Riva-Venlafaxine XR Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults

RIVA-VENLAFAXINE XR (Venlafaxine Hydrochloride) Extended Release Capsules is indicated for:

• Depression:

  RIVA-VENLAFAXINE XR (extended release capsules) are indicated for the symptomatic relief of major depressive disorder.

  The short-term efficacy of venlafaxine hydrochloride extended release capsules has been demonstrated in placebo-controlled trials of up to 12 weeks.

  The efficacy of venlafaxine hydrochloride extended release capsules in maintaining an antidepressant response for up to 26 weeks following response to 8 weeks of acute treatment was demonstrated in a placebo-controlled trial (see CLINICAL TRIALS, Depression).

• Generalized Anxiety Disorder (GAD):

  RIVA-VENLAFAXINE XR capsules are indicated for the symptomatic relief of anxiety causing clinically significant distress in patients with GAD. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of venlafaxine hydrochloride extended release capsules in long-term use has been evaluated for up to 6 months in controlled clinical trials (see CLINICAL TRIALS, Generalized Anxiety Disorder).

• Social Anxiety Disorder (Social Phobia):

  RIVA-VENLAFAXINE XR Capsules is indicated for the symptomatic relief of Social Anxiety Disorder, also known as Social Phobia.

  Social Anxiety Disorder is characterized by a marked and persistent fear of one or more social or performance situations, in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. Fear, anxious anticipation, distress in the feared situation(s) or avoidance of social and/or performance situations that does not interfere significantly with the person's normal routine, occupational or academic functioning, or social life usually does not require treatment with an anxiolytic.

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

• Panic Disorder:

  RIVA-VENLAFAXINE XR is indicated for the symptomatic relief of Panic Disorder, with or without agoraphobia, as defined in DSM-IV. Panic Disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behaviour related to the attacks.

  Panic Disorder (DSM-IV) is characterized by recurrent, unexpected panic attacks, i.e., a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: 1) palpitations, pounding heart, or accelerated heart rate; 2) sweating; 3) trembling or shaking; 4) sensations of shortness of breath or smothering; 5) feeling of choking; 6) chest pain or discomfort; 7) nausea or abdominal distress; 8) feeling dizzy, unsteady, light-headed, or faint; 9) derealization (feelings of unreality) or depersonalization (being detached from oneself); 10) fear of losing control; 11) fear of dying; 12) paresthesias (numbness or tingling sensations); 13) chills or hot flushes.

  The efficacy of venlafaxine hydrochloride extended release capsules in the treatment of Panic Disorder was established in two 12 week placebo-controlled trials in adult outpatients with Panic Disorder (DSM-IV). The efficacy of venlafaxine hydrochloride extended release capsules in prolonging time to relapse in Panic Disorder for up to 6 months in responders of a 12-week acute treatment was demonstrated in a placebo-controlled trial (see CLINICAL TRIALS, Panic Disorder).

Long-term use of RIVA-VENLAFAXINE XR: The physician who elects to use RIVA-VENLAFAXINE XR for extended periods in the treatment of depression, GAD, Social Anxiety Disorder, or Panic Disorder should periodically re-evaluate the long-term usefulness of the drug for the individual patient (See DOSAGE AND ADMINISTRATION).

Geriatrics (> 65 years of age): Caution should be exercised in treating the elderly. In Phase II and III clinical trials, 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.

Pediatrics (< 18 years of age): RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, GENERAL, POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

CONTRAINDICATIONS

• Hypersensitivity: Patients who are hypersensitive to RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) or to any ingredient in the formulation or component of the container.

• Monoamine Oxidase Inhibitors (MAOIs):

  RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) 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 RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) therapy.

  Adverse reactions, some serious, have been reported when venlafaxine hydrochloride therapy is initiated soon after discontinuing an MAOI and when an MAOI is initiated soon after discontinuation of venlafaxine hydrochloride. 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/psychomotor restlessness, 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.

An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients ages 18 to 24 years with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo.

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

Aggression

Aggression may occur in some patients who have received antidepressants, including venlafaxine treatment, dose reduction, or discontinuation. As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.

