before increasing to 75 mg/day. Each capsule should be swallowed whole with water. It should not be divided, crushed, chewed, or placed in water. While the relationship between dose and antidepressant response for EFFEXOR XR has not been adequately explored patients not responding to the initial 75 mg may benefit from dose increases. Depending on tolerability and the need for further clinical effect, the dose should be increased by up to 75 mg/day up to a maximum of 225 mg/day as a single dose for moderately depressed outpatients. Dose increments should be made at intervals of approximately 2 weeks or more, but not less than 4 days. There is very limited experience with EFFEXOR XR at doses higher than 225 mg/day, or in severely depressed inpatients.

Patients with Generalized Anxiety Disorder (GAD)

The recommended starting dose of EFFEXOR XR is 37.5 mg/day administered as a single dose, taken with food, for 4-7 days. The usual dose is 75 mg/day administered as a single dose. Subsequent dosage increments of up to 75 mg/day may be considered, if clinically warranted. Dose increments should be made as needed at intervals of not less than 4 days. The maximum recommended daily dose is 225 mg/day as a single dose.

Patients with Social Anxiety Disorder (Social Phobia)

For most patients, the recommended dose for EFFEXOR XR is 75 mg/day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Depending on tolerability and if clinically warranted, dose increases should be in increments of up to 75 mg/day, as needed, up to a maximum of 225 mg/day. Dose increments should be made at intervals of not less than 4 days.

Panic Disorder

It is recommended that initial single doses of 37.5 mg/day of Effexor XR be used for 7 days. The recommended treatment dose is 75 mg/day, administered in a single dose. Although a dose response relationship for effectiveness in patients with Panic Disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of at least 7 days.

Maintenance/Continuation/Extended Treatment

There is no body of evidence available to answer the question of how long a patient should continue to be treated with EFFEXOR XR for depression, GAD, Social Anxiety Disorder or Panic Disorder.

During long-term therapy for any indication, the Effexor XR dosage should be maintained at the lowest effective dose and the need for continuing treatment should be periodically reassessed.

Depression:

It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacotherapy beyond response to the acute episode. Whether the dose needed to induce remission is identical to the dose needed for maintenance is unknown.

Maintenance of efficacy of EFFEXOR XR has been shown in a placebo controlled study in which patients responding during 8 weeks of acute treatment with EFFEXOR XR were assigned randomly to placebo or to the same dose of EFFEXOR XR [75, 150, or 225 mg/day, in the morning (i.e. qAM)] during 26 weeks of maintenance treatment (see CLINICAL TRIALS, Depression).

It is not known whether or not the dose of EFFEXOR XR 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.

Social Anxiety Disorder

In patients with Social Anxiety Disorder, there are no efficacy data beyond 6 months of treatment with EFFEXOR XR. The need for continuing medication in patients with Social Anxiety Disorder who improve with EFFEXOR XR treatment should be periodically reassessed.

Panic Disorder

In one study in Panic Disorder, in which patients who were responders in the final 2 weeks of a 12-week acute treatment with Effexor XR were assigned randomly to placebo or to the same

dose of Effexor XR (75, 150, or 225 mg/day) during 6 months of maintenance treatment, patients continuing Effexor XR treatment showed a significant longer time to relapse than patients switched to placebo.

Special Patient Populations:

Treatment of Pregnant Women During the Third Trimester

WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women

Post-marketing reports indicate that some neonates exposed to immediate release venlafaxine or EFFEXOR XR, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. (See

). When treating a pregnant woman with EFFEXOR XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Due to the potential for discontinuation symptoms, if a decision is taken to discontinue Effexor XR treatment, a gradual reduction in the dose rather than an abrupt cessation is recommended (See WARNINGS AND PRECAUTIONS, Discontinuation Symptoms).

Elderly Patients

No dose adjustment is recommended for elderly patients solely on the basis of their age. As with any antidepressant or anxiolytic, drug for treatment of Social Anxiety Disorder, or Panic Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

Pediatrics

EFFEXOR XR is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

Patients With Hepatic Impairment:

Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared with normal subjects (see ACTION AND CLINICAL PHARMACOLOGY, Hepatic Insufficiency), the total daily dose must be reduced by about 50% in patients with mild to moderate hepatic impairment. For such patients, it may be desirable to start at 37.5 mg/day. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose by even more than 50%, and individualization of dosing may be desirable in some patients.

Patients with Renal Impairment

Given the decrease in clearance for venlafaxine and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects (see ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency) the total daily dose must be decreased by 25%-50%. In patients undergoing hemodialysis, the total daily dose must be reduced by 50% and the dose be withheld until the

dialysis treatment is completed (4 hrs). For such patients, it may be desirable to start at 37.5

mg/day. Since there is so much individual variability in clearance among patients with renal impairment, individualization of dosing may be desirable.

Missed Dose

If a dose is missed, it should not be made up for it by doubling up on the dose next time. The next dose should be taken as scheduled.

Administration

Administer once daily with food, either in the morning or in the evening.

OVERDOSAGE

Venlafaxine Immediate Release Tablets

There were 14 reports of acute overdose with immediate release tablets (venlafaxine HCl), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g and 2.5 g. The resultant peak plasma levels of venlafaxine for the

latter 2 patients were 6.24 and 2.35 :g/mL, respectively, and the peak plasma levels of O- desmethylvenlafaxine were 3.37 and 1.30 :g/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients.

EFFEXOR XR Capsules

Among the patients included in the premarketing evaluation of venlafaxine extended release capsules, there were 2 reports of acute overdosage with EFFEXOR XR in depression trials, either alone or in combination with other drugs. One patient took a combination of 6 g of EFFEXOR(r) XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of EFFEXOR XR. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with EFFEXOR XR in anxiety trials. One patient took a combination of 0.75 g EFFEXOR XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of EFFEXOR XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. There were no reports of acute overdose with EFFEXOR XR in Social Anxiety Disorder trials. There were 2 reports of acute overdose with Effexor XR in Panic Disorder trials. One patient took 0.675 g of Effexor XR once and the other patient took 0.45 g of Effexor XR for 2 days. No signs or symptoms were associated with either overdose and no actions were taken to treat them.

Postmarketing Experience with EFFEXOR (Dosage Form Unknown)

In postmarketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, delayed rise in plasma creatine kinase levels, rhabdomyolysis, liver necrosis, serotonin syndrome, vertigo, and death have been reported. Muscle enzymes should be monitored in patients with venlafaxine overdose to detect development of rhabdomyolysis at an early stage and to initiate appropriate treatment. According to post-marketing overdose reports

with venlafaxine (where overdose amounts were provided) fatal acute overdoses have been

reported with venlafaxine alone at doses as low as approximately 1 gram.

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

54

of venlafaxine in overdosage as opposed to some characteristics of venlafaxine-treated patients is not clear. Prescriptions for venlafaxine should be written for the smallest quantity of drug consistent with good patient management, in order to reduce the risk of overdose.

Overdosage Management

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control centre for current information on the treatment of any overdose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Venlafaxine is a phenethylamine bicyclic derivative, chemically unrelated to tricyclic, tetracyclic or other available antidepressant or anxiolytic agents.

The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

Pharmacodynamics

Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or a1- 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.

Pharmacokinetics

Venlafaxine Immediate Release Formulation

Venlafaxine is well absorbed, with peak plasma concentrations occurring approximately 2 hours after dosing. Venlafaxine is extensively metabolized, with O-desmethylvenlafaxine, (ODV, the only major active metabolite) peak plasma levels occurring approximately 4 hours after dosing. Following single doses of 25 to 75 mg, mean (+- SD) peak plasma concentrations of venlafaxine range from 37 +- 14 to 102 +- 41 ng/mL, respectively, and are reached in 2 +- 1 hours, and mean peak ODV plasma concentrations range from 61 +- 13 to 168 +- 37 ng/mL and are reached in 4 +- 2 hours. Approximately 87% of a single dose of venlafaxine is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%),

or other minor inactive metabolites (27%), and 92% of the radioactive dose is recovered within 72 hours. Therefore, renal elimination of venlafaxine and its metabolites is the primary route of excretion.

EFFEXOR XR Capsules

After administration of EFFEXOR XR (venlafaxine hydrochloride, extended release capsules) the peak plasma concentrations of venlafaxine and ODV are attained within 6.0+-1.5 and 8.8+-2.2 hours, respectively. The rate of absorption of venlafaxine from the EFFEXOR XR capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of EFFEXOR(r) XR (15+-6 hours) is actually the absorption half-life instead of the true disposition half-life (5+-2) hours observed following administration of a venlafaxine hydrochloride immediate release tablet.

Multiple-Dose Pharmacokinetic Profile (Immediate Release Tablets and Extended Release Capsules)

Steady-state concentrations of both venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. The clearance of venlafaxine is slightly (15%) lower following multiple doses than following a single dose.

Venlafaxine and ODV exhibited approximately linear kinetics over the dose range of 75 to 450 mg/day.

The mean +-SD steady-state plasma clearances of venlafaxine and ODV are 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 renal clearances are 49 +- 27 and 94 +- 56 mL/h/kg, respectively, which correspond to 5 +- 3.0% and 25 +- 13% of an administered venlafaxine dose recovered in urine as venlafaxine and ODV, respectively.

When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended release capsule, the exposure (AUC, area under the concentration curve) to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower following treatment with the extended release capsule. Therefore, the EFFEXOR XR capsules provide a slower rate of absorption, but the same extent of absorption (i.e., AUC), as the venlafaxine immediate release tablet.

Results of testing in healthy volunteers demonstrated differences in the gastrointestinal tolerability of different formulations of venlafaxine. Data from healthy volunteers showed reduced incidence and severity of nausea with EFFEXOR XR capsules, compared with immediate release tablets.

Venlafaxine and ODV are 27 and 30% bound to human plasma proteins, respectively. Therefore, administration of venlafaxine to a patient taking another drug that is highly protein- bound should not cause increased free concentrations of the other drug. Following intravenous administration, the steady-state volume of distribution of venlafaxine is 4.4 +-1.9L/kg, indicating that venlafaxine distributes well beyond the total body water.

Absorption: Venlafaxine is well absorbed; after administration of EFFEXOR XR (venlafaxine hydrochloride, extended release capsules), the peak plasma concentrations of venlafaxine and ODV are attained within 6.0 +-1.5 and 8.8 +-2.2 hours, respectively. The rate of absorption of venlafaxine from the EFFEXOR XR capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of EFFEXOR(r) XR (15 +-6 hours) is actually the absorption half-life instead of the true disposition half-life (5 +-2) hours observed following administration of a venlafaxine hydrochloride immediate release tablet. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed.

Food has no significant effect on the absorption of venlafaxine or on the subsequent formation of ODV.

Distribution:

Following intravenous administration, the steady-state volume of distribution of venlafaxine is 4.4 +-1.9L/kg, indicating that venlafaxine distributes well beyond the total body water. Venlafaxine and ODV are 27 and 30% bound to human plasma proteins, respectively. Therefore, administration of venlafaxine to a patient taking another drug that is highly protein- bound should not cause increased free concentrations of the other drug.

Metabolism: Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. The absolute bioavailability of venlafaxine is approximately 45%. The primary metabolite of venlafaxine is ODV, which is an active metabolite. Venlafaxine is also metabolized to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalysed by CYP2D6 and that the formation of N-desmethylvenlafaxine is catalysed by CYP3A3/4. The results of the in vitro studies have been confirmed in a clinical study with subjects who are CYP2D6 poor and extensive metabolizers. However, despite the metabolic differences between the CYP2D6 poor and extensive metabolizers, the total exposure to the sum of the two active species (venlafaxine and ODV, which have comparable activity) was similar in the two metabolizer groups.

Excretion:

Approximately 87% of a single dose of venlafaxine is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%), and 92% of the radioactive dose is recovered within 72 hours. Therefore, renal elimination of venlafaxine and its metabolites is the primary route of excretion.

Special Populations and Conditions

Pediatrics:

Safety and efficacy in children below the age of 18 have not been established. EFFEXOR XR (venlafaxine) is not indicated for use in children under 18 years of age.

Geriatrics:

Population pharmacokinetic analyses of 547 venlafaxine-treated patients from three studies involving both venlafaxine immediate release tablets and venlafaxine extended release capsules showed that age does not significantly affect the pharmacokinetics of venlafaxine. A 20% reduction in clearance was noted for ODV in subjects over 60 years old; this was possibly caused by the decrease in renal function that typically occurs with aging. Dosage adjustment based upon age is generally not necessary.

Gender:

Population pharmacokinetic analyses of 547 venlafaxine-treated patients from three studies involving both venlafaxine immediate release tablets and venlafaxine extended release capsules showed that sex does not significantly affect the pharmacokinetics of venlafaxine. Dosage adjustment based upon gender is generally not necessary.

