Antidepressant Pharmascience Inc. 6111 Royalmount Ave., Suite 100 Montreal, Quebec H4P 2T4 Date of Preparation: July 6, 2007 Date of Revision : October 2, 2008

Submission Control No: 124554

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 14 DRUG INTERACTIONS 22 DOSAGE AND ADMINISTRATION 27 OVERDOSAGE 31 ACTION AND CLINICAL PHARMACOLOGY 32 STORAGE AND STABILITY 35 SPECIAL HANDLING INSTRUCTIONS 35 DOSAGE FORMS, COMPOSITION AND PACKAGING 35

PART II: SCIENTIFIC INFORMATION 37

PHARMACEUTICAL INFORMATION 37 CLINICAL TRIALS 38 DETAILED PHARMACOLOGY 42 TOXICOLOGY 42 REFERENCES 46

PART III: CONSUMER INFORMATION. 50

Venlafaxine Hydrochloride Extended Release Capsules

mg, 75 mg and 150 mg venlafaxine (as venlafaxine hydrochloride)

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)

: pms-VENLAFAXINE 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 pms- VENLAFAXINE XR therapy.

Adverse reactions, some serious, have been reported when venlafaxine hydrochloride extended release capsules therapy is initiated soon after discontinuing an MAOI and when an MAOI is initiated soon after discontinuation of venlafaxine hydrochloride extended release capsules. 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 BEHAVIORAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.

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 behavioral and emotional changes, including an increased risk of suicidal ideation and behavior 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.

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 behavior 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 behavior, 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 pms-VENLAFAXINE XR capsules 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

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.

: 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.

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.

Sustained hypertension, defined as treatment-emergent supine diastolice 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

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.

: In placebo-controlled premarketing depression studies with venlafaxine hydrochloride extended release capsules, a final on-therapy mean increase in supine diastolic pressure (SDBP) of < 1.2 mm Hg was observed for venlafaxine-treated patients compared with a mean decrease of 0.2 mm Hg for placebo-treated patients. Less than 3% of venlafaxine hydrochloride extended release capsules 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 venlafaxine hydrochloride extended release capsules >300 mg/day to evaluate systematically sustained blood pressure increases. Less than 1% of venlafaxine-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.

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 Malignat Syndrome, and DRUG INTERACTIONS, (Serotonergic Drugs).

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, diarrhea, 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 ADVERSE EVENTS, Discontinuation Symptoms; DOSAGE AND ADMINISTRATION, Discontinuing Venlafaxine).

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 pms-VENLAFAXINE 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).

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

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. The electrocardiograms for 357 patients who received venlafaxine hydrochloride extended release capsules 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 venlafaxine-treated patients in depression studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine hydrochloride extended release capsules and decrease of 1.9 msec for placebo). The clinical significance of this change is unknown. Three of 705 venlafaxine-treated patients in phase III studies experienced QTC prolongation to 500 msec during treatment. Baseline QTC was >450 msec for all 3 patients. No case of sudden unexplained death or serious ventricular arrhythmia, which are possible clinical sequelae of QTC prolongation, was reported in venlafaxine hydrochloride extended- release capsules 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. 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.

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.

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).

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). 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.

Treatment-emergent anorexia and weight loss were more commonly reported for venlafaxine- treated patients than for placebo-treated patients in depression trials. Significant weight loss, especially in underweight depressed 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 include the possibility of serotonin syndrome. (See, PRECAUTIONS, Drug Interactions, Serotonergic Drugs).

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 venlafaxine hydrochloride extended release capsules, compared with immediate release tablets. In a 12-week study comparing immediate release tablets with venlafaxine hydrochloride extended release capsules, once daily, venlafaxine hydrochloride extended release capsules 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 venlafaxine hydrochloride extended release capsules than with immediate release tablets. Additionally, the incidence of vomiting was lower with venlafaxine hydrochloride extended release capsules than with immediate release tablets.

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.

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 hydrochloride. Although the reported events occurred coincident with treatment with venlafaxine, the relationship to treatment is unknown.

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.