Discontinuation

Discontinuation effects are well known to occur with antidepressants, and sometimes these effects can be protracted and severe (see ADVERSE REACTIONS). Suicide/suicidal thoughts and aggression have been observed in patients during changes in venlafaxine dosing regimen, including during discontinuation (see WARNINGS AND PRECAUTIONS, Adults and Pediatrics: Additional data). It is therefore recommended that the dosage of venlafaxine be tapered gradually and individually and the patients be closely monitored during discontinuation (see DOSAGE AND ADMINISTRATION). In some patients, discontinuation could take months or longer.

Sexual Dysfunction

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see ADVERSE REACTIONS). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SNRIs.

Bone Fracture Risk

Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including SSRIs/SNRIs. The risks appear to be greater at the initial stages of treatment, but significant increased risks were also observed at later stages of treatment. The possibility of fracture should be considered in the care of patients treated with RIVA-VENLAFAXINE XR. Elderly patients and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal. Preliminary data from observational studies show association of SSRIs/SNRIs and low bone mineral density in older men and women. Until further information becomes available, a possible effect on bone mineral density with long term treatment with SSRIs/SNRIs, including RIVA-VENLAFAXINE XR, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.

General

Allergic Reactions

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

Hypertension

General

Dose-related increases in blood pressure have been reported in some patients treated with venlafaxine. Also, rare cases of hypertensive crisis and malignant hypertension have been reported in normotensive and treated-hypertensive patients in post-marketing experience (see Acute Severe Hypertension below).

Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure.

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

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

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 mmHg, SDBP.

Depression: 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 mmHg was observed for venlafaxine hydrochloride extended release capsules-treated patients compared with a mean decrease of 0.2 mmHg 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 mmHg and ≥ 10 mmHg 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 hydrochloride 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.

Generalized Anxiety Disorder (GAD): In placebo-controlled premarketing anxiety studies with venlafaxine hydrochloride extended release capsules 37.5-225 mg/day, a final on-drug mean increase in SDBP of 0.4 mmHg was observed for venlafaxine hydrochloride extended release capsules treated patients compared with a mean decrease of 0.8 mmHg for placebo treated patients.

Social Anxiety Disorder (Social Phobia): In 4 placebo-controlled premarketing Social Anxiety Disorder studies with venlafaxine hydrochloride extended release capsules 75-225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 0.9 mmHg was observed for venlafaxine hydrochloride extended release capsules-treated patients compared with a mean decrease of 1.6 mmHg for placebo-treated patients. In one placebo-controlled premarketing Social Anxiety Disorder study with venlafaxine hydrochloride extended release capsules up to 6 months, a final on-drug mean decrease in SDBP of 0.2 mm Hg was observed for venlafaxine hydrochloride extended release capsules-treated patients who received fixed doses of 75 mg/day and a mean increase of 1.5 mmHg was observed for venlafaxine hydrochloride extended release capsules-treated patients who received flexible doses of 150 to 225 mg/day, compared with a mean decrease of 0.6 mmHg for placebo-treated patients.

Among patients treated with 75-225 mg per day of venlafaxine hydrochloride extended release capsules in all premarketing Social Anxiety Disorder studies, 0.6% (5/771) experienced sustained hypertension.

In all premarketing Social Anxiety Disorder studies with patients treated with 75-225 mg per day, 0.6% (5/771) of the venlafaxine hydrochloride extended release capsules-treated patients discontinued treatment because of elevated blood pressure.

Panic Disorder: In placebo-controlled premarketing Panic Disorder studies with venlafaxine hydrochloride extended release capsules 75-225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 0.3 mmHg was observed for venlafaxine hydrochloride extended release capsules-treated patients compared with a mean decrease of 1.1 mmHg for placebo-treated patients.

Among patients treated with 75 to 225 mg/day of venlafaxine hydrochloride extended release capsules in premarketing Panic Disorder studies up to 12 weeks, 0.9% (9/973) experienced sustained hypertension.

In premarketing Panic Disorder studies up to 12 weeks, 0.5% (5/1001) of the venlafaxine hydrochloride extended release capsules-treated patients discontinued treatment because of elevated blood pressure.

Serotonin Syndrome

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

Discontinuation Symptoms

Discontinuation symptoms have been assessed both in patients with depression and those with anxiety. Abrupt discontinuation, dose reduction, or tapering of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. If venlafaxine is used until or shortly before birth, discontinuation effects in the newborn should be considered.