Hepatic Impairment:

In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered. Venlafaxine elimination half-life was prolonged by about 30%, and clearance was decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic patients compared to normal subjects.

A large degree of inter-subject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. Dosage adjustment is necessary in patients with hepatic impairment (see DOSAGE AND ADMINISTRATION, Special Patient Populations).

Renal Impairment:

In patients with moderate to severe impairment of renal function (GFR = 10-70 mL/min), venlafaxine elimination half-life was prolonged by 50%, and clearance was decreased by about 24% compared to normal subjects. ODV elimination half-life was prolonged by about 40%, but clearance was unchanged.

In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was decreased by about 57%. In dialysis patients, ODV elimination half-life was prolonged by about 142%, and clearance was reduced by about 56% compared to normal subjects.

A large degree of inter-subject variability was noted.

Dosage adjustment is necessary in patients with renal impairment DOSAGE AND ADMINISTRATION, Special Patient Populations.

(see

)

Genetic Polymorphism:

Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, there is no need for different venlafaxine dosing regimens for these two groups.

STORAGE AND STABILITY

Store at room temperature (15-30EC), in a dry place.

SPECIAL HANDLING INSTRUCTIONS

None.

DOSAGE FORMS, COMPOSITION AND PACKAGING

PrEFFEXOR XR (venlafaxine HCl) extended-release capsules are available in bottles of 100 capsules, in the following dosage strengths (potency is expressed in terms of venlafaxine base):

37.5 mg

Hard gelatin capsule with gray cap and peach body, with "W" and "Effexor XR" on the cap and "37.5" on the body, in red ink.

75 mg

Hard gelatin capsule with peach cap and body, with "W" and "Effexor XR" on the cap and "75" on the body, in red ink.

150 mg

Hard gelatin capsule with dark orange cap and body, with "W" and "Effexor XR" on the cap and "150" on the body, in white ink.

The appearance of these capsules is a trademark of Wyeth Canada.

Composition:

Medicinal Ingredients Non-medicinal Ingredients:

Venlafaxine Hydrochloride Ethylcellulose, NF

Gelatin, NF

Hydroxypropylmethyl Cellulose, USP Iron Oxide, NF

Microcrystalline Cellulose, NF Titanium Dioxide, USP

White Tek SB-0007 and/or Opacode Red S-1-15034 ink Talc, USP

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Venlafaxine Hydrochloride

Chemical name: (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride;

or

(+-)-1-[a[(dimethylamino)methyl]-p-methoxy-benzyl] cyclohexanol hydrochloride.

Molecular formula and molecular mass: C17H27NO2 *HCl; 313.87 Structural formula:

Physicochemical properties:

Physical Form: White to off-white crystalline solid

Solubility:

Water: 540, 542, 501 and 21.6 mg/mL at pH 1.0, 5.38, 7.09

and 7.97

Ethanol: 91.7 mg/mL

Propylene Glycol: 200 mg/mL

Glycerin: 115 mg/mL

pKa value: 9.4

CLINICAL TRIALS DEPRESSION

Venlafaxine Immediate Release Tablet Formulation

The efficacy of immediate release tablets in the treatment of depression was established in 6- week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-II or DSM-III-R category of major depressive disorder and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depressive disorder with melancholia.

In one longer term study, outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had "responded" * during an initial 26 weeks of treatment on a venlafaxine immediate release tablet (100 to 200 mg/day, on a b.i.d. schedule) and continued to be "improved" *, were randomized to continuation of their same venlafaxine immediate release tablet dose or to placebo. The follow-up period to observe patients for "relapse" * was for up to 52 weeks. Patients receiving continued venlafaxine immediate release tablet treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.

*For the purposes of this study:

"Responded" was defined as HAM-D-21 total score # 12 at the day 56 evaluation)

"Improved" was 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).

"Relapse" was defined as a CGI Severity of Illness item score >4 during the double-blind phase.

EFFEXOR XR Capsules (Extended release)

The efficacy of EFFEXOR XR (venlafaxine hydrochloride extended release) capsules as a treatment for depression was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depression. An 8- week study utilizing EFFEXOR XR doses in a range 75-225 mg/day (mean dose for completers was 177 mg/day) and a 12-week study utilizing EFFEXOR XR doses in a range 75-150 mg/day (mean dose for completers was 136 mg/day) both demonstrated superiority of EFFEXOR XR over placebo on the HAM-D total score, the HAM-D Depressed Mood Item, the MADRS total score, the CGI Severity of illness scale, and the CGI Global Improvement scale. In both studies, EFFEXOR XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score.

In the 12-week study comparing immediate release tablets with EFFEXOR XR capsules, once daily, EFFEXOR XR was significantly more effective at weeks 8 and 12, compared with immediate release tablets given twice daily for treating major depression. Analysis of safety data from this trial showed that the incidence of treatment-emergent nausea and nausea severity over time were lower with EFFEXOR XR than with immediate release tablets. Additionally, the incidence of vomiting was lower with EFFEXOR XR than with immediate release tablets.

In one longer term study, outpatients meeting DSM-IV criteria for major depressive disorder who had "responded" * during an 8-week open trial on EFFEXOR XR capsules (75, 150, or 225

mg, in the morning (qAM) were randomized to continuation of their same EFFEXOR XR dose or to placebo, for up to 26 weeks of observation for "relapse" *. Patients receiving continued EFFEXOR XR treatment experienced significantly lower "relapse" * rates compared with those on placebo.

*For the purposes of this study:

"Responded" during the open phase was defined as a CGI Severity of Illness item score <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:

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 consecutive CGI Severity of Illness item scores of > 4, ora final CGI Severity of Illness item score of >4 for any patient who withdrew from the study for any reason.

Generalized Anxiety Disorder (GAD)

The efficacy of EFFEXOR XR capsules in the treatment of GAD has been demonstrated in three fixed dose studies and one flexible dose study for time periods ranging from 8 to 28 weeks. In these studies, EFFEXOR XR was shown to have a statistically significant superiority over placebo on the following three measures: Hamilton Anxiety Rating Scale (total score), Hamilton anxious mood item, and Clinical Global Impression of Severity of Illness rating.

In the three fixed dose studies, response rates at week 8 of treatment, as defined by the proportion of patients achieving Clinical Global Impression of Improvement Scores of "much" or "very much improved", were as follows (last observation carried forward):

Study #Placebo37.5 mg75.0 mg150 mg225 mgN%N%N%N%N%210 US9649%8657%8158%8665%378 EU13045%13859%13069%13178%214 US9839%8762%8749%

For the two long-term studies, response rates at month 6 were as follows for last observation carried forward (LOCF):

Study #Placebo37.5 mg75.0 mg150 mg75-225 mgN%N%N%N%N%378 EULOCF12333%11567%218 USLOCF13048%13866%13075%13181%

Social Anxiety Disorder (Social Phobia)

The efficacy of EFFEXOR XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was demonstrated in four 12-week, multi-center, placebo-controlled, flexible- dose studies and one 6-month, fixed/flexible-dose study in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. These studies evaluating EFFEXOR XR doses in a range of 75-225 mg/day demonstrated that EFFEXOR XR was significantly more effective than placebo for the Liebowitz Social Anxiety Scale Total score, Clinical Global Impressions of Severity of Illness rating, and Social Phobia Inventory.

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

Panic Disorder

Two fixed-dose and two flexible-dose placebo-controlled studies have been performed to investigate the efficacy of Effexor XR capsules as a treatment for Panic Disorder. In the two double-blind, 12-week, multi-center, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for Panic Disorder, with or without agoraphobia, patients received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study. In these two trials, Effexor XR doses of 75 mg, 150 mg and 225 mg were significantly more effective than placebo for the primary outcome, the percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS), and for the two key secondary outcomes: 1) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score, and (2) percentage of patients rated as responders (much improved or very much improved) in the Clinical Global Impressions (CGI) Improvement scale.

In one flexible-dose study (75 mg to 225 mg daily doses), the primary outcome, the percentage of patients free of full-symptom panic attacks, approached significance (p=0.056). In this study, Effexor XR was significantly more effective than placebo for the two key secondary outcomes,

(1) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score, and (2) percentage of patients rated as responders (much improved or very much improved) in the Clinical Global Impressions (CGI) Improvement scale.

In another flexible-dose study (dose range 75mg-225 mg/day), Effexor XR was not significantly more effective than placebo for the primary outcome, the percentage of patients free of full- symptom panic attacks, but it was significantly more effective than placebo for the secondary outcome: percentage of patients rated as responders (much improved or very much improved) in the Clinical Global Impressions (CGI) Improvement scale.

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, adult outpatients meeting DSM-IV criteria for Panic Disorder who had responded at the end of a 12-week open phase with Effexor XR (75 to 225 mg/day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse during a 6-month double-blind phase. 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) during that same 2-week period. 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 investigator. Patients receiving continued Effexor XR treatment experienced significantly longer time to relapse over the subsequent 6 months compared with those receiving placebo.

DETAILED PHARMACOLOGY

Venlafaxine (Wy-45,030) is a novel bicyclic 2-phenyl-2-(1-hydroxy-cycloalkyl) ethylamine racemate whose enantiomers are configured as R (-) venlafaxine and S (+) venlafaxine. The major human metabolite of venlafaxine is the racemate Wy-45,233 (O-desmethyl-venlafaxine) whose enantiomers are configured as R (-) Wy-45,233 and S (+) Wy-45,233.

Venlafaxine is a potent inhibitor of both norepinephrine and serotonin uptake that has demonstrated antidepressant activity in a number of preclinical models. Wy-45,233, the major human metabolite of venlafaxine, has a pharmacological profile quite similar to that of venlafaxine since it also inhibits norepinephrine and serotonin uptake and produces rapid noradrenergic desensitization. This indicates that Wy-45,233 is a biologically active metabolite of venlafaxine. While the enantiomers of Wy-45,233 effectively inhibit monoamine uptake, they were less effective in in vivo models of antidepressant activity.

Ancillary pharmacological effects of venlafaxine and Wy-45,233 were quite similar. In neuropharmacological studies, both compounds lacked activity at a wide range of CNS receptors and had a low abuse liability potential. The effects of venlafaxine and Wy-45,233 on arterial pressure and heart rate in animals are most likely related to the inhibition of monoamine uptake and are similar to those produced by tricyclic antidepressants. Lastly, venlafaxine and

Wy-45,233 produced only limited effects in immunological, gastrointestinal and endocrine studies which were generally at doses greater than those required to produce antidepressant effects in animals.

Venlafaxine is rapidly absorbed and excreted from laboratory animals and man. Differences in biotransformation pathways among species result in different pharmacokinetic profiles. Tissue uptake occurs, but without notable accumulation. Elimination of venlafaxine and its metabolites occurs via renal pathway in all species. O-Demethylation to a bioactive metabolite is the major transformation in man, dog and mouse, but further transformations occur in the animals. Other transformation pathways predominate in rat and rhesus monkey. While venlafaxine HCl is a racemic mixture, the animals in drug safety evaluation studies were exposed to similar or greater amounts of each venlafaxine enantiomer, as well as each Wy-45,233 enantiomer, than when humans received venlafaxine HCl at the highest recommended therapeutic dose. Stereoselective transformations, which were recognized in rats and rhesus monkeys, were not significant in humans.

TOXICOLOGY

The toxicologic profile of venlafaxine was evaluated for up to 18 months in mice, up to 2 years in rats, and up to 1 year in dogs. A single dose range finding study was done in monkeys. As part of its evaluation, the reproductive toxicologic potential of venlafaxine was evaluated in

segment I, II, and III studies in rats and a segment II study in rabbits. The major findings in the acute, long term, and reproductive toxicity studies are discussed below.

Acute Toxicity

Venlafaxine showed low acute toxicity with LD50s >=405 mg/kg in mice and 336 mg/kg in rats;

i.v. LD50s in mice were >=48 mg/kg. No drug-related macroscopic lesions were observed;

microscopic examinations were not performed.

Long Term Toxicity/Carcinogenicity

Subchronic toxicity of venlafaxine was evaluated in mice, rats, dogs and monkeys (1-month range finding study only); chronic toxicity was evaluated in dogs; and chronic toxicity/carcinogenicity was evaluated in mice and rats.