In patients with hepatic impairment, the pharmacokinetic disposition of both venlafaxine and ODV are significantly altered. Dosage adjustment is necessary in these patients (See Recommended Dose, Patients with Hepatic Impairment, Patients with Renal Impairment).

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.

pms-VENLAFAXINE XR capsules 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 EVENTS, Discontinuation Symptoms; DOSAGE AND ADMINISTRATION, Discontinuing Venlafaxine). During pre-marketing depression studies no seizures were seen in 705 venlafaxine hydrochloride extended release capsule-treated patients. However, patients with a history of convulsive disorders were excluded from most of the study. pms-VENLAFAXINE XR should be used cautiously in patients with a history of seizures, and should be promptly discontinued in any patient who develops seizures.

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).

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.

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 pms-VENLAFAXINE XR should be written for the smallest quantity of capsules consistent with good patient management.

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

TABLE 2: INCIDENCE OF INSOMNIA AND NERVOUSNESS IN PLACEBO- CONTROLLED DEPRESSION, GAD, AND SOCIAL ANXIETY DISORDER TRIALS

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with venlafaxine hydrochloride extended release capsules in depression studies.

During Phase II and III trials, mania or hypomania occurred 0.3% of venlafaxine hydrochloride extended release capsule-treated patients in depression. 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, pms-VENLAFAXINE 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.

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).

TOXICOLOGY, Reproductive Toxicity.

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.

WARNINGS and PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant SyndromeDOSAGE AND ADMINISTRATION, Treatment of Pregnant Women During the Third Trimester

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

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

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 pms-VENLAFAXINE XR while nursing, the potential for discontinuation effects in the infant upon cessation of nursing should be considered.

Pediatrics (<18 years of age): pms-VENLAFAXINE XR is not indicated for use in children under 18 years of age WARNINGS AND PRECAUTIONS, General, Potential Association with Behavioral and Emotional Changes, Including Self-Harm

Geriatrics (>65 years of age):

Forty three (4%) of the patients in premarketing, with venlafaxine hydrochloride extended release capsules were 65 years of age 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.

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

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. 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 WARNINGS and PRECAUTIONS, General, Hypertension.)

ADVERSE REACTIONS, Laboratory Changes - Cholesterol

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.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and

should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Commonly Observed Adverse Reactions

During depression trials, the most commonly observed adverse events associated with the use of venlafaxine hydrochloride extended release capsules (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for immediate release formulation / venlafaxine hydrochloride extended release capsules at least twice that for placebo), derived from the 2% incidence Table 4A, were: Venlafaxine Extended Release: abnormal dreams, anorexia, dizziness, dry mouth, nausea, nervousness, somnolence, sweating, and tremor as well as abnormal ejaculation/orgasm in men.

Adverse Events that Led to Discontinuation of Treatment in Clinical Trials

Twelve percent (88/705) of venlafaxine hydrochloride extended release-treated patients in Phase II and III depression studies discontinued treatment due to an adverse reaction. The more common events (>1%) associated with discontinuation of treatment in the 5 trials and considered to be drug-related (i.e., those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) are shown in Table 3.

TABLE 3: ADVERSE REACTIONS (PERCENTAGE) LEADING TO DISCONTINUATION OF TREATMENT

	Venlafaxine Hydrochloride Extended Release Capsules Depression Indication (n=705)	PLACEBO Depression Indication (n=285)
CNS	2	<1
Somnolence	2	<1
Insomnia	<1	<1
Dizziness	2	1
Nervousness	<1	1
Anxiety	<1	<1
Tremor	<1	<1
Gastrointestinal	<1	0
Dry Mouth	<1	0
Anorexia	<1	<1
Nausea	4	<1
Vomiting	1	0
Urogenital	<1	<1
Abnormal Ejaculation *	<1	<1
Impotence *	0	0
Other	2 #	1
Headache	2 #	1
Asthenia	<1	1
Sweating	<1	0

* : percentages based on the number of males

# : greater than 1% but active drug rate not twice rate for placebo

Incidence in Controlled Trials

The table that follows (Table 4A) enumerates adverse events that occurred at an incidence of 2% or more, and were more frequent than in the placebo group, among venlafaxine-treated depressed patients. Venlafaxine hydrochloride extended release capsules: patients participated in 8- to 12-week placebo-controlled trials in which doses in the range of 75 to 225 mg/day were administered. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The cited figures for venlafaxine hydrochloride extended release capsules, provide the prescribing physician with some basis for estimating the relative contribution of drug and non- drug factors to the side effect incidence rate in the population studied.