Reported symptoms include aggression, agitation, anorexia, anxiety, asthenia, confusion, convulsions, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headache, hypomania, impaired coordination and balance, insomnia, nausea, nightmares, nervousness, paresthesia, electric shock sensations, sensory disturbances (including shock like electrical sensations), sleep disturbances, somnolence, sweating, tinnitus, tremor, vertigo, and vomiting. Where such symptoms occurred they were usually self-limiting but in a few patients continued for several weeks. In premarketing studies, the majority of discontinuation reactions were mild and resolved without treatment.

Discontinuation effects are well known to occur with antidepressants, and, therefore, it is recommended that the dosage be tapered gradually whenever possible 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.)

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 RIVA-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

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.

ECG Changes in clinical trials

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 hydrochloride extended release capsules-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 hydrochloride 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.

Electrocardiograms are available for 815 patients who received venlafaxine hydrochloride extended release capsules and 379 patients who received placebo in up to 6-month, double-blind, placebo-controlled trials in Generalized Anxiety Disorder. The mean change from baseline in the corrected QT interval (QTc) for venlafaxine hydrochloride extended release capsules-treated patients in the GAD studies did not differ significantly from that with placebo. One of the 815 venlafaxine hydrochloride extended release capsules-treated patients experienced QTc prolongation to 593 msec. Baseline QTc was 460 msec for this one patient.

Electrocardiograms were evaluated for 401 patients who received venlafaxine hydrochloride extended release capsules and 444 patients who received placebo in four 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline in QT_c for venlafaxine hydrochloride extended release capsules-treated patients in the 12-week Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 4.1 msec for

venlafaxine hydrochloride extended release capsules and decrease of 1.4 msec for placebo). Electrocardiograms were evaluated for 101 patients who received venlafaxine hydrochloride extended release capsules 75 mg/day, 96 patients who received 150-225 mg/day, and 90 patients who received placebo in one 6-month double-blind, placebo-controlled trial in Social Anxiety Disorder. A mean decrease from baseline in QT_c of 0.05 ms was observed for patients treated with venlafaxine hydrochloride extended release capsules 75 mg/day, a mean increase from baseline in QT_c of 3.4 ms was observed for patients treated with venlafaxine hydrochloride extended release capsules 150-225 mg/day, and a mean increase from baseline in QT_c of 0.5 ms was observed for patients treated with placebo in the 6-month Social Anxiety Disorder study.

Electrocardiograms were evaluated for 661 patients who received venlafaxine hydrochloride extended release capsules and 395 patients who received placebo in three 10-to 12-week double-blind, placebo-controlled trials in Panic Disorder. The mean change from baseline in QT_c for venlafaxine hydrochloride extended release capsules-treated patients in the Panic Disorder studies was increased relative to that for placebo-treated patients (increase of 1.5 msec for venlafaxine hydrochloride extended release capsules and decrease of 0.7 msec for placebo).

No case of sudden unexplained death or serious ventricular arrhythmia, which are possible clinical sequelae of QTc prolongation, was reported in 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 and GAD. The mean change from baseline in heart rate for venlafaxine hydrochloride extended release capsules-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for venlafaxine hydrochloride extended release capsules and no change for placebo).

The mean change from baseline in heart rate for venlafaxine hydrochloride extended release capsules-treated patients in the Panic Disorder studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for venlafaxine hydrochloride extended release capsules and a mean decrease of less than 1 beat per minute for placebo).

Increases in heart rate can occur, particularly with higher doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.

QTc prolongation, Torsade de Pointes (TdP)

The QT effect of venlafaxine was evaluated in a thorough QTc study. In healthy subjects, venlafaxine did not prolong the QTc interval at a dose of 450 mg/day (given as 225 mg twice a day). Cases of QTc prolongation, Torsade de Pointes (TdP), ventricular tachycardia and sudden death have been reported during the postmarketing use of venlafaxine, including at therapeutic doses. Caution should be exercised when venlafaxine is prescribed in patients with cardiovascular disease or family history of QT prolongation, or in patients taking medicines known to increase QT interval, especially for patients with increased risk of QT prolongation, i.e., the elderly, patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalemia, or hypomagnesemia (see DRUG INTERACTIONS, as well as OVERDOSAGE).