Mice

Venlafaxine was administered to mice for 3 months at 0, 24, 96, 138, 180 and 240 mg/kg to establish doses for a subsequent 18 month carcinogenicity study. Drug-related tonic/clonic convulsions occurring in both 180 and 240 mg/kg groups were regarded as limiting for subsequent studies of longer duration due to anticipated mortality associated with convulsions of this magnitude. Based on these results, a maximum dose of 120 mg/kg was selected for chronic carcinogenicity studies which was regarded to provide a minimal margin below the convulsive threshold which would limit survival in a chronic study. In the 18 month study, mice were thus dosed at 10, 35, and 120 mg/kg. No carcinogenic effect was noted in males or females. A slight decrease in survival occurred in the 120 mg/kg males, but was not associated with specific microscopic lesions. The cause of death in the 120 mg/kg mice could not be clearly established. Male and female mice receiving 120 mg/kg were noted to have increased motor activity.

Rats

Rats were dosed with venlafaxine at 0, 4.5, 40, 170, and 340 mg/kg in the 6 month toxicity study and at 0, 10, 35, and 120 mg/kg in the 2 year study. No drug-related histologic lesions occurred in either study. In the six month study, an increased mortality was seen at 170 and 340 mg/kg.

Deaths were generally associated with convulsions. Effects noted included decreased body weight and food consumption at 170 and 340 mg/kg and increased incidence of physical examination findings at 40 mg/kg and above. Due to mortality, body weight, and food consumption effects, the maximum tolerated dose for the chronic study was considered to be below 170 mg/kg. The rat carcinogenicity study was conducted at dosages of 0, 10, 35, and 120 mg/kg for 2 years. As with the mouse, no carcinogenic effect was observed. An increased mortality was seen at 120 mg/kg; however, no clear drug-related lesion was associated with mortality. Mortality at lower dosages was comparable to historical limits (50-65%).

Dogs

In dogs, venlafaxine was administered for 6 months at 0, 2, 7, and 22 mg/kg and for 12 months at 0, 4, 10, and 24 mg/kg. As with the other species tested, no drug-related histologic lesions occurred. In the 6 month dog study, slightly decreased heart rate occurred in two dogs (during weeks 6, 12, 18, and 25 in one dog and week 25 in the other dog) receiving 22 mg/kg. Although effects on cardiovascular parameters have been seen with other antidepressants, including ECG alterations consisting of T wave changes (inversions, bifid T wave), prolongation of conduction

and sinus tachycardia seen with tricyclic antidepressants, these effects were not seen after administration of venlafaxine. Blood pressure and ECGs were measured periodically throughout treatment at multiple intervals after ECG abnormalities in these or any other dogs in the 6 month or 1 year studies. A slight decrease in body weight gain was seen at the high dose in both studies. Mydriasis, a pharmacologic effect, occurred at all dosages. Other minor drug-related effects were generally limited to the high dose.

Monkeys

In monkeys, a range finding assay was conducted using one monkey/sex at dosages of 0, 25, 80, 125, 170, and 260 mg/kg for up to 27 days. Deaths occurred in the first 5 days in one of two monkeys at 125 mg/kg and all monkeys at higher dosages. No drug-related histologic changes were found in these animals, and deaths were considered secondary to drug-induced convulsions. Electrocardiograms were only measured on the 80 mg/kg monkeys and showed no drug-related effects. Due to pharmacokinetic considerations, additional monkey studies were not conducted.

Mutagenicity

Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (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, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow.

Reproductive Toxicity

The reproductive toxicology of venlafaxine was studied in rats and rabbits. No teratogenic effect

was observed and no deaths occurred.

Pharmacotoxic signs were seen in paternal and maternal rats given venlafaxine doses of 30 and 60 mg/kg/day (4 and 8 times the maximum recommended human dose, respectively), but no adverse effect was noted in fertility or general reproductive performance. Decreased fetal size and pup weight at birth with 60 mg/kg/day may be correlated with maternal toxicity. In a perinatal toxicity study, decreased fetal survival following birth was observed at 40 and 80 mg/kg/day (approximately 5 to 11 times the maximum recommended human dose, respectively) and was considered secondary to drug-related decreased maternal care. No teratogenic effect was seen. Evidence of carcinogenesis, mutagenesis, and impairment of fertility was not noted in preclinical toxicology studies.

Reproductive Toxicity with the Major Metabolite of Venlafaxine

Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV). This ODV exposure was approximately 2 to 3 times that which would result from a human dose of 225 mg/day of venlafaxine. The human relevance of this finding is unknown.

In this study, administration of ODV as the succinate salt in male and female rats resulted in disrupted estrous cycles and increased time-to-mating at >=30 mg/kg/day; decreased fertility rates

at >=100 mg/kg/day; and increased preimplantation loss and decreased fetal weight at 300 mg/kg/day. There was decreased prostate weight at >=30 mg/kg/day associated with prostate atrophy at >=100 mg/kg/day; however, there were no compound-related macroscopic or microscopic findings in the epididymides, seminal vesicles, or testes. The no-observed-adverse- effect level (NOAEL) for effects on fertility was 30 mg/kg/day and the developmental NOAEL was 100 mg/kg/day.

REFERENCES

Ballenger JC. Clinical Evaluation of Venlafaxine. J Clin Psychopharmacol 1996; 16 (3, Suppl 2):29S-35S.Ballenger JC. Clinical Evaluation of Venlafaxine: Commentary. J Clin Psychopharmacol 1996; 16(3, Suppl 2):35S-36S.Ballus C, Quiros G, De Flores T, de la Torre J, Palao D, Rojo L, et al. The efficacy and tolerability of venlafaxine and paroxetine in outpatients with depressive disorder or dysthymia. International Clinical Psychopharmacology 2000; 15(1):43-48.Benkert O, Grunder G, Wetzel H, Hackett D. A Randomized, Double-Blind Comparison of a Rapidly Escalating Dose of Venlafaxine and Imipramine in Patients with Major Depression and Melancholia. J Psychiat Res 1996; 30(6):441-451.Clerc GE, Ruimy P, Verdeau-Palles J. A Double-Blind Comparison of Venlafaxine and Fluoxetine in Patients Hospitalized for Major Depression and Melancholia. International Clinical Psychopharmacology 1994; 9:139-143.Costa e Silva J. Randomized, double-blind comparison of venlafaxine and fluoxetine in outpatients with major depression. J Clin Psychiatry 1998; 59:352-357.Cunningham LA, Borison RL, Carman JS, Chouinard G, Crowder JE, Diamond BI. et al. A Comparison of Venlafaxine, Trazodone, and Placebo in Major Depression. J Clin Psychopharmacol 1994; 14(2):99-106.Dierick M. An Open Label Evaluation of the Long-Term Safety of Oral Venlafaxine in Depressed Elderly Patients. Annals of Clin Psychiatry 1996; 8(3):169-178.Entsuah R, Upton GV, Rudolph R. Efficacy of Venlafaxine Treatment in Depressed Patients with Psychomotor Retardation or Agitation: A Meta-Analysis. Human Psychopharmacol 1995; 10:195-200.Entsuah R, Rudolph R, Chitra R. Effectiveness of Venlafaxine Treatment in a Broad Spectrum of Depressed Patients: A Meta-Analysis. Psychopharmacol Bull 1995; 31(4):759-766.Ereshefsky L. Drug-Drug Interactions Involving Antidepressants: Focus on Venlafaxine.

J Clin Psychopharmacol 1996; 16(3) Suppl 2: 37S-49S.

Feighner JP. The Role of Venlafaxine in Rational Antidepressant Therapy. J Clin Psychiatry 1994; 55 (9, Suppl A):62-68.

Guelfi JD, White C, Hackett D, Guichoux JY, Magni G. Effectiveness of Venlafaxine in Patients Hospitalized for Major Depression and Melancholia. J Clin Psych 1995; 56(10): 450-458.

Khan A, Fabre LF, Rudolph R. Venlafaxine in Depressed Outpatients. Psychopharmacol Bull 1991; 27(2):141-144.

Kuzel RJ. Treating Comorbid Depression and Anxiety. J Family Practice 1996; 43(6, Suppl):S45-S53.

Lecrubier Y, Bourin M, Moon CA, Schifano F, Blanchard C, Danjou P. et al. Efficacy of venlafaxine in depressive illness in general practice. Acta Psychiatr Scand 1997; 95:485-493.

Mehtonen O-P, Sogaard J, Roponen P, Behnke K. Randomized, double-blind comparison of venlafaxine and sertraline in outpatients with major depressive disorder. J Clin Psychiatry 2000; 61(2):95-100.

Mendels J, Johnston R, Mattes J, Riesenberg R. Efficacy and Safety of BID Doses Of Venlafaxine In A Dose-Response Study. Psychopharmacol Bull 1993; 29(2):169-174.

Montgomery SA. Venlafaxine: A New Dimension in Antidepressant Pharmacotherapy.

J Clin Psychiatry 1993; 54(3):119-126.

Muth EA, Moyer JA, Haskins JT, Andree TH, Husbands GEM. Biochemical, Neurophysiological, and Behavioral Effects of Wy-45,233 and Other Identified Metabolites of the Antidepressant Venlafaxine. Drug Development Research 1991; 23:191-199.

Nierenberg A, Feighner J, Rudolph R, Cole J, Sullivan J. Venlafaxine For Treatment- Resistant Unipolar Depression. J Clin Psychopharmacol 1994; 14:419-423.

Pollack MH, Worthington JJ III, Otto MW, Maki KM, Smoller JW, Manfro GG, et al.

Clinical Trials - Anxiety Disorders: Venlafaxine for Panic Disorder: Results From a Double-Blind, Placebo-Controlled Study. Psychopharmacol Bull 1996; 32(4):667-670.

Rudolph RL, Entsuah R, Chitra R. A Meta-Analysis of Effects of Venlafaxine on Anxiety Associated with Depression. J Clin Psychopharmacol 1998; 18:136-144.

Rudolph RI, Feiger AD. A double-blind, randomized, placebo-controlled trial of once- daily venlafaxine extended release (XR) and fluoxetine for the treatment of depression. J Affective Disorders 1999; 56:171-181.

Schweizer E, Weise C, Clary C, Fox I, Rickels K. Placebo-Controlled Trial of Venlafaxine for the Treatment of Major Depression. J Clin Psychopharmacol 1991; 11(4):233-236.

Schweizer E, Feighner J, Mandos LA, Rickels K. Comparison of Venlafaxine and Imipramine in the Acute Treatment of Major Depression in Outpatients. J Clin Psychiatry 1994; 55(3):104-108.

Shrivastava RK, Cohn C, Crowder J, Davidson J, Dunner D, Feighner J. et al. Long- Term Safety and Clinical Acceptability of Venlafaxine and Imipramine in Outpatients with Major Depression. J Clin Psychopharmacol 1994; 14(5):322-329.

Zajecka JM, Fawcett J, Guy C. Co-existing Major Depression and Obsessive-compulsive Disorder treated with Venlafaxine. J Clin Psychopharmacol 1990; 10(2): 152-153.

PART III: CONSUMER INFORMATION

EFFEXOR(r) XR

(Venlafaxine Hydrochloride) Extended Release Capsules

This leaflet is part III of a three-part "Product Monograph" published when EFFEXOR XR was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about EFFEXOR XR. Contact your doctor or pharmacist if you have any questions about the drug.

Please read this information carefully before you start to take your medicine, even if you have taken this drug before. Do not throw away this leaflet until you have finished your medicine as you may need to read it again. For further information or advice, please see your doctor or pharmacist.

ABOUT THIS MEDICATION

What the medication is used for:

EFFEXOR XR has been prescribed to you by your doctor to relieve your symptoms of the following conditions:

• Depression (feeling sad, a change in appetite or weight, difficulty concentrating or sleeping, feeling tired, headaches, unexplained aches and pain)

• Generalized anxiety or nervousness

• Social phobia (social anxiety disorder) - avoidance and/or fear of social situations

• Panic disorder (repeated, unexpected panic attacks) What it does: EFFEXOR XR belongs to a group of medicines called anti- depressants. EFFEXOR XR is thought to work by affecting two naturally occurring brain chemicals, serotonin and norepinephrine. When it should not be used:

• Do not use EFFEXOR XR if you are allergic to it or to any of the components of its formulation (see list of components at the end of this section). Stop taking the drug and contact your doctor immediately if you experience an allergic reaction or any severe or unusual side effects.