TABLE 4A: TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS (PERCENTAGE)1 IN DEPRESSED PATIENTS

Body System	Preferred Term	Venlafaxine HCl Extended Release (n = 357)	Placebo (n = 285)
Body as a whole	Headache	26 #	33
	Asthenia	8	7
	Infection	6 #	9
	Chills	<1	1
Cardiovascular	Vasodilatation	4	2
	Increased blood pressure/
	hypertension	4	1
	Tachycardia	<1	<1
Dermatological	Sweating	14	3
Dermatological	Rash	1	1
Gastrointestinal	Nausea	31	12
	Constipation	8	5
	Anorexia	8	4
	Diarrhoea	8 #	9
	Vomiting	4	2
	Dyspepsia	7 #	9
	Flatulence	4	3
Metabolic	Weight loss	3	0
Nervous	Somnolence	17	8
	Dry mouth	12	6
	Dizziness	20	9
	Insomnia	17	11
	Nervousness	10	5
	Anxiety	2 #	5
	Tremor	5	2
	Abnormal Dreams	7	2
	Hypertonia	1	0
Body System	Preferred Term	Venlafaxine HCl Extended Release (n = 357)	Placebo (n = 285)
	Paraesthesia	3	1
	Libido decreased	3	<1
	Agitation	3	1
	Depression	3	<1
	Thinking abnormal	<1	1
Respiration	Pharyngitis	7	6
Respiration	Yawn	3	0
Special Senses	Abnormal vision	4	<1
Special Senses	Taste Perversion	1	<1
Urogenital	Abnormal	16 2	<1 2
system	Ejaculation/orgasm	16 2	<1 2
	Impotence	4 2	<1 2
	Anorgasmia	3 3	<1 3
	Urinary frequency	1	1
	Urination impaired	<1	0

Events reported by at least 2% of patients treated with venlafaxine hydrochloride extended release are included, and are rounded to the nearest %. Events for which the venlafaxine hydrochloride extended release incidence was equal to or less than placebo included the following: abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhoea, dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis and sinusitis.

# Incidence greater than 2%, but active drug incidence less than incidence for placebo

Incidence based on number of male patients (For venlafaxine hydrochloride extended release: n = 126, Placebo: n = 108)

Incidence based on number of female patients ( For venlafaxine hydrochloride extended release n = 231, Placebo: n = 177)

Adaptation to Certain Adverse Events

In premarketing experience with venlafaxine hydrochloride extended release capsules over a 12 week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., dizziness and nausea), but less to other effects (e.g., abnormal ejaculation and dry mouth).

Discontinuation Symptoms

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. Symptoms associated with discontinuation include but are not limited to: 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. Patients should be monitored for these or any other symptoms when discontinuing treatment, regardless of the indication for which venlafaxine hydrochloride is being prescribed. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (See WARNINGS AND PRECAUTIONS, Discontinuation Symptoms and DOSAGE AND ADMINISTRATION, Discontinuing Venlafaxine for details).

Vital Sign Changes

Treatment with venlafaxine hydrochloride extended release capsules for up to 12 weeks in premarketing depression trials was associated with a mean increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. It was associated with mean increases in diastolic blood pressure ranging from 0.7 to 0.9 mm Hg, compared with mean decreases ranging from 0.5 to 1.4 mm Hg for placebo.

Laboratory Changes - Cholesterol

Clinically and statistically relevant increases in cholesterol levels have been noted in studies using venlafaxine hydrochloride extended release capsules (see WARNINGS AND PRECAUTIONS, Serum Cholesterol Elevation).