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 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 central nervous system (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. (Monitoring Laboratory Changes, Serum Cholesterol Elevation).

Consistent with the above findings, elevations of High Density Lipoprotein Cholesterol (HDL), Low Density Lipoprotein Cholesterol (LDL) and the overall ratio of Total Cholesterol/HDL have been observed in

placebo controlled clinical trials for Social Anxiety Disorder (SAD) and Panic Disorder.

Measurement of serum cholesterol levels (including a complete lipid profile/fractionation and an assessment of the patient’s individual risk factors) should be considered especially during long- term treatment.

Changes in Appetite and Weight

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

Gastrointestinal

Results of testing in healthy volunteers demonstrated differences in the gastrointestinal tolerability of different formulations of venlafaxine. Data from healthy volunteers showed reduced incidence and severity of nausea with 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 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.

Genitourinary

Hyponatremia

Cases of hyponatremia may occur with venlafaxine, usually in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volume depleted, may be at greater risk for this event.

The hyponatremia appeared to be reversible when venlafaxine was discontinued.

Inappropriate Antidiuretic Hormone Secretion

Cases of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with venlafaxine, usually in volume-depleted or dehydrated patients. Elderly patients, and patients taking diuretics, and patients who are otherwise volume depleted, may be at greater risk for this event.

Hematologic

Abnormal Bleeding

SSRIs and SNRIs, including RIVA-VENLAFAXINE XR, may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of RIVA-VENLAFAXINE XR and NSAIDs, ASA, or other drugs that affect coagulation (see DRUG INTERACTIONS, Drugs Affecting Platelet Function). Caution is advised in patients with a history of bleeding disorder or predisposing conditions (e.g. thrombocytopenia).

Hepatic/Biliary/Pancreatic

In patients with hepatic impairment, the pharmacokinetic disposition of both venlafaxine and

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

Neurologic

Seizures

RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) 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 REACTIONS, Discontinuation Symptoms; DOSAGE AND ADMINISTRATION, Discontinuing Venlafaxine).

During premarketing depression studies no seizures were seen in 705 venlafaxine hydrochloride extended release capsule-treated patients. Premarketing, no seizures occurred among 1381 venlafaxine hydrochloride extended release capsule-treated patients in Generalized Anxiety Disorder studies or among 277 venlafaxine hydrochloride extended release capsule-treated patients in Social Anxiety Disorder Studies. In Panic Disorder studies, 1 seizure occurred among 1001 Venlafaxine hydrochloride extended release-treated patients (0.1%). However, patients with a history of convulsive disorders were excluded from most of these studies. RIVA-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 (NMS)

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 drugs (including SSRIs, SNRIs, amphetamines, and triptans), with drugs that may impair metabolism of serotonin (including MAOIs (including linezolid, an antibiotic, and methylene blue)), neuroleptics/antipsychotics or other dopamine antagonist 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 (e.g., tachycardia, labile blood pressure) with possible rapid fluctuations of vital signs, neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea), mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma and supportive symptomatic treatment should be initiated. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome (NMS). Due to the risk of serotonergic syndrome or NMS 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).

If concomitant treatment with venlafaxine and other agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.

Ophthalmologic

Angle-Closure Glaucoma

As with other antidepressants, venlafaxine can cause mydriasis, which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles. Healthcare providers should inform patients to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.

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.

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

The risk of suicide attempt must be considered, especially in depressed patients; the smallest quantity of drug, consistent with good patient management, should be provided to reduce the risk of overdose with this drug.

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

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

Insomnia and Nervousness

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

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

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

In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with venlafaxine hydrochloride extended release capsules up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with venlafaxine hydrochloride extended release capsules up to 6 months. In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in 2% and 1%, respectively, of the patients treated with venlafaxine hydrochloride extended release capsules up to 12 weeks and 2% and 3%, respectively, of the patients treated with venlafaxine hydrochloride extended release capsules up to 6 months. In Panic Disorder trials, insomnia and nervousness led to drug discontinuation in 1% and 0.1%, respectively, of the patients treated with venlafaxine hydrochloride extended release capsules up to 12 weeks.