• Do not use EFFEXOR XR if you are currently taking or have recently taken monoamine oxidase inhibitor antidepressants (e.g. phenelzine sulphate, moclobemide). What the medicinal ingredient is: Venlafaxine Hydrochloride What the nonmedicinal ingredients are: Black Iron Oxide NF * *, Ethylcellulose NF, Gelatin NF, Hydroxypropyl-methylcellulose USP, Microcrystalline cellulose NF, Opacode Red Ink S-1-15034 * * * *, Red Iron Oxide *, Talc, Titanium Dioxide *, White Ink TekPrint SB-0007P * * *, Yellow Iron Oxide *. Present (in capsule) in all strengths * * Present (in capsule) in 37.5 mg strength only * * * 150 mg strength * * * * 37.5 and 75 mg strengths What dosage forms it comes in: EFFEXOR XR is available in extended release capsules containing 37.5 mg (grey and peach), 75 mg (peach) and 150 mg (dark orange) venlafaxine. WARNINGS AND PRECAUTIONS During treatment with these types of medication it is important that you and your doctor have good ongoing communication about how you are feeling. EFFEXOR XR is not for use in children under 18 years of age. New or Worsened Emotional or Behavioural Problems Particularly in the first few weeks or when doses are adjusted, a small number of patients taking drugs of this type may feel worse instead of better; for example, they may experience unusual feelings of agitation, hostility or anxiety, or have impulsive or disturbing thoughts such as thoughts of self-harm or harm to others. Should this happen to you, or to those in your care if you are a caregiver or guardian, consult your doctor immediately. Close observation by a doctor is necessary in this situation. Do not discontinue your medication on your own. Before taking EFFEXOR XR tell your doctor or pharmacist: if you have ever had any allergic reaction to medications, food, etc; all your medical conditions, including a history of seizures, liver disease, kidney disease, heart problems or high cholesterol, or history of any abnormal bleeding; if you have blood pressure problems; any medications (prescription or non-prescription) which you are taking, especially monoamine oxidase (MAO) inhibitors (e.g. phenelzine sulfate, tranylcypromine sulfate, moclobemide or selegeline) or any other antidepressants, weight-loss medication, sleeping pills, antianxiety drugs, or medication to control blood pressure; if you are pregnant or thinking about becoming pregnant, or if you are breast feeding; your habits of alcohol and/or street drug consumption; any natural or herbal products you are taking (e.g., St. John's Wort). if you drive a vehicle or perform hazardous tasks during your work. Discontinuing Effexor XR It is very important that you do NOT stop taking these medications without first consulting your doctor. See SIDE EFFECTS AND WHAT TO DO ABOUT THEM section for more information. Effects on Pregnancy and Newborns Post-marketing reports indicate that some newborns whose mothers took an SSRI (selective serotonin reuptake inhibitor) or other newer anti-depressants, such as EFFEXOR XR, during pregnancy have developed complications at birth requiring prolonged hospitalization, breathing support and tube feeding. Reported symptoms included feeding and/or breathing difficulties, seizures, tense or overly relaxed muscles, jitteriness and constant crying. In most cases, the SSRI or other newer anti-depressant was taken during the third trimester of pregnancy. These symptoms are consistent with either a direct adverse effect of the anti- depressant on the baby, or possibly a discontinuation syndrome caused by sudden withdrawal from the drug. These symptoms normally resolve over time. However, if your baby experiences any of these symptoms, contact your doctor as soon as you can. If you are pregnant and taking an SSRI, or other newer anti- depressant, you should discuss the risks and benefits of the various treatment options with your doctor. It is very important that you do NOT stop taking these medications without first consulting your doctor. See SIDE EFFECTS AND WHAT TO DO ABOUT THEM section for more information. improve within about 2 weeks but significant improvement can take several weeks.

• EFFEXOR XR should be taken once a day with food, as prescribed; do not divide, crush or chew the capsules. REMEMBER: This medicine has been prescribed only for you. Do not give it to anybody else. If you have any further questions, please ask your doctor or pharmacist. Overdose: In case of overdose, contact your doctor or the nearest hospital emergency department, even though you may not feel sick. Missed Dose: If you happen to miss a dose, do not try to make up for it by doubling up on the dose next time. Just take your next regularly scheduled dose and try not to miss any more. INTERACTIONS WITH THIS MEDICATION Do not use EFFEXOR XR if you are taking or have recently taken monoamine oxidase inhibitors. You should avoid taking St. John's Wort if you are taking EFFEXOR XR. You should tell your doctor if you are taking or have recently taken any medications (prescription, non-prescription or natural/herbal), especially:

• other antidepressants, such as SSRIs and certain tricyclics

• other drugs that affect serotonin such as, lithium, linezolid, sibutramine, tramadol, tryptophan, triptans used to treat migraines

• certain medicines used to treat schizophrenia

• certain medicines used to treat bipolar depression, such as lithium

• metoprolol or other medications used to treat high blood pressure and angina

• certain medicines which may affect blood clotting and increase bleeding, such as oral anti-coagulants (e.g. warfarin), aspirin and other non-steroidal anti-inflammatory drugs (e.g. ibuprofen)

• certain medicines used to treat epilepsy

• cimetidine

• In general, drinking alcoholic beverages should be kept to a minimum or avoided completely while taking EFFEXOR XR.

• Ketoconazole. PROPER USE OF THIS MEDICATION Usual dose:

• It is very important that you take EFFEXOR XR exactly as your doctor has instructed.

• Never increase or decrease the amount of EFFEXOR XR you, or those in your care if you are a caregiver or guardian, are taking unless your doctor tells you to and do not stop taking this medication without consulting your doctor.

• As with all antidepressants improvement with EFFEXOR XR is gradual. You may not have noticeable effect in the first few days of treatment. Some symptoms may begin to SIDE EFFECTS AND WHAT TO DO ABOUT THEM Like all medications, EFFEXOR XR can cause some side effects. You may not experience any of them. For most patients these side effects are likely to be minor and temporary. However, some may be serious. Some of these side effects may be dose related. Consult your doctor if you experience these or other side effects, as the dose may have to be adjusted. If you experience an allergic reaction (including red skin, hives, itching, swelling of the lips, face, tongue, throat, trouble breathing, wheezing, shortness of breath, skin rashes, blisters of the skin, sores or pain in the mouth or eyes) or any severe or unusual side effects, stop taking the drug and contact your doctor immediately. Some side effects of EFFEXOR XR are:

• headache

• nausea

• dry mouth

• constipation

• loss of appetite

• vomiting

• sleepiness

• dizziness

• insomnia

• sexual problems

• weakness

• sweating

• nervousness

• abnormal vision Particularly in the first few weeks or when doses are adjusted, a small number of patients taking drugs of this type may feel worse instead of better; for example, they may experience unusual feelings of agitation, hostility or anxiety, or have impulsive or disturbing thoughts such as thoughts of self-harm or harm to others. Should this happen to you, or to those in your care if you are a caregiver or guardian, consult your doctor immediately; do not discontinue your medication on your own. EFFEXOR XR does not usually affect people's normal activities. However, some people feel sleepy while taking it, in which case they should not drive or operate machinery. SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEMSymptom / effectTalk with your doctor or pharmacist right awaySeek urgent medical attentionOnly if severeIn all casesCommonIncreased blood pressurethat persists [see also SevereHypertension below][? ]CommonFast heartbeat[? ]UncommonAllergic reactions [redskin, hives, itching, swelling of the lips,face, tongue, throat, trouble breathing, wheezing, shortness ofbreath, skin rashes, blisters of the skin, sores or pain in the mouth oreyes][? ]UncommonLow sodium level inblood [symptoms of tiredness, weakness,confusion combined with achy, stiff oruncoordinated muscles][? ]UncommonBruising or unusualbleeding from the skin or other areas[? ]UncommonMania/hypomania[elevated or irritable mood, decreased needfor sleep, racing thoughts][? ]UncommonAkathisia [feelingrestless and unable to sit or stand still][? ]UncommonHallucinations [strangevisions or sounds][? ]UncommonUncontrollablemovements of the body or face[? ]UncommonInability to urinate[? ]UncommonGastrointestinalbleeding [vomiting blood or passing blood in stools][? ]RareSeizures [loss ofconsciousness with uncontrollable shaking"fit"][?] Although psychiatric disorders may be associated with decreases in sexual desire, performance and satisfaction, treatment with this medication may also affect sexual functioning. Effexor XR may increase blood pressure in some people. You should have your blood pressure measured prior to starting Effexor XR and during treatment. High blood pressure should be controlled before starting Effexor XR. Blood pressure changes may sometimes be sudden and without warning. Consult your doctor if you have symptoms that may indicate a sudden rise in your blood pressure, such as headache (particularly in the back of head/neck when waking up); stronger, possibly more rapid, or irregular heart beat; chest pain; dizziness; excessive tiredness; or blurred vision. Effexor XR may raise cholesterol levels in some patients. Blood cholesterol tests may be required by your doctor during treatment with Effexor XR. New or Worsened Emotional or Behavioural Problems A small number of patients taking drugs of this type may feel worse instead of better; for example, they may experience new or worsened feelings of agitation, hostility or anxiety, or thoughts about suicide. Your doctor should be informed of such changes immediately. Close observation by a doctor is necessary in this situation. Do not discontinue your medication on your own. See also the WARNINGS AND PRECAUTIONS section. Discontinuation Symptoms Contact your doctor before stopping or reducing your dosage of EFFEXOR XR. Symptoms such as anorexia (loss of appetite, loss of weight), anxiety, agitation (restlessness), aggression, confusion, convulsions, coordination problems, diarrhea, dizziness, dry mouth, fatigue, headache, hypomania (rapid mood swings), insomnia, nausea, nervousness, nightmares, paresthesia (sensation of tingling, burning or crawling of the skin), electric shock sensations, sleep disturbances, somnolence (drowsiness), sweating, tinnitus (ringing in the ears), vertigo (sensation that the world is spinning), vomiting and other symptoms have been reported after stopping treatment, reducing the dosage of EFFEXOR XR, or when a dose is missed. These symptoms usually disappear without needing treatment. Tell your doctor immediately if you have these or any other symptoms. Your doctor may adjust the dosage of EFFEXOR XR to alleviate the symptoms. Effects on Newborns Some newborns whose mothers took an SSRI (Selective Serotonin Reuptake Inhibitor) or other newer anti-depressant, such as EFFEXOR XR, during pregnancy have shown such symptoms as breathing and feeding difficulties, jitteriness and constant crying. If your baby experiences any of these symptoms, contact your doctor as soon as you can. See WARNINGS AND PRECAUTIONS section for more information. SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEMSymptom / effectTalk with your doctor or pharmacist right awaySeek urgent medical attentionOnly if severeIn all casesRareSerotonin syndrome [acombination of most or all of the following; confusion, restlessness, sweating, shaking, shivering, suddenjerking of the muscles, hallucinations, fast heartbeat][? ]RareLiver disorder[symptoms include nausea, vomiting, loss ofappetite combined with itching, yellowing of theskin or eyes, dark urine][? ]Very rareIncreased pressure in theeyes [symptoms of eye pain, decreased orblurred vision, red eye, swelling of eye][? ]See Warnings and PrecautionsNew or worsenedemotional or behavioural problems[? ]See Side Effects and What to Do About ThemSevere Hypertension[symptoms include headache, stronger andpossibly faster heartbeat, chest pain, dizziness,excessive tiredness, blurred vision][?] REPORTING SUSPECTED SIDE EFFECTS To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance by: toll-free telephone: 866-234-2345 toll-free fax 866-678-6789 By email: CanadaVigilance @hc-sc.gc.ca By regular mail: Canada Vigilance National Office Marketed Health Products Safety and Effectiveness Information Division Marketed Health Products Directorate Health Products and Food Branch Health Canada Tunney=s Pasture, AL 0701C Ottawa ON K1A 0K9 NOTE: Before contacting Canada Vigilance, you should contact your physician or pharmacist. This is not a complete list of side effects. For any unexpected effects while taking EFFEXOR XR, contact your doctor or pharmacist. MORE INFORMATION This document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor, WYETH CANADA 1025 Marcel Laurin Blvd. Saint Laurent, Quebec H4R 1J6 1-800-461-8844 or at http://www.wyeth.ca/en. This leaflet was prepared by WYETH CANADA Last revised: .June 16, 2008 HOW TO STORE IT

• Store EFFEXOR XR at room temperature (15-30EC), in a dry place.

• Keep container tightly closed.

• Keep all medicines out of the reach of children.

• If your doctor tells you to stop taking EFFEXOR XR please return any left over medicine to your pharmacist.

EFFEXOR XR is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

Discontinuing Venlafaxine

When discontinuing venlafaxine after more than 1 week of therapy, it is generally recommended that the dose be tapered gradually to minimize the risk of discontinuation symptoms. Discontinuation symptoms have been assessed both in patients with depression and in those with GAD. Abrupt discontinuation, dose reduction, or tapering of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with higher dose levels and with longer duration of treatment. Reported symptoms include but are not limited to the following: aggression, agitation, anorexia, anxiety, asthenia, confusion, convulsions, coordination impaired, diarrhoea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headache, hypomania, insomnia, nausea, nightmares, nervousness, paresthesia, electric shock sensations, sensory disturbances (including shock like electrical sensations), sleep disturbances, somnolence, sweating, tinnitus, vertigo, and vomiting. Where such symptoms occurred they were usually self-limiting but in a few patients continued for several weeks. It is therefore recommended that the dosage of EFFEXOR XR be tapered gradually and the patient monitored. The period required for tapering may depend on the dose, duration of therapy and the individual patient. If venlafaxine has been used for more than 6 weeks, tapering over at least a two week period is recommended (see WARNINGS AND PRECAUTIONS, POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM,

and also Discontinuation Symptoms; ADVERSE REACTIONS, Discontinuation

Symptoms).

