(Venlafaxine Hydrochloride)

Extended Release Capsules

(37.5, 75, and 150 mg venlafaxine as venlafaxine hydrochloride)

ANTIDEPRESSANT

Genpharm ULC Date of Preparation: 85 Advance Rd. May 07, 2008 Etobicoke, Ontario M8Z 2S6

Control Number: 115299

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 14 DRUG INTERACTIONS 26 DOSAGE AND ADMINISTRATION 31 OVERDOSAGE 34 ACTION AND CLINICAL PHARMACOLOGY 36 STORAGE AND STABILITY 39 SPECIAL HANDLING INSTRUCTIONS 39 DOSAGE FORMS, COMPOSITION AND PACKAGING 39

PART II: SCIENTIFIC INFORMATION 41

PHARMACEUTICAL INFORMATION 41 CLINICAL TRIALS 42 DETAILED PHARMACOLOGY 46 TOXICOLOGY 46 REFERENCES 50

PART III: CONSUMER INFORMATION. 53

GEN-VENLAFAXINE 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):

GEN-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 GEN-VENLAFAXINE XR therapy. Adverse reactions, some serious, have been reported when Venlafaxine Extended Release Capsules therapy is initiated soon after discontinuing an MAOI and when an MAOI is initiated soon after discontinuation of Venlafaxine 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 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.

Discontinuation Symptoms

Patients currently taking GEN-VENLAFAXINE 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).

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.

Venlafaxine Extended Release Capsules

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

Discontinuation Symptoms

Discontinuation symptoms have been assessed 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 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 EVENTS, 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 GEN-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.

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 Venlafaxine 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 Extended Release Capsules-treated patients in depression studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for Venlafaxine Extended Release Capsules and decrease of 1.9 msec for placebo). The clinical significance of this change is unknown. Three of 705 Venlafaxine Extended Release Capsules-treated patients in phase III studies experienced QTc prolongation to 500 msec during treatment. Baseline QTc was >450 msec for all 3 patients. 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). 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 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 coadministration include the possibility of serotonin syndrome. (See PRECAUTIONS, 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 Venlafaxine Extended Release Capsules, compared with immediate release tablets. In a 12-week study comparing immediate release tablets with Venlafaxine Extended Release Capsules, once daily, Venlafaxine 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 Extended Release Capsules than with immediate release tablets. Additionally, the incidence of vomiting was lower with Venlafaxine Extended Release Capsules 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

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).

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

GEN-VENLAFAXINE 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 EVENTS, 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 Venlafaxine Extended Release Capsules-treated patients.. GEN-VENLAFAXINE 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 GEN-VENLAFAXINE XR (venlafaxine HCl) Capsules should be written for the smallest quantity of capsules consistent with good patient management.

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, as shown in Table 2.

Table 2

Incidence of Insomnia and Nervousness in Placebo-Controlled Depression Trials

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Venlafaxine Extended Release Capsules in depression studies.

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% of Venlafaxine Extended Release Capsules-treated patients in depression studies. As with all antidepressants, GEN-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.

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.

WARNINGS and PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant DOSAGE 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

Syndrome). When treating a pregnant woman with GEN-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 GEN-VENLAFAXINE XR while nursing, the potential for discontinuation effects in the infant upon cessation of nursing should be considered. Pediatrics (<18 years of age): GEN-VENLAFAXINE XR (venlafaxine) is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, General, 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 trials with Venlafaxine 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.

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. 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.)

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). 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.

PRECAUTIONS, Cardiac Disease).

An analysis of ECGs obtained in 357 patients treated with Venlafaxine 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 Extended Release Capsules-treated patients was increased relative to that for placebo-treated patients in the clinical trials for depression (see WARNINGS AND

Other Events Observed During the Premarketing Evaluation of Venlafaxine

During the premarketing assessment of venlafaxine immediate release tablets, multiple doses were administered to 2897 patients in phase II-III depression studies. Multiple doses of Venlafaxine Extended Release Capsules were administered to 705 patients in phase III depression studies (as well as 96 patients on venlafaxine immediate release tablets). The conditions and duration of exposure to venlafaxine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine immediate release tablets only) and 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 7212 patients exposed to multiple doses of either formulation 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), 4B (MDD dose related), 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 important 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:

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

Rare: ,

alcohol intolerance, bilirubinemia

BUN increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesterolemia, 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, diarrhoea 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.