Venlafaxine Hydrochloride Extended Release Capsules:

Venlafaxine hydrochloride extended release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL (0.0381 mmol/L) compared with a mean final decrease of 7.4 mg/dL (0.1919 mmol/L) for placebo. 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.

ECG Changes

An analysis of ECGs obtained in 357 patients treated with venlafaxine hydrochloride extended release capsules and 285 patients treated with placebo in controlled clinical trials in depression, were analyzed. The mean change from baseline in corrected QT interval (QTC) for venlafaxine hydrochloride extended release-treated patients was increased relative to that for placebo-treated patients in the clinical trials for depression and Social Anxiety Disorder (see WARNINGS AND PRECAUTIONS, Cardiac Disease).

Other Events Observed During the Premarketing Evaluation of Venlafaxine

Multiple doses of venlafaxine hydrochloride extended release were administered to 705 patients in phase III depression studies. The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double- blind studies, uncontrolled and controlled studies, outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 7,212 patients exposed to multiple doses of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in 4A MDD, and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is I mportant to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare adverse events are those occurring in fewer than 1/1000 patients.

Body as a whole:

Frequent:

chest pain substernal.

Infrequent:

face edema, intentional injury, malaise, moniliasis, neck rigidity, overdose, pelvic pain, photosensitivity reaction, suicide attempt.

Rare:

anaphylaxis, appendicitis, bacteremia, body odor, carcinoma, cellulitis, granuloma, halitosis.

Cardiovascular system:

Infrequent:

angina pectoris, arrhythmia, bradycardia, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope.

Rare:aortic aneurysm, arteritis, first degree atrioventricular block, bigeminy, bundle branch block, capillary fragility, cardiovascular disorder (includes mitral valve and circulatory disturbances), cerebral ischemia, coronary artery disease, heart arrest, congestive heart failure, hematoma, mucocutaneous hemorrhage, myocardial infarct, pallor, QT and QTC interval prolonged, sinus arrhythmia, thrombophlebitis, varicose vein, venous insufficiency.

Digestive system:

Frequent:

increased appetite.

Infrequent:

bruxism, colitis, dysphagia, tongue edema, eructation, esophagitis, gastritis , gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration.

Rare:

abdominal distension, biliary pain, cheilitis, cholecystitis, cholelithiasis, duodenitis, esophageal spasms, hematemesis, gastrointestinal hemorrhage, gastroesophageal reflux disease, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, liver tenderness, parotitis, periodontitis, proctitis, rectal disorder, increased salivation, salivary gland enlargement, soft stools, tongue discoloration.

Endocrine system:

Rare:

galactorrhea, goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis.

Hemic and lymphatic system:

Infrequent:

anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, mucous

membrane bleeding.

Rare:

basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura, thrombocytopenia.

Metabolic and nutritional:

Frequent:

edema, serum cholesterol increase.

Infrequent: Rare:

alkaline phosphatase increased, dehydration, hypercholesterolemia, hyperglycemia, hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst, SIADH.

alcohol intolerance, bilirubinemia, BUN increased, creatinine increased, diabetes mellitis, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia.

Musculoskeletal system:

Infrequent:

arthritis, arthrosis, bone spurs, bursitis, myasthenia.

Rare:

bone pain, muscle cramp, muscle spasm, musculoskeletal stiffness, pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture.

Nervous system

: Frequent:

hypesthesia.

Infrequent:

akathisia, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesias, hypotonia, incoordination, manic reaction, myoclonus, neuralgia, neuropathy, psychosis, serotonergic syndrome, seizure, abnormal speech, stupor, suicidal ideation.

Rare:

abnormal/changed behaviour, adjustment disorder, akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident, convulsion, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial paralysis, abnormal gait, Guillain-Barre Syndrome, homicidal ideation, hyperchlorhydria, hysteria, impulse control difficulties, hypokinesia, motion sickness, neuritis, nystagmus, paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, torticollis.

Respiratory system:

Infrequent:

chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration.

Rare:

atelectasis, hemoptysis, hiccup, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea, sputum increased.

Skin and appendages

: Frequent:

pruritus.