Patients With Hepatic or Renal Impairment:

Dosage adjustments are required (see DOSAGE AND ADMINISTRATION, Special Patient Populations below).

Switching Patients to or from a Monoamine Oxidase Inhibitor:

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with EFFEXOR XR. In addition, at least 14 days should be allowed after stopping EFFEXOR XR before starting an MAOI (see CONTRAINDICATIONS).

Switching Patients from Immediate Release Tablets:

Depressed patients who are currently being treated at a therapeutic dose with immediate release tablets may be switched to EFFEXOR XR at the nearest equivalent dose (mg/day), e.g., 37.5 mg immediate release two-times-a-day to 75 mg EFFEXOR XR once daily. However, individual dosage adjustments may be necessary.

Recommended Dose and Dosage Adjustment

ADULTS:

Patients with Major Depressive Disorder

The recommended dose for EFFEXOR XR is 75 mg/day, administered once daily with food, either in the morning or in the evening. For some patients, it may be desirable to start at 37.5 mg/day for 4-7 days to allow new patients to adjust to the medication before increasing to 75 mg/day. Each capsule should be swallowed whole with water. It should not be divided, crushed, chewed, or placed in water. While the relationship between dose and antidepressant response for EFFEXOR XR has not been adequately explored patients not responding to the initial 75 mg may benefit from dose increases. Depending on tolerability and the need for further clinical effect, the dose should be increased by up to 75 mg/day up to a maximum of 225 mg/day as a single dose for moderately depressed outpatients. Dose increments should be made at intervals of approximately 2 weeks or more, but not less than 4 days. There is very limited experience with EFFEXOR XR at doses higher than 225 mg/day, or in severely depressed inpatients.

Patients with Generalized Anxiety Disorder (GAD)

The recommended starting dose of EFFEXOR XR is 37.5 mg/day administered as a single dose, taken with food, for 4-7 days. The usual dose is 75 mg/day administered as a single dose. Subsequent dosage increments of up to 75 mg/day may be considered, if clinically warranted. Dose increments should be made as needed at intervals of not less than 4 days. The maximum recommended daily dose is 225 mg/day as a single dose.

Patients with Social Anxiety Disorder (Social Phobia)

For most patients, the recommended dose for EFFEXOR XR is 75 mg/day, administered in a single dose. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to the medication before increasing to 75 mg/day. Depending on tolerability and if clinically warranted, dose increases should be in increments of up to 75 mg/day, as needed, up to a maximum of 225 mg/day. Dose increments should be made at intervals of not less than 4 days.

Panic Disorder

It is recommended that initial single doses of 37.5 mg/day of Effexor XR be used for 7 days. The recommended treatment dose is 75 mg/day, administered in a single dose. Although a dose response relationship for effectiveness in patients with Panic Disorder was not clearly established in fixed-dose studies, certain patients not responding to 75 mg/day may benefit from dose increases to a maximum of 225 mg/day. Dose increases should be in increments of up to 75 mg/day, as needed, and should be made at intervals of at least 7 days.

Maintenance/Continuation/Extended Treatment

There is no body of evidence available to answer the question of how long a patient should continue to be treated with EFFEXOR XR for depression, GAD, Social Anxiety Disorder or Panic Disorder. During long-term therapy for any indication, the Effexor XR dosage should be maintained at the lowest effective dose and the need for continuing treatment should be periodically reassessed.

Depression:

It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacotherapy beyond response to the acute episode. Whether the dose needed to induce remission is identical to the dose needed for maintenance is unknown. Maintenance of efficacy of EFFEXOR XR has been shown in a placebo controlled study in which patients responding during 8 weeks of acute treatment with EFFEXOR XR were assigned randomly to placebo or to the same dose of EFFEXOR XR [75, 150, or 225 mg/day, in the morning (i.e. qAM)] during 26 weeks of maintenance treatment (see CLINICAL TRIALS, Depression). It is not known whether or not the dose of EFFEXOR XR 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.

Social Anxiety Disorder

In patients with Social Anxiety Disorder, there are no efficacy data beyond 6 months of treatment with EFFEXOR XR. The need for continuing medication in patients with Social Anxiety Disorder who improve with EFFEXOR XR treatment should be periodically reassessed.

Panic Disorder

In one study in Panic Disorder, in which patients who were responders in the final 2 weeks of a 12-week acute treatment with Effexor XR were assigned randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day) during 6 months of maintenance treatment, patients continuing Effexor XR treatment showed a significant longer time to relapse than patients switched to placebo.

Special Patient Populations:

Treatment of Pregnant Women During the Third Trimester

WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women

Post-marketing reports indicate that some neonates exposed to immediate release venlafaxine or EFFEXOR XR, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. (See

). When treating a pregnant woman with EFFEXOR XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Due to the potential for discontinuation symptoms, if a decision is taken to discontinue Effexor XR treatment, a gradual reduction in the dose rather than an abrupt cessation is recommended (See WARNINGS AND PRECAUTIONS, Discontinuation Symptoms).

Elderly Patients

No dose adjustment is recommended for elderly patients solely on the basis of their age. As with any antidepressant or anxiolytic, drug for treatment of Social Anxiety Disorder, or Panic Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

Pediatrics

EFFEXOR XR is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

Patients With Hepatic Impairment:

Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared with normal subjects (see ACTION AND CLINICAL PHARMACOLOGY, Hepatic Insufficiency), the total daily dose must be reduced by about 50% in patients with mild to moderate hepatic impairment. For such patients, it may be desirable to start at 37.5 mg/day. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose by even more than 50%, and individualization of dosing may be desirable in some patients.

Patients with Renal Impairment

Given the decrease in clearance for venlafaxine and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10-70 mL/min) compared to normal subjects (see ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency) the total daily dose must be decreased by 25%-50%. In patients undergoing hemodialysis, the total daily dose must be reduced by 50% and the dose be withheld until the dialysis treatment is completed (4 hrs). For such patients, it may be desirable to start at 37.5 mg/day. Since there is so much individual variability in clearance among patients with renal impairment, individualization of dosing may be desirable.

Missed Dose

If a dose is missed, it should not be made up for it by doubling up on the dose next time. The next dose should be taken as scheduled.

Administration

Administer once daily with food, either in the morning or in the evening.

OVERDOSAGE

Venlafaxine Immediate Release Tablets

There were 14 reports of acute overdose with immediate release tablets (venlafaxine HCl), either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 :g/mL, respectively, and the peak plasma levels of O- desmethylvenlafaxine were 3.37 and 1.30 :g/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients.

EFFEXOR XR Capsules

Among the patients included in the premarketing evaluation of venlafaxine extended release capsules, there were 2 reports of acute overdosage with EFFEXOR XR in depression trials, either alone or in combination with other drugs. One patient took a combination of 6 g of EFFEXOR(r) XR and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of EFFEXOR XR. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with EFFEXOR XR in anxiety trials. One patient took a combination of 0.75 g EFFEXOR XR and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of EFFEXOR XR. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. There were no reports of acute overdose with EFFEXOR XR in Social Anxiety Disorder trials. There were 2 reports of acute overdose with Effexor XR in Panic Disorder trials. One patient took 0.675 g of Effexor XR once and the other patient took 0.45 g of Effexor XR for 2 days. No signs or symptoms were associated with either overdose and no actions were taken to treat them.

Postmarketing Experience with EFFEXOR (Dosage Form Unknown)

In postmarketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, delayed rise in plasma creatine kinase levels, rhabdomyolysis, liver necrosis, serotonin syndrome, vertigo, and death have been reported. Muscle enzymes should be monitored in patients with venlafaxine overdose to detect development of rhabdomyolysis at an early stage and to initiate appropriate treatment. According to post-marketing overdose reports with venlafaxine (where overdose amounts were provided) fatal acute overdoses have been reported with venlafaxine alone at doses as low as approximately 1 gram. 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 burden of suicide risk factors than SSRI 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 characteristics of venlafaxine-treated patients is not clear. Prescriptions for venlafaxine should be written for the smallest quantity of drug consistent with good patient management, in order to reduce the risk of overdose.

Overdosage Management

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control centre for current information on the treatment of any overdose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Venlafaxine is a phenethylamine bicyclic derivative, chemically unrelated to tricyclic, tetracyclic or other available antidepressant or anxiolytic agents. The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.

Pharmacodynamics

Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or a1- 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.

Pharmacokinetics

Venlafaxine Immediate Release Formulation

Venlafaxine is well absorbed, with peak plasma concentrations occurring approximately 2 hours after dosing. Venlafaxine is extensively metabolized, with O-desmethylvenlafaxine, (ODV, the only major active metabolite) peak plasma levels occurring approximately 4 hours after dosing. Following single doses of 25 to 75 mg, mean (+- SD) peak plasma concentrations of venlafaxine range from 37 +- 14 to 102 +- 41 ng/mL, respectively, and are reached in 2 +- 1 hours, and mean peak ODV plasma concentrations range from 61 +- 13 to 168 +- 37 ng/mL and are reached in 4 +- 2 hours. Approximately 87% of a single dose of venlafaxine is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%), and 92% of the radioactive dose is recovered within 72 hours. Therefore, renal elimination of venlafaxine and its metabolites is the primary route of excretion.

EFFEXOR XR Capsules

After administration of EFFEXOR XR (venlafaxine hydrochloride, extended release capsules) the peak plasma concentrations of venlafaxine and ODV are attained within 6.0+-1.5 and 8.8+-2.2 hours, respectively. The rate of absorption of venlafaxine from the EFFEXOR XR capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of EFFEXOR(r) XR (15+-6 hours) is actually the absorption half-life instead of the true disposition half-life (5+-2) hours observed following administration of a venlafaxine hydrochloride immediate release tablet.

Multiple-Dose Pharmacokinetic Profile (Immediate Release Tablets and Extended Release Capsules) Steady-state concentrations of both venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. The clearance of venlafaxine is slightly (15%) lower following multiple doses than following a single dose. Venlafaxine and ODV exhibited approximately linear kinetics over the dose range of 75 to 450 mg/day. The mean +-SD steady-state plasma clearances of venlafaxine and ODV are 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 renal clearances are 49 +- 27 and 94 +- 56 mL/h/kg, respectively, which correspond to 5 +- 3.0% and 25 +- 13% of an administered venlafaxine dose recovered in urine as venlafaxine and ODV, respectively. When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended release capsule, the exposure (AUC, area under the concentration curve) to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower following treatment with the extended release capsule. Therefore, the EFFEXOR XR capsules provide a slower rate of absorption, but the same extent of absorption (i.e., AUC), as the venlafaxine immediate release tablet. Results of testing in healthy volunteers demonstrated differences in the gastrointestinal tolerability of different formulations of venlafaxine. Data from healthy volunteers showed reduced incidence and severity of nausea with EFFEXOR XR capsules, compared with immediate release tablets. Venlafaxine and ODV are 27 and 30% bound to human plasma proteins, respectively. Therefore, administration of venlafaxine to a patient taking another drug that is highly protein- bound should not cause increased free concentrations of the other drug. Following intravenous administration, the steady-state volume of distribution of venlafaxine is 4.4 +-1.9L/kg, indicating that venlafaxine distributes well beyond the total body water. Absorption: Venlafaxine is well absorbed; after administration of EFFEXOR XR (venlafaxine hydrochloride, extended release capsules), the peak plasma concentrations of venlafaxine and ODV are attained within 6.0 +-1.5 and 8.8 +-2.2 hours, respectively. The rate of absorption of venlafaxine from the EFFEXOR XR capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of EFFEXOR(r) XR (15 +-6 hours) is actually the absorption half-life instead of the true disposition half-life (5 +-2) hours observed following administration of a venlafaxine hydrochloride immediate release tablet. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Food has no significant effect on the absorption of venlafaxine or on the subsequent formation of ODV.

Distribution:

Following intravenous administration, the steady-state volume of distribution of venlafaxine is 4.4 +-1.9L/kg, indicating that venlafaxine distributes well beyond the total body water. Venlafaxine and ODV are 27 and 30% bound to human plasma proteins, respectively. Therefore, administration of venlafaxine to a patient taking another drug that is highly protein- bound should not cause increased free concentrations of the other drug.