Activation of Mania/Hypomania

During Phase II and III trials, mania or hypomania occurred in 0.3% and 0% of venlafaxine hydrochloride extended release capsules-treated patients in depression and anxiety studies respectively. In premarketing Social Anxiety Disorder studies, 0.2% of venlafaxine hydrochloride extended release capsules-treated patients and no placebo-treated patients experienced mania or hypomania. In premarketing Panic Disorder studies, 0.1% of venlafaxine hydrochloride extended release capsules-treated patients and 0.0% placebo-treated patients experienced mania or hypomania. Mania or hypomania occurred in 0.4% of all venlafaxine-treated patients. Mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, venlafaxine hydrochloride extended release capsules should be used cautiously in patients with a history or family history of bipolar disorder.

A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.

Renal

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

Sexual Function/Reproduction

See ADVERSE REACTIONS and PART II: SCIENTIFIC INFORMATION, TOXICOLOGY, Reproductive Toxicity.

Special Populations

Pregnant Women:

There are no adequate and well controlled studies with venlafaxine in pregnant women. Therefore, venlafaxine should only be used during pregnancy if clearly needed. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Post-marketing reports indicate that some neonates exposed to venlafaxine, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, or, possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS AND PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant Syndrome). When treating a pregnant woman with RIVA-VENLAFAXINE XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. (see DOSAGE AND ADMINISTRATION, Treatment of Pregnant Women During the Third Trimester).

Any change in antidepressant medication (including dosage) during pregnancy should be discussed with the attending physician beforehand to discuss the benefits/risks with the patient.

Exposure to SNRIs in mid to late pregnancy may increase the risk for preeclampsia, and exposure to SNRIs near delivery may increase the risk for postpartum hemorrhage.

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

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

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

Monitoring and Laboratory Tests

Self-Harm

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes (see WARNINGS AND PRECAUTIONS, POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

Sustained Hypertension and Acute Severe Hypertension

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

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).

Consistent with the above findings, elevations of High Density Lipoprotein Cholesterol (HDL), Low Density Lipoprotein Cholesterol (LDL) and the overall ratio of Total Cholesterol/HDL have been observed in placebo controlled clinical trials for Social Anxiety Disorder (SAD) and Panic Disorder.

Measurement of serum cholesterol levels (including a complete lipid profile/fractionation and an assessment of the patient’s individual risk factors) should be considered especially during long- term treatment.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

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 venlafaxine at least twice that for placebo), derived from the 2% incidence Table 4, were: abnormal dreams, anorexia, dizziness, dry mouth, nausea, nervousness, somnolence, sweating, and tremor as well as abnormal ejaculation/orgasm in men.

During GAD trials, the most commonly observed adverse events associated with the use of venlafaxine hydrochloride extended release capsules, derived from the 2% incidence Table 5A were: nausea, dry mouth, anorexia, abnormal ejaculation, constipation, sweating, abnormal vision, impotence in men, vasodilatation, dizziness, somnolence, libido decreased, abnormal dreams, yawn and tremor.

During Social Anxiety Disorder trials, the following adverse events occurred in at least 5% of the venlafaxine hydrochloride extended release capsules patients and at a rate at least twice that of the placebo group for the four 12-week placebo-controlled trials for the Social Anxiety Disorder indication (Table 6A): asthenia, nausea, anorexia, constipation, insomnia, dry mouth, somnolence, nervousness, libido decreased, tremor, yawn, sweating, abnormal vision, as well as abnormal ejaculation, impotence, and anorgasmia in men. In a 6-month Social Anxiety Disorder trial, the following adverse events occurred in at least 5% of the patients who received either dose of venlafaxine hydrochloride extended release capsules and at a rate at least twice that of the placebo group (Table 6B): asthenia, vasodilatation, anorexia, constipation, nausea, dizziness, dry mouth, libido decreased, nervousness, paresthesia, somnolence, tremor, twitching, pharyngitis, yawn, sweating, abnormal vision, as well as abnormal ejaculation and impotence in men, and dysmenorrhea in women.