Infrequent:

acne, alopecia, dry skin, maculopapular rash, psoriasis.

Rare:

brittle nails, erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism, leukoderma, miliaria, petechial rash, pruritic rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin hypertrophy, skin striae, sweating decreased.

Special senses

Infrequent:

diplopia, dry eyes, eye pain, otitis media, parosmia, photophobia, taste loss.

Rare:

blepharitis, cataract, chromatopsia, conjunctival edema, corneal lesion, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, retinal hemorrhage, subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis, visual field defect, vitreous disorder.

Urogenital system

Frequent:

erectile dysfunction.

Infrequent:

albuminuria, cystitis, hematuria, leukorrhea *, kidney calculus, kidney pain, kidney function abnormal, nocturia, breast pain, prostatic disorder (includes prostatitis, enlarged prostate, and prostate irritability) *, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage *, vaginitis *.

Rare:

abortion *, anuria, balanitis *, bladder pain, breast discharge, breast engorgement, breast enlargement, endometriosis *, fibrocystic breast, calcium crystalluria, cervicitis *, ovarian cyst *, prolonged erection *, female lactation *, gynecomastia *, hypomenorrhea *, mastitis *, menopause *, oliguria, orchitis, pyelonephritis, salpingitis *, urolithiasis, uterine hemorrhage *, vaginal dryness *.

Based on the number of men and women, as appropriate.

Post-Market Adverse Drug Reactions Not Listed as Clinical Trial Adverse Event

Voluntary reports of adverse events other than those above, temporally associated with the use of venlafaxine, that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following:

Body as a whole:

anaphylaxis, congenital anomalies, neuroleptic malignant syndrome-like events (including the case of a 10-year old boy who may have been taking methylphenidate, was treated and recovered), serotonin syndrome

Cardiovascular system:

congestive heart failure, deep vein thrombosis, heart arrest, hemorrhage, myocardial infarction, ECG abnormalities (such as atrial fibrillation, bigeminy, supraventricular tachycardia, ventricular extrasystole, ventricular fibrillation and ventricular tachycardia, including torsades de pointes)

Digestive system:

bruxism, diarrhoea, gastrointestinal bleeding, hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; fatty liver, liver damage, necrosis or failure, fulminant hepatitis, including rare fatalities), pancreatitis, diarrhea

Endocrine system:

prolactin increased

Hemic and lymphatic system: agranulocytosis, aplastic anemia, neutropenia, pancytopenia Metabolic and Nutritional: CPK increased, dehydration, hepatitis, LDH increased, syndrome of inappropriate antidiuretic hormone secretion, weight loss

Musculoskeletal:

rhabdomyolysis

Nervous system:

abnormal gait, agitation, catatonia, delirium, extrapyramidal symptoms (including dyskinesia, dystonia, tardive dyskinesia), grand mal seizures, increased muscle tonus, involuntary movements, panic, paresthesia, neuroleptic malignant syndrome, sedation, shock- like electrical sensations (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), aggressive ideation and acts, including harm to others.

Respiratory system:

interstitial lung disease (including pulmonary eosinophilia)

Skin and appendages:

epidermal necrosis/Stevens-Johnson syndrome, erythema multiform, sweating including night sweats

Special senses: angle closure glaucoma, eye hemorrhage, tinnitus Urogenital system: renal failure.

DRUG INTERACTIONS

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS

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.

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

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.

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 venlafaxine hydrochloride extended release capsules 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.)

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

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).

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.

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.

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.

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 patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.

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.

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.

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 ql2h). 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.

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. The clinical relevance of this finding is unknown. 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).

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 veniafaxine 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 CYP2CI9 (see Diazepam above).

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.

There are no clinical data on the use of electroconvulsive therapy combined with venlafaxine hydrochloride extended release capsules treatment.

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

In common with SSRI's, pharmacodynamic interactions between venlafaxine hydrochloride extended release capsules and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.