Metabolism: Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. The absolute bioavailability of venlafaxine is approximately 45%. The primary metabolite of venlafaxine is ODV, which is an active metabolite. Venlafaxine is also metabolized to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalysed by CYP2D6 and that the formation of N-desmethylvenlafaxine is catalysed by CYP3A3/4. The results of the in vitro studies have been confirmed in a clinical study with subjects who are CYP2D6 poor and extensive metabolizers. However, despite the metabolic differences between the CYP2D6 poor and extensive metabolizers, the total exposure to the sum of the two active species (venlafaxine and ODV, which have comparable activity) was similar in the two metabolizer groups.

Excretion:

Approximately 87% of a single dose of venlafaxine is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%), and 92% of the radioactive dose is recovered within 72 hours. Therefore, renal elimination of venlafaxine and its metabolites is the primary route of excretion.

Special Populations and Conditions

Pediatrics:

Safety and efficacy in children below the age of 18 have not been established. EFFEXOR XR (venlafaxine) is not indicated for use in children under 18 years of age.

Geriatrics:

Population pharmacokinetic analyses of 547 venlafaxine-treated patients from three studies involving both venlafaxine immediate release tablets and venlafaxine extended release capsules showed that age does not significantly affect the pharmacokinetics of venlafaxine. A 20% reduction in clearance was noted for ODV in subjects over 60 years old; this was possibly caused by the decrease in renal function that typically occurs with aging. Dosage adjustment based upon age is generally not necessary.

Gender:

Population pharmacokinetic analyses of 547 venlafaxine-treated patients from three studies involving both venlafaxine immediate release tablets and venlafaxine extended release capsules showed that sex does not significantly affect the pharmacokinetics of venlafaxine. Dosage adjustment based upon gender is generally not necessary.

Hepatic Impairment:

In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered. Venlafaxine elimination half-life was prolonged by about 30%, and clearance was decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic patients compared to normal subjects.

A large degree of inter-subject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. Dosage adjustment is necessary in patients with hepatic impairment (see DOSAGE AND ADMINISTRATION, Special Patient Populations).

Renal Impairment:

In patients with moderate to severe impairment of renal function (GFR = 10-70 mL/min), venlafaxine elimination half-life was prolonged by 50%, and clearance was decreased by about 24% compared to normal subjects. ODV elimination half-life was prolonged by about 40%, but clearance was unchanged.

In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was decreased by about 57%. In dialysis patients, ODV elimination half-life was prolonged by about 142%, and clearance was reduced by about 56% compared to normal subjects. A large degree of inter-subject variability was noted.

Dosage adjustment is necessary in patients with renal impairment DOSAGE AND ADMINISTRATION, Special Patient Populations.

(see

)

Genetic Polymorphism:

Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, there is no need for different venlafaxine dosing regimens for these two groups.

STORAGE AND STABILITY

Store at room temperature (15-30EC), in a dry place.

SPECIAL HANDLING INSTRUCTIONS

None.

DOSAGE FORMS, COMPOSITION AND PACKAGING

PrEFFEXOR XR (venlafaxine HCl) extended-release capsules are available in bottles of 100 capsules, in the following dosage strengths (potency is expressed in terms of venlafaxine base):

mg

Hard gelatin capsule with gray cap and peach body, with "W" and "Effexor XR" on the cap and "37.5" on the body, in red ink.

mg

Hard gelatin capsule with peach cap and body, with "W" and "Effexor XR" on the cap and "75" on the body, in red ink.

mg

Hard gelatin capsule with dark orange cap and body, with "W" and "Effexor XR" on the cap and "150" on the body, in white ink.

The appearance of these capsules is a trademark of Wyeth Canada.

Composition:

Medicinal Ingredients Non-medicinal Ingredients:

Venlafaxine Hydrochloride Ethylcellulose, NF

Gelatin, NF Hydroxypropylmethyl Cellulose, USP Iron Oxide, NF Microcrystalline Cellulose, NF Titanium Dioxide, USP White Tek SB-0007 and/or Opacode Red S-1-15034 ink Talc, USP

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Venlafaxine Hydrochloride Chemical name: (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride; or (+-)-1-[a[(dimethylamino)methyl]-p-methoxy-benzyl] cyclohexanol hydrochloride. Molecular formula and molecular mass: C17H27NO2 *HCl; 313.87 Structural formula: Physicochemical properties: Physical Form: White to off-white crystalline solid Solubility: Water: 540, 542, 501 and 21.6 mg/mL at pH 1.0, 5.38, 7.09 and 7.97 Ethanol: 91.7 mg/mL Propylene Glycol: 200 mg/mL Glycerin: 115 mg/mL pKa value: 9.4

CLINICAL TRIALS DEPRESSION

Venlafaxine Immediate Release Tablet Formulation

The efficacy of immediate release tablets in the treatment of depression was established in 6- week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-II or DSM-III-R category of major depressive disorder and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depressive disorder with melancholia. In one longer term study, outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had "responded" * during an initial 26 weeks of treatment on a venlafaxine immediate release tablet (100 to 200 mg/day, on a b.i.d. schedule) and continued to be "improved" *, were randomized to continuation of their same venlafaxine immediate release tablet dose or to placebo. The follow-up period to observe patients for "relapse" * was for up to 52 weeks. Patients receiving continued venlafaxine immediate release tablet treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.

*For the purposes of this study:

"Responded" was defined as HAM-D-21 total score # 12 at the day 56 evaluation)

"Improved" was 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).

"Relapse" was defined as a CGI Severity of Illness item score >4 during the double-blind phase.

EFFEXOR XR Capsules (Extended release)

The efficacy of EFFEXOR XR (venlafaxine hydrochloride extended release) capsules as a treatment for depression was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depression. An 8- week study utilizing EFFEXOR XR doses in a range 75-225 mg/day (mean dose for completers was 177 mg/day) and a 12-week study utilizing EFFEXOR XR doses in a range 75-150 mg/day (mean dose for completers was 136 mg/day) both demonstrated superiority of EFFEXOR XR over placebo on the HAM-D total score, the HAM-D Depressed Mood Item, the MADRS total score, the CGI Severity of illness scale, and the CGI Global Improvement scale. In both studies, EFFEXOR XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score. In the 12-week study comparing immediate release tablets with EFFEXOR XR capsules, once daily, EFFEXOR XR was significantly more effective at weeks 8 and 12, compared with immediate release tablets given twice daily for treating major depression. Analysis of safety data from this trial showed that the incidence of treatment-emergent nausea and nausea severity over time were lower with EFFEXOR XR than with immediate release tablets. Additionally, the incidence of vomiting was lower with EFFEXOR XR than with immediate release tablets. In one longer term study, outpatients meeting DSM-IV criteria for major depressive disorder who had "responded" * during an 8-week open trial on EFFEXOR XR capsules (75, 150, or 225 mg, in the morning (qAM) were randomized to continuation of their same EFFEXOR XR dose or to placebo, for up to 26 weeks of observation for "relapse" *. Patients receiving continued EFFEXOR XR treatment experienced significantly lower "relapse" * rates compared with those on placebo.

*For the purposes of this study:

"Responded" during the open phase was defined as a CGI Severity of Illness item score <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.

Generalized Anxiety Disorder (GAD)

The efficacy of EFFEXOR XR capsules in the treatment of GAD has been demonstrated in three fixed dose studies and one flexible dose study for time periods ranging from 8 to 28 weeks. In these studies, EFFEXOR XR was shown to have a statistically significant superiority over placebo on the following three measures: Hamilton Anxiety Rating Scale (total score), Hamilton anxious mood item, and Clinical Global Impression of Severity of Illness rating. In the three fixed dose studies, response rates at week 8 of treatment, as defined by the proportion of patients achieving Clinical Global Impression of Improvement Scores of "much" or "very much improved", were as follows (last observation carried forward):

For the two long-term studies, response rates at month 6 were as follows for last observation carried forward (LOCF):

Social Anxiety Disorder (Social Phobia)

The efficacy of EFFEXOR XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was demonstrated in four 12-week, multi-center, placebo-controlled, flexible- dose studies and one 6-month, fixed/flexible-dose study in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. These studies evaluating EFFEXOR XR doses in a range of 75-225 mg/day demonstrated that EFFEXOR XR was significantly more effective than placebo for the Liebowitz Social Anxiety Scale Total score, Clinical Global Impressions of Severity of Illness rating, and Social Phobia Inventory. Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of age or gender.

Panic Disorder

Two fixed-dose and two flexible-dose placebo-controlled studies have been performed to investigate the efficacy of Effexor XR capsules as a treatment for Panic Disorder. In the two double-blind, 12-week, multi-center, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for Panic Disorder, with or without agoraphobia, patients received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study. In these two trials, Effexor XR doses of 75 mg, 150 mg and 225 mg were significantly more effective than placebo for the primary outcome, the percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS), and for the two key secondary outcomes: 1) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score, and (2) percentage of patients rated as responders (much improved or very much improved) in the Clinical Global Impressions (CGI) Improvement scale. In one flexible-dose study (75 mg to 225 mg daily doses), the primary outcome, the percentage of patients free of full-symptom panic attacks, approached significance (p=0.056). In this study, Effexor XR was significantly more effective than placebo for the two key secondary outcomes, (1) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score, and (2) percentage of patients rated as responders (much improved or very much improved) in the Clinical Global Impressions (CGI) Improvement scale. In another flexible-dose study (dose range 75mg-225 mg/day), Effexor XR was not significantly more effective than placebo for the primary outcome, the percentage of patients free of full- symptom panic attacks, but it was significantly more effective than placebo for the secondary outcome: percentage of patients rated as responders (much improved or very much improved) in the Clinical Global Impressions (CGI) Improvement scale. 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, adult outpatients meeting DSM-IV criteria for Panic Disorder who had responded at the end of a 12-week open phase with Effexor XR (75 to 225 mg/day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse during a 6-month double-blind phase. 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) during that same 2-week period. 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 investigator. Patients receiving continued Effexor XR treatment experienced significantly longer time to relapse over the subsequent 6 months compared with those receiving placebo.

DETAILED PHARMACOLOGY

Venlafaxine (Wy-45,030) is a novel bicyclic 2-phenyl-2-(1-hydroxy-cycloalkyl) ethylamine racemate whose enantiomers are configured as R (-) venlafaxine and S (+) venlafaxine. The major human metabolite of venlafaxine is the racemate Wy-45,233 (O-desmethyl-venlafaxine) whose enantiomers are configured as R (-) Wy-45,233 and S (+) Wy-45,233. Venlafaxine is a potent inhibitor of both norepinephrine and serotonin uptake that has demonstrated antidepressant activity in a number of preclinical models. Wy-45,233, the major human metabolite of venlafaxine, has a pharmacological profile quite similar to that of venlafaxine since it also inhibits norepinephrine and serotonin uptake and produces rapid noradrenergic desensitization. This indicates that Wy-45,233 is a biologically active metabolite of venlafaxine. While the enantiomers of Wy-45,233 effectively inhibit monoamine uptake, they were less effective in in vivo models of antidepressant activity. Ancillary pharmacological effects of venlafaxine and Wy-45,233 were quite similar. In neuropharmacological studies, both compounds lacked activity at a wide range of CNS receptors and had a low abuse liability potential. The effects of venlafaxine and Wy-45,233 on arterial pressure and heart rate in animals are most likely related to the inhibition of monoamine uptake and are similar to those produced by tricyclic antidepressants. Lastly, venlafaxine and Wy-45,233 produced only limited effects in immunological, gastrointestinal and endocrine studies which were generally at doses greater than those required to produce antidepressant effects in animals. Venlafaxine is rapidly absorbed and excreted from laboratory animals and man. Differences in biotransformation pathways among species result in different pharmacokinetic profiles. Tissue uptake occurs, but without notable accumulation. Elimination of venlafaxine and its metabolites occurs via renal pathway in all species. O-Demethylation to a bioactive metabolite is the major transformation in man, dog and mouse, but further transformations occur in the animals. Other transformation pathways predominate in rat and rhesus monkey. While venlafaxine HCl is a racemic mixture, the animals in drug safety evaluation studies were exposed to similar or greater amounts of each venlafaxine enantiomer, as well as each Wy-45,233 enantiomer, than when humans received venlafaxine HCl at the highest recommended therapeutic dose. Stereoselective transformations, which were recognized in rats and rhesus monkeys, were not significant in humans.

TOXICOLOGY

The toxicologic profile of venlafaxine was evaluated for up to 18 months in mice, up to 2 years in rats, and up to 1 year in dogs. A single dose range finding study was done in monkeys. As part of its evaluation, the reproductive toxicologic potential of venlafaxine was evaluated in segment I, II, and III studies in rats and a segment II study in rabbits. The major findings in the acute, long term, and reproductive toxicity studies are discussed below.