During Panic Disorder trials, the following adverse events occurred in at least 5% of the venlafaxine hydrochloride extended release capsules patients and at a rate at least twice that of the placebo group for the placebo-controlled trials for the Panic Disorder indication (Table 7): anorexia, constipation, dry mouth, somnolence, tremor, abnormal ejaculation in men, and sweating.

Adverse Events that Led to Discontinuation of Treatment in Clinical Trials

Twelve percent (88/705) of venlafaxine hydrochloride extended release capsules-treated patients in Phase II and III depression studies discontinued treatment due to an adverse reaction. Approximately 18% of the 1381 patients who received venlafaxine hydrochloride extended release capsules for up to 8 weeks in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 14% of the 562 patients who received venlafaxine hydrochloride extended release capsules for up to 12 weeks in 4 placebo-controlled clinical trials for social anxiety disorder discontinued treatment due to an adverse experience, compared with 5% of the 566 placebo-treated patients in those studies. Approximately 20% of the 257 patients who received venlafaxine hydrochloride extended release capsules in a 6-month placebo-controlled clinical trial for social anxiety disorder discontinued treatment due to an adverse experience, compared with 7% of the 129 placebo-treated patients in that study. The more common events (> 1%) associated with discontinuation of treatment in all 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

* : 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 4) 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 prescriber should be aware that the cited frequencies for venlafaxine hydrochloride extended release capsules cannot be compared with figures obtained from other clinical investigations of venlafaxine which involved different treatments, uses and investigators. The cited figures for venlafaxine hydrochloride extended release capsules, however, do 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 4: TREATMENT-EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS (PERCENTAGE)¹ IN DEPRESSED PATIENTS

¹ Events reported by at least 2% of patients treated with venlafaxine hydrochloride extended release capsules are included, and are rounded to the nearest %. Events for which the venlafaxine hydrochloride extended release capsules 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.

² Incidence based on number of male patients (For venlafaxine hydrochloride extended release capsules: n = 126, Placebo: n=108)

³ Incidence based on number of female patients (For venlafaxine hydrochloride extended release capsules: n = 231, Placebo: n = 177)

Dose Dependency of Adverse Events

The tables that follow (Table 5A and 5B) enumerate adverse events that occurred at an incidence of 2% or more, and at a higher rate than the placebo group, among venlafaxine hydrochloride extended release capsules-treated anxious patients.

TABLE 5A: TREATMENT-EMERGENT ADVERSE EVENT INCIDENCE (%) IN PLACEBO-CONTROLLED VENLAFAXINE HYDROCHLORIDE EXTENDED RELEASE NORTH AMERICAN CLINICAL TRIALS (210 US, 214 US and 218 US) IN GAD PATIENTS ^1,2 (8-28 WEEKS, DOSAGE RANGE 75-225 MG)

1 Incidence rounded to the nearest %, for events reported by at least 2% of patients treated with venlafaxine hydrochloride extended release capsules, except the following events which had an incidence equal to or less than placebo: abdominal pain, agitation, anxiety, arthralgia, back pain, chest pain, depression, dyspepsia, flu syndrome, headache, infection, migraine, myalgia, neck pain, pain, palpitation, pharyngitis, rash, rhinitis, sinusitis, and tinnitus

2 < 1% indicates an incidence greater than zero but less than 1%.

3 Incidence is based on number of male patients (For venlafaxine hydrochloride extended release capsules: n=242, Placebo: n=131)

4 Incidence is based on number of female patients (For venlafaxine hydrochloride extended release capsules: n=358, Placebo: n=197)

TABLE 5B: TREATMENT-EMERGENT ADVERSE EVENT INCIDENCE (%) IN A DOSE COMPARISON TRIAL (378 EU, 24 WEEKS) WITH GAD PATIENTS^1,2

1 Incidence rounded to the nearest %, for events reported by at least 2% of patients in any venlafaxine hydrochloride extended release capsules treatment group and at a incidence greater than the respective placebo incidence. # indicates that the incidence is less than 2% but rounds to 2%.

2 < 1% indicates an incidence greater than zero but less than 1%.