Respiratorv 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

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

Based on the known mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems (such as triptans, selective serotonin reuptake inhibitors, or lithium). 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 GEN-VENLAFAXINE 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 fenfluramine, tryptophan and silbutramine; the antibiotic linezolid; 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 (t 1/2) 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. Because CYP3A3/4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A3/4-mediated metabolism and venlafaxine is small.

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 141% 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. The clinical relevance of this finding is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethyl venlafaxine. (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 coadministration 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 Venlafaxine Extended Release Capsules 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 GEN-VENLAFAXINE 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 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

Dosing Considerations

General

GEN-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. 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 GEN-VENLAFAXINE 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 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 GEN-VENLAFAXINE XR. In addition, at least 14 days should be allowed after stopping GEN-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 GEN-VENLAFAXINE XR at the nearest equivalent dose (mg/day), e.g., 37.5 mg immediate release two-times-a-day to 75 mg GEN- VENLAFAXINE 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 GEN-VENLAFAXINE 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 Venlafaxine Extended Release 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 Extended Release Capsules at doses higher than 225 mg/day, or in severely depressed inpatients.

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 Venlafaxine Extended Release Capsules for depression. During long-term therapy for any indication, the GEN-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 Extended Release Capsules has been shown in a placebo controlled study in which patients responding during 8 weeks of acute treatment with Venlafaxine Extended Release Capsules were assigned randomly to placebo or to the same dose of Venlafaxine 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 of GEN-VENLAFAXINE 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.

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 Venlafaxine Extended Release Capsules, 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 GEN-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 GEN- 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, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

Pediatrics

GEN-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 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 ug/mL, respectively, and the peak plasma levels of O- desmethylvenlafaxine were 3.37 and 1.30 ug/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.

Venlafaxine 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 Extended Release Capsules in depression trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Venlafaxine 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 Extended Release Capsules. This patient reported paresthesia of all four limbs but recovered without sequelae. 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. 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 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.

Venlafaxine 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 Extended Release Capsules is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of Venlafaxine 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 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 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+-1.9L/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 Extended Release Capsules is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of Venlafaxine 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. 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 +-1.9 L/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. GEN-VENLAFAXINE 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 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 (see 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

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

SPECIAL HANDLING INSTRUCTIONS

None.

DOSAGE FORMS, COMPOSITION AND PACKAGING

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

venlafaxine base):

mg:

Hard gelatine size 0 capsule with a flesh opaque body and a light gray opaque cap, imprinted in red ink "G" on the body and "VEN XR" over "37.5" on the cap, the capsule contains one white round biconvex tablet with approximate diameter of 6.0 mm.

mg:

Hard gelatine size 0 capsule with a flesh opaque body and a flesh opaque cap, imprinted in red ink "G" on the body and "VEN XR" over "75" on the cap, the capsule contains two white round biconvex tablet with approximate diameter of

6.0 mm.

mg:

Hard gelatine size 00 capsule with a swedish orange opaque body and a swedish orange opaque cap, imprinted in white ink "G" on the body and "VEN XR" over "150" on the cap, the capsule contains three white round biconvex tablet with approximate diameter of 6.8 mm.

Composition: Medicinal Ingredients

Venlafaxine Hydrochloride

Non-medicinal Ingredients: Acetone Ammonio Methacrylate Copolymer Basic Butylated Methacrylate Copolymer

Gelatin USP

Hypromellose Ph.Eur Iron Oxide Black NF Iron Oxide Red NF Iron Oxide Yellow NF

Isopropyl Alcohol

Magnesium Stearate Ph.Eur Sodium Lauryl Sulphate Ph.Eur Titanium Dioxide Ph.Eur