Acute Toxicity

Venlafaxine showed low acute toxicity with LD50s >=405 mg/kg in mice and 336 mg/kg in rats; i.v. LD50s in mice were >=48 mg/kg. No drug-related macroscopic lesions were observed; microscopic examinations were not performed.

Long Term Toxicity/Carcinogenicity

Subchronic toxicity of venlafaxine was evaluated in mice, rats, dogs and monkeys (1-month range finding study only); chronic toxicity was evaluated in dogs; and chronic toxicity/carcinogenicity was evaluated in mice and rats.

Mice

Venlafaxine was administered to mice for 3 months at 0, 24, 96, 138, 180 and 240 mg/kg to establish doses for a subsequent 18 month carcinogenicity study. Drug-related tonic/clonic convulsions occurring in both 180 and 240 mg/kg groups were regarded as limiting for subsequent studies of longer duration due to anticipated mortality associated with convulsions of this magnitude. Based on these results, a maximum dose of 120 mg/kg was selected for chronic carcinogenicity studies which was regarded to provide a minimal margin below the convulsive threshold which would limit survival in a chronic study. In the 18 month study, mice were thus dosed at 10, 35, and 120 mg/kg. No carcinogenic effect was noted in males or females. A slight decrease in survival occurred in the 120 mg/kg males, but was not associated with specific microscopic lesions. The cause of death in the 120 mg/kg mice could not be clearly established. Male and female mice receiving 120 mg/kg were noted to have increased motor activity.

Rats

Rats were dosed with venlafaxine at 0, 4.5, 40, 170, and 340 mg/kg in the 6 month toxicity study and at 0, 10, 35, and 120 mg/kg in the 2 year study. No drug-related histologic lesions occurred in either study. In the six month study, an increased mortality was seen at 170 and 340 mg/kg. Deaths were generally associated with convulsions. Effects noted included decreased body weight and food consumption at 170 and 340 mg/kg and increased incidence of physical examination findings at 40 mg/kg and above. Due to mortality, body weight, and food consumption effects, the maximum tolerated dose for the chronic study was considered to be below 170 mg/kg. The rat carcinogenicity study was conducted at dosages of 0, 10, 35, and 120 mg/kg for 2 years. As with the mouse, no carcinogenic effect was observed. An increased mortality was seen at 120 mg/kg; however, no clear drug-related lesion was associated with mortality. Mortality at lower dosages was comparable to historical limits (50-65%).

Dogs

In dogs, venlafaxine was administered for 6 months at 0, 2, 7, and 22 mg/kg and for 12 months at 0, 4, 10, and 24 mg/kg. As with the other species tested, no drug-related histologic lesions occurred. In the 6 month dog study, slightly decreased heart rate occurred in two dogs (during weeks 6, 12, 18, and 25 in one dog and week 25 in the other dog) receiving 22 mg/kg. Although effects on cardiovascular parameters have been seen with other antidepressants, including ECG alterations consisting of T wave changes (inversions, bifid T wave), prolongation of conduction and sinus tachycardia seen with tricyclic antidepressants, these effects were not seen after administration of venlafaxine. Blood pressure and ECGs were measured periodically throughout treatment at multiple intervals after ECG abnormalities in these or any other dogs in the 6 month or 1 year studies. A slight decrease in body weight gain was seen at the high dose in both studies. Mydriasis, a pharmacologic effect, occurred at all dosages. Other minor drug-related effects were generally limited to the high dose.

Monkeys

In monkeys, a range finding assay was conducted using one monkey/sex at dosages of 0, 25, 80, 125, 170, and 260 mg/kg for up to 27 days. Deaths occurred in the first 5 days in one of two monkeys at 125 mg/kg and all monkeys at higher dosages. No drug-related histologic changes were found in these animals, and deaths were considered secondary to drug-induced convulsions. Electrocardiograms were only measured on the 80 mg/kg monkeys and showed no drug-related effects. Due to pharmacokinetic considerations, additional monkey studies were not conducted.

Mutagenicity

Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (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, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow.

Reproductive Toxicity

The reproductive toxicology of venlafaxine was studied in rats and rabbits. No teratogenic effect was observed and no deaths occurred. Pharmacotoxic signs were seen in paternal and maternal rats given venlafaxine doses of 30 and 60 mg/kg/day (4 and 8 times the maximum recommended human dose, respectively), but no adverse effect was noted in fertility or general reproductive performance. Decreased fetal size and pup weight at birth with 60 mg/kg/day may be correlated with maternal toxicity. In a perinatal toxicity study, decreased fetal survival following birth was observed at 40 and 80 mg/kg/day (approximately 5 to 11 times the maximum recommended human dose, respectively) and was considered secondary to drug-related decreased maternal care. No teratogenic effect was seen. Evidence of carcinogenesis, mutagenesis, and impairment of fertility was not noted in preclinical toxicology studies.

Reproductive Toxicity with the Major Metabolite of Venlafaxine

Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV). This ODV exposure was approximately 2 to 3 times that which would result from a human dose of 225 mg/day of venlafaxine. The human relevance of this finding is unknown. In this study, administration of ODV as the succinate salt in male and female rats resulted in disrupted estrous cycles and increased time-to-mating at >=30 mg/kg/day; decreased fertility rates at >=100 mg/kg/day; and increased preimplantation loss and decreased fetal weight at 300 mg/kg/day. There was decreased prostate weight at >=30 mg/kg/day associated with prostate atrophy at >=100 mg/kg/day; however, there were no compound-related macroscopic or microscopic findings in the epididymides, seminal vesicles, or testes. The no-observed-adverse- effect level (NOAEL) for effects on fertility was 30 mg/kg/day and the developmental NOAEL was 100 mg/kg/day.

REFERENCES

1. Ballenger JC. Clinical Evaluation of Venlafaxine. J Clin Psychopharmacol 1996; 16 (3, Suppl 2):29S-35S.

2. Ballenger JC. Clinical Evaluation of Venlafaxine: Commentary. J Clin Psychopharmacol 1996; 16(3, Suppl 2):35S-36S.

3. Ballus C, Quiros G, De Flores T, de la Torre J, Palao D, Rojo L, et al. The efficacy and tolerability of venlafaxine and paroxetine in outpatients with depressive disorder or dysthymia. International Clinical Psychopharmacology 2000; 15(1):43-48.

4. Benkert O, Grunder G, Wetzel H, Hackett D. A Randomized, Double-Blind Comparison of a Rapidly Escalating Dose of Venlafaxine and Imipramine in Patients with Major Depression and Melancholia. J Psychiat Res 1996; 30(6):441-451.

5. Clerc GE, Ruimy P, Verdeau-Palles J. A Double-Blind Comparison of Venlafaxine and Fluoxetine in Patients Hospitalized for Major Depression and Melancholia. International Clinical Psychopharmacology 1994; 9:139-143.

6. Costa e Silva J. Randomized, double-blind comparison of venlafaxine and fluoxetine in outpatients with major depression. J Clin Psychiatry 1998; 59:352-357.

7. Cunningham LA, Borison RL, Carman JS, Chouinard G, Crowder JE, Diamond BI. et al. A Comparison of Venlafaxine, Trazodone, and Placebo in Major Depression. J Clin Psychopharmacol 1994; 14(2):99-106.

8. Dierick M. An Open Label Evaluation of the Long-Term Safety of Oral Venlafaxine in Depressed Elderly Patients. Annals of Clin Psychiatry 1996; 8(3):169-178.

9. Entsuah R, Upton GV, Rudolph R. Efficacy of Venlafaxine Treatment in Depressed Patients with Psychomotor Retardation or Agitation: A Meta-Analysis. Human Psychopharmacol 1995; 10:195-200.

10. Entsuah R, Rudolph R, Chitra R. Effectiveness of Venlafaxine Treatment in a Broad Spectrum of Depressed Patients: A Meta-Analysis. Psychopharmacol Bull 1995; 31(4):759-766.

11. Ereshefsky L. Drug-Drug Interactions Involving Antidepressants: Focus on Venlafaxine.

J Clin Psychopharmacol 1996; 16(3) Suppl 2: 37S-49S. Feighner JP. The Role of Venlafaxine in Rational Antidepressant Therapy. J Clin Psychiatry 1994; 55 (9, Suppl A):62-68. Guelfi JD, White C, Hackett D, Guichoux JY, Magni G. Effectiveness of Venlafaxine in Patients Hospitalized for Major Depression and Melancholia. J Clin Psych 1995; 56(10): 450-458. Khan A, Fabre LF, Rudolph R. Venlafaxine in Depressed Outpatients. Psychopharmacol Bull 1991; 27(2):141-144. Kuzel RJ. Treating Comorbid Depression and Anxiety. J Family Practice 1996; 43(6, Suppl):S45-S53. Lecrubier Y, Bourin M, Moon CA, Schifano F, Blanchard C, Danjou P. et al. Efficacy of venlafaxine in depressive illness in general practice. Acta Psychiatr Scand 1997; 95:485-493. Mehtonen O-P, Sogaard J, Roponen P, Behnke K. Randomized, double-blind comparison of venlafaxine and sertraline in outpatients with major depressive disorder. J Clin Psychiatry 2000; 61(2):95-100. Mendels J, Johnston R, Mattes J, Riesenberg R. Efficacy and Safety of BID Doses Of Venlafaxine In A Dose-Response Study. Psychopharmacol Bull 1993; 29(2):169-174. Montgomery SA. Venlafaxine: A New Dimension in Antidepressant Pharmacotherapy. J Clin Psychiatry 1993; 54(3):119-126. Muth EA, Moyer JA, Haskins JT, Andree TH, Husbands GEM. Biochemical, Neurophysiological, and Behavioral Effects of Wy-45,233 and Other Identified Metabolites of the Antidepressant Venlafaxine. Drug Development Research 1991; 23:191-199. Nierenberg A, Feighner J, Rudolph R, Cole J, Sullivan J. Venlafaxine For Treatment- Resistant Unipolar Depression. J Clin Psychopharmacol 1994; 14:419-423. Pollack MH, Worthington JJ III, Otto MW, Maki KM, Smoller JW, Manfro GG, et al. Clinical Trials - Anxiety Disorders: Venlafaxine for Panic Disorder: Results From a Double-Blind, Placebo-Controlled Study. Psychopharmacol Bull 1996; 32(4):667-670. Rudolph RL, Entsuah R, Chitra R. A Meta-Analysis of Effects of Venlafaxine on Anxiety Associated with Depression. J Clin Psychopharmacol 1998; 18:136-144. Rudolph RI, Feiger AD. A double-blind, randomized, placebo-controlled trial of once- daily venlafaxine extended release (XR) and fluoxetine for the treatment of depression. J Affective Disorders 1999; 56:171-181. Schweizer E, Weise C, Clary C, Fox I, Rickels K. Placebo-Controlled Trial of Venlafaxine for the Treatment of Major Depression. J Clin Psychopharmacol 1991; 11(4):233-236. Schweizer E, Feighner J, Mandos LA, Rickels K. Comparison of Venlafaxine and Imipramine in the Acute Treatment of Major Depression in Outpatients. J Clin Psychiatry 1994; 55(3):104-108. Shrivastava RK, Cohn C, Crowder J, Davidson J, Dunner D, Feighner J. et al. Long- Term Safety and Clinical Acceptability of Venlafaxine and Imipramine in Outpatients with Major Depression. J Clin Psychopharmacol 1994; 14(5):322-329. Zajecka JM, Fawcett J, Guy C. Co-existing Major Depression and Obsessive-compulsive Disorder treated with Venlafaxine. J Clin Psychopharmacol 1990; 10(2): 152-153.

PART III: CONSUMER INFORMATION

EFFEXOR(r) XR

(Venlafaxine Hydrochloride) Extended Release Capsules

This leaflet is part III of a three-part "Product Monograph" published when EFFEXOR XR was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about EFFEXOR XR. Contact your doctor or pharmacist if you have any questions about the drug.

Please read this information carefully before you start to take your medicine, even if you have taken this drug before. Do not throw away this leaflet until you have finished your medicine as you may need to read it again. For further information or advice, please see your doctor or pharmacist.

ABOUT THIS MEDICATION

What the medication is used for:

EFFEXOR XR has been prescribed to you by your doctor to relieve your symptoms of the following conditions:

Depression (feeling sad, a change in appetite or weight, difficulty concentrating or sleeping, feeling tired, headaches, unexplained aches and pain)

Generalized anxiety or nervousness

Social phobia (social anxiety disorder) - avoidance and/or fear of social situations

Panic disorder (repeated, unexpected panic attacks)What it does:EFFEXOR XR belongs to a group of medicines called anti- depressants. EFFEXOR XR is thought to work by affecting twonaturally occurring brain chemicals, serotonin and norepinephrine.When it should not be used:

Do not use EFFEXOR XR if you are allergic to it or to any of the components of its formulation (see list of components at the end of this section). Stop taking the drug and contact your doctor immediately if you experience an allergic reaction or any severe or unusual side effects.