Physical and Psychological Dependence

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

DOSAGE AND ADMINISTRATION

General

pms-VENLAFAXINE 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. 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, diarrhea, 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 pms- VENLAFAXINE XR capsules 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 EVENTS , 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 pms-VENLAFAXINE XR. In addition, at least 14 days should be allowed after stopping pms-VENLAFAXINE 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 venlafaxine hydrochloride extended release at the nearest equivalent dose (mg/day), e.g., 37.5 mg immediate release two-times-a-day to 75 mg venlafaxine hydrochloride extended release once daily. However, individual dosage adjustments may be necessary.

The recommended dose for pms-VENLAFAXINE XR capsules 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 pms-VENLAFAXINE XR capsules 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 venlafaxine hydrochloride extended release capsules at doses higher than 225 mg/day, or in severely depressed inpatients.

There is no body of evidence available to answer the question of how long a patient should continue to be treated with pms-VENLAFAXINE XR for depression. During long-term therapy for any indication, the pms-VENLAFAXINE 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 venlafaxine hydrochloride extended release capsules has been shown in a placebo controlled study in which patients responding during 8 weeks of acute treatment with venlafaxine hydrochloride extended release capsules were assigned randomly to placebo or to the same dose of venlafaxine hydrochloride extended release capsules (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 for venlafaxine hydrochloride extended release capsules needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.

Treatment of Pregnant Women During the Third Trimester

WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women

Post-marketing reports indicate that some neonates exposed to venlafaxine hydrochloride extended release, 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 pms-VENLAFAXINE 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 pms- VENLAFAXINE 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, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

Pediatrics

pms-VENLAFAXINE 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 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

ACTION AND CLINICAL PHARMACOLOGY, Renal Insufficiency

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

), 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.

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.

OVERDOSAGE

For management of a suspected overdose, please contact your regional poison centre

Venlafaxine Hydrochloride Extended Release Capsules

Among the patients included in the premarketing evaluation of venlafaxine extended release capsules, there were 2 reports of acute overdosage with venlafaxine hydrochloride extended release capsules in depression trials, either alone or in combination with other drugs. One patient took a combination of 6 g of venlafaxine hydrochloride extended release capsules 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 venlafaxine hydrochloride extended release capsules. This patient reported paresthesia of all four limbs but recovered without sequelae. There were 2 reports of acute overdose with venlafaxine hydrochloride extended release trials. One patient took 0.675g of venlafaxine hydrochloride extended release once and the other patient took 0.45g of venlafaxine hydrochloride extended release for 2 days. No signs or symptoms were associated with either overdose and no actions were taken to treat them.

Postmarketing Experience with Venlafaxine

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 changed (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. 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 tircyclic 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 overdosages 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 information on the treatment of any overdose.

ACTION AND CLINICAL PHARMACOLOGY

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.

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.

Venlafaxine Hydrochloride Extended Release Capsules

After administration of 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 venlafaxine hydrochloride extended release capsules is slower than its rate of elimination. Therefore, the apparent elimination half- life of venlafaxine following administration of venlafaxine hydrochloride extended release capsules (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 venlafaxine hydrochloride extended release 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 venlafaxine hydrochloride extended release 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 +- 1.9 L/kg, indicating that venlafaxine distributes well beyond the total body water.

Absorption:

Venlafaxine is well absorbed; after administration of 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 venlafaxine hydrochloride extended release capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of venlafaxine hydrochloride extended release (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.

Pediatrics:

Safety and efficacy in children below the age of 18 have not been established. pms-VENLAFAXINE XR (venlafaxine hydrochloride extended release) 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 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 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 intersubject 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 intersubject variability was noted.

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

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

SPECIAL HANDLING INSTRUCTIONS

DOSAGE FORMS, COMPOSITION AND PACKAGING

pms-VENLAFAXINE XR (venlafaxine hydrochloride extended release) capsules are available in bottles of 100 capsules and 500 capsules, in the following dosage strengths (potency is expressed in terms of venlafaxine base):

Hard gelatin capsule with light grey opaque cap and peach opaque body, with "P" logo on the cap and "37.5" on the body, in red ink

Hard gelatin capsule with peach opaque cap and body, with "P" logo on the cap and "75" on the body, in red ink.