3 Incidence is based on number of male patients (For venlafaxine hydrochloride extended release capsules: n = 60 (37.5 mg), 51 (75 mg), 48 (150 mg); Placebo: n = 54)

4 Incidence is based on number of female patients (For venlafaxine hydrochloride extended release capsules: n = 80 (37.5 mg), 83 (75 mg), 89 (150 mg); Placebo: n = 76)

The tables that follow (Tables 6A and 6B) enumerate adverse events that occurred at an incidence of 2% or more, and were more frequent than in the placebo group, among venlafaxine-treated patients with Social Anxiety Disorder in 12-week and 6-month studies, respectively.

TABLE 6A: TREATMENT-EMERGENT ADVERSE EVENT INCIDENCE (%) IN SHORT-TERM, PLACEBO-CONTROLLED VENLAFAXINE HYDROCHLORIDE EXTENDED RELEASE CAPSULES CLINICAL TRIALS (387 EU/CA, 388 EU, 392-US, and 393 US) IN SOCIAL ANXIETY DISORDER PATIENTS ^1,2 (12 WEEKS, DOSAGE RANGE 75-225 MG)

1 Incidence rounded to the nearest %, for events reported by at least 2% of patients in any venlafaxine hydrochloride extended release capsules treatment group, and at an incidence greater than the respective placebo incidence. # indicates that the incidence is less than 2% but rounds to 2%.

2 <1% means greater than zero but less than 1%.

3 Percentage based on the number of males (venlafaxine hydrochloride extended release capsules = 308, placebo = 284).

4 Percentage based on the number of females (venlafaxine hydrochloride extended release capsules = 254, placebo = 282).

TABLE 6B: TREATMENT-EMERGENT ADVERSE EVENT INCIDENCE (%) IN A LONG-TERM, PLACEBO-CONTROLLED VENLAFAXINE HYDROCHLORIDE EXTENDED RELEASE CAPSULES CLINICAL TRIAL (390 US) IN SOCIAL ANXIETY DISORDER PATIENTS^1,2 (6 MONTHS, DOSAGE RANGE 75-225 MG)

1 Incidence rounded to the nearest %, for events reported by at least 2% of patients in any venlafaxine hydrochloride extended release capsules treatment group, and at an incidence greater than the respective placebo incidence. # indicates that the incidence is less than 2% but rounds to 2%.

2 <1% means greater than zero but less than 1%.

3 Percentage based on the number of males (venlafaxine hydrochloride extended release 75 mg capsules = 67, venlafaxine hydrochloride extended release 150 - 225 mg capsules = 79, placebo = 73).

4 Percentage based on the number of females (venlafaxine hydrochloride extended release 75 mg capsules = 61, venlafaxine hydrochloride extended release 150 - 225 mg capsules = 50, placebo = 56).

The table that follows (Table 7) enumerates adverse events that occurred at an incidence of 2% or more, and were more frequent than in the placebo group, among venlafaxine-treated patients with Panic Disorder.

TABLE 7: TREATMENT-EMERGENT ADVERSE EVENT INCIDENCE (%) IN SHORT-TERM PLACEBO-CONTROLLED VENLAFAXINE HYDROCHLORIDE EXTENDED RELEASE CAPSULES CLINICAL TRIALS (391-CA/EU, 353-US/CA, 398-EU AND 399-AC) IN PANIC DISORDER PATIENTS^1,2 (10-12 WEEKS, DOSAGE RANGE 37.5-225 MG)

1 Adverse events for which the venlafaxine hydrochloride extended release capsules reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, abnormal vision, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, nervousness, pain, paresthesia, pharyngitis, rash, rhinitis, and vomiting.

2 <1% means greater than zero but less than 1%.

3 Percentage based on the number of males (venlafaxine hydrochloride extended release capsules = 335, placebo = 238).

* Occurred at less than 2% but frequency rounded up to 2%

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). The incidence of nausea in the GAD studies, during weeks 1 and 2 were 28% and 14% for venlafaxine hydrochloride extended release capsules-treated patients and 6% and 4% for placebo-treated patients, respectively. The incidence of dizziness during weeks 1 and 2 were 12% and 6% for venlafaxine hydrochloride extended release treated capsules-patients and 4% and 4% for placebo-treated patients, respectively.