Do not use EFFEXOR XR if you are currently taking or have recently taken monoamine oxidase inhibitor antidepressants (e.g. phenelzine sulphate, moclobemide).What the medicinal ingredient is:Venlafaxine HydrochlorideWhat the nonmedicinal ingredients are:Black Iron Oxide NF * *, Ethylcellulose NF, Gelatin NF, Hydroxypropyl-methylcellulose USP, Microcrystalline celluloseNF, Opacode Red Ink S-1-15034 * * * *, Red Iron Oxide *, Talc,Titanium Dioxide *, White Ink TekPrint SB-0007P * * *, Yellow Iron Oxide *.Present (in capsule) in all strengths * * Present (in capsule) in 37.5 mg strength only * * * 150 mg strength * * * * 37.5 and 75 mg strengthsWhat dosage forms it comes in:EFFEXOR XR is available in extended release capsules containing 37.5 mg (grey and peach), 75 mg (peach) and 150 mg(dark orange) venlafaxine.WARNINGS AND PRECAUTIONSDuring treatment with these types of medication it is important that you and your doctor have good ongoing communication about how you are feeling.EFFEXOR XR is not for use in children under 18 years of age.New or Worsened Emotional or Behavioural Problems Particularly in the first few weeks or when doses are adjusted, a small number of patients taking drugs of this type may feel worse instead of better; for example, they may experience unusual feelings of agitation, hostility or anxiety, or have impulsive or disturbing thoughts such as thoughts of self-harm or harm to others. Should this happen to you, or to those in your care if you are a caregiver or guardian, consult your doctor immediately. Close observation by a doctor is necessary in this situation. Do not discontinue your medication on your own.Before taking EFFEXOR XR tell your doctor or pharmacist:if you have ever had any allergic reaction to medications, food, etc; all your medical conditions, including a history of seizures, liver disease, kidney disease, heart problemsor high cholesterol, or history of any abnormalbleeding; if you have blood pressure problems; any medications (prescription or non-prescription) which you are taking, especially monoamine oxidase (MAO) inhibitors (e.g. phenelzine sulfate, tranylcypromine sulfate, moclobemide or selegeline) or any other antidepressants, weight-loss medication, sleeping pills, antianxiety drugs, or medication to control blood pressure; if you are pregnant or thinking about becoming pregnant, or if you are breast feeding; your habits of alcohol and/or street drug consumption; any natural or herbal products you are taking (e.g., St.John's Wort).if you drive a vehicle or perform hazardous tasks during your work.Discontinuing Effexor XRIt is very important that you do NOT stop taking these medications without first consulting your doctor. See SIDEEFFECTS AND WHAT TO DO ABOUT THEM section formore information.Effects on Pregnancy and NewbornsPost-marketing reports indicate that some newborns whosemothers took an SSRI (selective serotonin reuptake inhibitor) or other newer anti-depressants, such as EFFEXOR XR, during pregnancy have developed complications at birth requiring prolonged hospitalization, breathing support and tube feeding. Reported symptoms included feeding and/or breathing difficulties, seizures, tense or overly relaxed muscles, jitterinessand constant crying.In most cases, the SSRI or other newer anti-depressant was taken during the third trimester of pregnancy. These symptoms are consistent with either a direct adverse effect of the anti- depressant on the baby, or possibly a discontinuation syndrome caused by sudden withdrawal from the drug. These symptoms normally resolve over time. However, if your baby experiences any of these symptoms, contact your doctor as soon as you can.If you are pregnant and taking an SSRI, or other newer anti- depressant, you should discuss the risks and benefits of the various treatment options with your doctor. It is very important that you do NOT stop taking these medications without first consulting your doctor. See SIDE EFFECTS AND WHAT TO DO ABOUT THEM section for more information.improve within about 2 weeks but significant improvement can take several weeks.

EFFEXOR XR should be taken once a day with food, as prescribed; do not divide, crush or chew the capsules.REMEMBER: This medicine has been prescribed only for you. Do not give it to anybody else. If you have any further questions, please ask your doctor or pharmacist.Overdose:In case of overdose, contact your doctor or the nearest hospital emergency department, even though you may not feel sick.Missed Dose:If you happen to miss a dose, do not try to make up for it by doubling up on the dose next time. Just take your next regularlyscheduled dose and try not to miss any more.INTERACTIONS WITH THIS MEDICATIONDo not use EFFEXOR XR if you are taking or have recently taken monoamine oxidase inhibitors.You should avoid taking St. John's Wort if you are takingEFFEXOR XR.You should tell your doctor if you are taking or have recently taken any medications (prescription, non-prescription or natural/herbal), especially:

other antidepressants, such as SSRIs and certain tricyclics

other drugs that affect serotonin such as, lithium, linezolid, sibutramine, tramadol, tryptophan, triptans used to treat migraines

certain medicines used to treat schizophrenia

certain medicines used to treat bipolar depression, such as lithium

metoprolol or other medications used to treat high blood pressure and angina

certain medicines which may affect blood clotting and increase bleeding, such as oral anti-coagulants (e.g. warfarin), aspirin and other non-steroidal anti-inflammatory drugs (e.g. ibuprofen)

certain medicines used to treat epilepsy

cimetidine

In general, drinking alcoholic beverages should be kept to a minimum or avoided completely while taking EFFEXOR XR.

Ketoconazole.PROPER USE OF THIS MEDICATIONUsual dose:

It is very important that you take EFFEXOR XR exactly as your doctor has instructed.

Never increase or decrease the amount of EFFEXOR XR you, or those in your care if you are a caregiver or guardian, are taking unless your doctor tells you to and do not stop taking this medication without consulting your doctor.

As with all antidepressants improvement with EFFEXOR XR is gradual. You may not have noticeable effect in the first few days of treatment. Some symptoms may begin toSIDE EFFECTS AND WHAT TO DO ABOUT THEMLike all medications, EFFEXOR XR can cause some side effects. You may not experience any of them. For most patients these side effects are likely to be minor and temporary. However, some may be serious. Some of these side effects may be dose related. Consult your doctor if you experience these or other side effects, as the dose may have to be adjusted.If you experience an allergic reaction (including red skin, hives, itching, swelling of the lips, face, tongue, throat, trouble breathing, wheezing, shortness of breath, skin rashes, blisters of the skin, sores or pain in the mouth or eyes) or any severe or unusual side effects, stop taking the drug and contact your doctor immediately.Some side effects of EFFEXOR XR are:

headache

nausea

dry mouth

constipation

loss of appetite

vomiting

sleepiness

dizziness

insomnia

sexual problems

weakness

sweating

nervousness

abnormal visionParticularly in the first few weeks or when doses are adjusted, a small number of patients taking drugs of this type may feel worse instead of better; for example, they may experience unusual feelings of agitation, hostility or anxiety, or have impulsive or disturbing thoughts such as thoughts of self-harm or harm to others. Should this happen to you, or to those in your care if you are a caregiver or guardian, consult your doctor immediately; do not discontinue your medication on your own.EFFEXOR XR does not usually affect people's normal activities. However, some people feel sleepy while taking it, in which case they should not drive or operate machinery.SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEMSymptom / effectTalk with your doctor or pharmacist right awaySeek urgent medical attentionOnly if severeIn all casesCommonIncreased blood pressurethat persists [see also SevereHypertension below][? ]CommonFast heartbeat[? ]UncommonAllergic reactions [redskin, hives, itching, swelling of the lips,face, tongue, throat, trouble breathing, wheezing, shortness ofbreath, skin rashes, blisters of the skin, sores or pain in the mouth oreyes][? ]UncommonLow sodium level inblood [symptoms of tiredness, weakness,confusion combined with achy, stiff oruncoordinated muscles][? ]UncommonBruising or unusualbleeding from the skin or other areas[? ]UncommonMania/hypomania[elevated or irritable mood, decreased needfor sleep, racing thoughts][? ]UncommonAkathisia [feelingrestless and unable to sit or stand still][? ]UncommonHallucinations [strangevisions or sounds][? ]UncommonUncontrollablemovements of the body or face[? ]UncommonInability to urinate[? ]UncommonGastrointestinalbleeding [vomiting blood or passing blood in stools][? ]RareSeizures [loss ofconsciousness with uncontrollable shaking"fit"][? ]Although psychiatric disorders may be associated with decreases in sexual desire, performance and satisfaction, treatment with this medication may also affect sexual functioning.Effexor XR may increase blood pressure in some people. You should have your blood pressure measured prior to starting Effexor XR and during treatment. High blood pressure should be controlled before starting Effexor XR. Blood pressure changes may sometimes be sudden and without warning. Consult your doctor if you have symptoms that may indicate a sudden rise in your blood pressure, such as headache (particularly in the back of head/neck when waking up); stronger, possibly more rapid, or irregular heart beat; chest pain; dizziness; excessive tiredness; or blurred vision.Effexor XR may raise cholesterol levels in some patients. Blood cholesterol tests may be required by your doctor during treatment with Effexor XR.New or Worsened Emotional or Behavioural ProblemsA small number of patients taking drugs of this type may feel worse instead of better; for example, they may experience newor worsened feelings of agitation, hostility or anxiety, or thoughts about suicide. Your doctor should be informed of suchchanges immediately. Close observation by a doctor isnecessary in this situation. Do not discontinue your medication on your own. See also the WARNINGS AND PRECAUTIONS section.Discontinuation SymptomsContact your doctor before stopping or reducing your dosage of EFFEXOR XR. Symptoms such as anorexia (loss of appetite,loss of weight), anxiety, agitation (restlessness), aggression,confusion, convulsions, coordination problems, diarrhea, dizziness, dry mouth, fatigue, headache, hypomania (rapid mood swings), insomnia, nausea, nervousness, nightmares, paresthesia (sensation of tingling, burning or crawling of the skin), electric shock sensations, sleep disturbances, somnolence (drowsiness), sweating, tinnitus (ringing in the ears), vertigo (sensation that the world is spinning), vomiting and other symptoms have been reported after stopping treatment, reducing the dosage of EFFEXOR XR, or when a dose is missed. These symptoms usually disappear without needing treatment. Tell your doctor immediately if you have these or any other symptoms. Your doctor may adjust the dosage of EFFEXOR XR to alleviate the symptoms.Effects on NewbornsSome newborns whose mothers took an SSRI (Selective Serotonin Reuptake Inhibitor) or other newer anti-depressant,such as EFFEXOR XR, during pregnancy have shown such symptoms as breathing and feeding difficulties, jitteriness andconstant crying. If your baby experiences any of thesesymptoms, contact your doctor as soon as you can. See WARNINGS AND PRECAUTIONS section for more information.SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEMSymptom / effectTalk with your doctor or pharmacist right awaySeek urgent medical attentionOnly if severeIn all casesRareSerotonin syndrome [acombination of most or all of the following; confusion, restlessness, sweating, shaking, shivering, suddenjerking of the muscles, hallucinations, fast heartbeat][? ]RareLiver disorder[symptoms include nausea, vomiting, loss ofappetite combined with itching, yellowing of theskin or eyes, dark urine][? ]Very rareIncreased pressure in theeyes [symptoms of eye pain, decreased orblurred vision, red eye, swelling of eye][? ]See Warnings and PrecautionsNew or worsenedemotional or behavioural problems[? ]See Side Effects and What to Do About ThemSevere Hypertension[symptoms include headache, stronger andpossibly faster heartbeat, chest pain, dizziness,excessive tiredness, blurred vision][? ]REPORTING SUSPECTED SIDE EFFECTSTo monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance by:toll-free telephone: 866-234-2345toll-free fax 866-678-6789By email: CanadaVigilance @hc-sc.gc.caBy regular mail:Canada Vigilance National OfficeMarketed Health Products Safety and Effectiveness Information DivisionMarketed Health Products Directorate Health Products and Food BranchHealth CanadaTunney=s Pasture, AL 0701C Ottawa ON K1A 0K9NOTE: Before contacting Canada Vigilance, you should contact your physician or pharmacist.This is not a complete list of side effects. For any unexpected effects while taking EFFEXOR XR, contact your doctor or pharmacist.MORE INFORMATIONThis document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor,WYETH CANADA1025 Marcel Laurin Blvd. Saint Laurent, Quebec H4R 1J61-800-461-8844or at http://www.wyeth.ca/en.This leaflet was prepared by WYETH CANADA Last revised: .June 16, 2008HOW TO STORE IT

Store EFFEXOR XR at room temperature (15-30EC), in a dry place.

Keep container tightly closed.

Keep all medicines out of the reach of children.

If your doctor tells you to stop taking EFFEXOR XR please return any left over medicine to your pharmacist.