Hard gelatin capsule with dark orange opaque cap and body, with "P" logo on the cap and "150" on the body, in white ink.

Venlafaxine hydrochloride is the active ingredient. The capsules also contain the following inactive ingredients: sugar spheres, povidone, ethyl cellulose (45 cps), dibutyl sebecate.

mg 150 mg Composition of Inks:

White Ink:

Shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, sodium hydroxide, povidone, titanium dioxide.

Red Ink:

Shellac glaze, iron oxide red, N-Butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide, simethicone.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedicinal Ingredients
Oral	Capsules, 37.5 mg, 75 mg and 150 mg	None. For a complete listing see Dosage Forms, Composition and Packaging section.

Treatment Group	(%) Incidence of Sustained Elevation in SDBP
Venlafaxine	Extended Release Venlafaxine Hydrochloride Capsules
< 100 mg/day	3
101-200 mg/day	2
201-300 mg/day	4
> 300 mg/day	NE *
Placebo	0

Venlafaxine Hydrochloride Extended-Release Capsules

mg, 75 mg and 150 mg venlafaxine (as venlafaxine hydrochloride)

Submission Control No: 124554

PART I: HEALTH PROFESSIONAL INFORMATION 3

PART II: SCIENTIFIC INFORMATION 37

PART III: CONSUMER INFORMATION. 50

Venlafaxine Hydrochloride Extended Release Capsules

mg, 75 mg and 150 mg venlafaxine (as venlafaxine hydrochloride)

THERAPEUTIC CLASSIFICATION

Antidepressant

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

pms-VENLAFAXINE XR (venlafaxine hydrochloride extended release capsules) is indicated for:

Long-term use of pms-VENLAFAXINE XRDOSAGE AND ADMINISTRATION

Geriatrics (> 65 years of age)

Pediatrics (< 18 years of age)

CONTRAINDICATIONS

Hypersensitivity

Monoamine Oxidase Inhibitors (MAOIs)

WARNINGS AND PRECAUTIONS

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

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.

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

Discontinuation Symptoms

General

Hypertension General

TABLE 1: PROBABILITY OF SUSTAINED ELEVATION IN SDBP

The following additional precautions are listed alphabetically. Carcinogenesis and Mutagenesis

Cardiac Disease

TABLE 2: INCIDENCE OF INSOMNIA AND NERVOUSNESS IN PLACEBO- CONTROLLED DEPRESSION, GAD, AND SOCIAL ANXIETY DISORDER TRIALS

TOXICOLOGY, Reproductive Toxicity.

WARNINGS and PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant SyndromeDOSAGE AND ADMINISTRATION, Treatment of Pregnant Women During the Third Trimester

Nursing Women:

Pediatrics (<18 years of age): pms-VENLAFAXINE XR is not indicated for use in children under 18 years of age WARNINGS AND PRECAUTIONS, General, Potential Association with Behavioral and Emotional Changes, Including Self-Harm

Geriatrics (>65 years of age):

ADVERSE REACTIONS, Laboratory Changes - Cholesterol

ADVERSE REACTIONS

Commonly Observed Adverse Reactions

TABLE 3: ADVERSE REACTIONS (PERCENTAGE) LEADING TO DISCONTINUATION OF TREATMENT

Incidence in Controlled Trials

TABLE 4A: TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS (PERCENTAGE)1 IN DEPRESSED PATIENTS

Adaptation to Certain Adverse Events

Vital Sign Changes

Laboratory Changes - Cholesterol

ECG Changes

Frequent:

Infrequent:

Rare:

Infrequent:

Frequent:

Infrequent:

Rare:

Rare:

Infrequent:

Rare:

Frequent:

Infrequent: Rare:

Infrequent:

Rare:

Infrequent:

Rare:

Infrequent:

Rare:

Infrequent:

Rare:

Infrequent:

Rare:

Frequent:

Infrequent:

Rare:

DRUG INTERACTIONS

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS

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

CYP2D6-Inhibitors:

CYP3A3/4 Inhibitors:

CYP2D6

CYP3A4

Indinavir

CYP1A2

CYP2C9