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, flu-like symptoms, headache, hypertension, hypomania, impaired coordination and balance, insomnia, nausea, nightmares, nervousness, paresthesia, electric shock sensations, sensory disturbances (including shock like electrical sensations), sleep disturbances, somnolence, sweating, tinnitus, tremor, vertigo, visual impairment and vomiting.While these events are generally self-limiting, there have been reports of serious discontinuation symptoms, and sometimes these effects can be protracted and severe. In premarketing studies, the majority of discontinuation reactions were mild and resolved without treatment.

Patients should be monitored for these or any other symptoms when discontinuing treatment, regardless of the indication for which RIVA-VENLAFAXINE XR 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 mmHg, compared with mean decreases ranging from 0.5 to 1.4 mmHg for placebo. Venlafaxine hydrochloride extended release capsules treatment for up to 6 months in premarketing placebo-controlled Generalized Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo.

Venlafaxine hydrochloride extended release capsules treatment for up to 12 weeks in 4 premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increase in pulse rate of approximately 3 beats per minute, compared with an increase of approximately 1 beat per minute for placebo. Venlafaxine hydrochloride extended release capsules treatment for up to 6 months in a premarketing placebo-controlled Social Anxiety Disorder trial was associated with mean final on-therapy increase of approximately 2 beats per minute in the 75 mg/day group and an increase of approximately 4 beats per minute in the 150 to 225 mg/day group, compared with an increase of approximately 2 beats per minute for placebo.

Mean changes in supine diastolic blood pressure were also associated with venlafaxine treatment in the Social Anxiety Disorder trials (see WARNINGS AND PRECAUTIONS, Sustained Hypertension).

Venlafaxine hydrochloride extended release capsules treatment for up to 12 weeks in premarketing placebo-controlled Panic Disorder trials was associated with mean final on-therapy increase in pulse rate of approximately 1 beat per minute, compared with a decrease of less than 1 beat per minute for placebo. A dose- dependence effect was noted in the 2 fixed-dose studies. In one study, no change in mean pulse rate was observed in the placebo and Venlafaxine hydrochloride extended release capsules 75 mg dosage groups, and a mean increase of 1 beat/min was observed in the venlafaxine hydrochloride extended release capsules 150 mg group. In another study, there was a mean increase of less than 1 beat/min in both placebo and venlafaxine hydrochloride extended release capsules 75 mg groups, and a mean increase of 3 beats/min in the venlafaxine hydrochloride extended release capsules 225 mg group.

Mean changes in supine diastolic blood pressure and sustained hypertension were also associated with venlafaxine hydrochloride extended release capsules treatment in the Panic Disorder trials (see WARNINGS AND PRECAUTIONS, Sustained Hypertension).

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 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.

Venlafaxine hydrochloride extended release capsules treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL (0.0247 mmol/L) and 2.3 mg/dL (0.0606 mmol/L), respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL (0.1278 mmol/L) and 7.7 (0.1990 mmol/L) mg/dL, respectively.

Elevations of total serum cholesterol, High Density Lipoprotein Cholesterol (HDL), Low Density Lipoprotein Cholesterol (LDL) and the overall ratio of Total Cholesterol/HDL have been observed in placebo controlled clinical trials for Social Anxiety Disorder and Panic Disorder.

Measurement of serum cholesterol levels (including a complete lipid profile/fractionation and an assessment of the patient's individual risk factors) should be considered especially during long-term treatment.

Patients treated with venlafaxine hydrochloride extended release capsules for up to 12 weeks in 4 premarketing placebo-controlled Social Anxiety Disorder trials had a mean final on-therapy increases in total serum cholesterol concentration of approximately 8.8 mg/dL (0.227 mmol/L), increases in HDL cholesterol of 2.3 mg/dL (0.059 mmol/L), and increases in LDL cholesterol of 5.4 mg/dL (0.139 mmol/L). Patients treated with venlafaxine hydrochloride extended release capsules 75 mg/day for up to 6 months in a premarketing placebo-controlled Social Anxiety Disorder trial had a mean final on-therapy decrease in total serum cholesterol concentration of approximately 0.5 mg/dL (0.013 mmol/L), decrease in HDL cholesterol of 1.0 mg/dL (0.025 mmol/L), and increase in LDL cholesterol of 0.2 mg/dL (0.006 mmol/L). Patients treated with venlafaxine hydrochloride extended release capsules 150-225 mg/day for up to 6 months in the same premarketing placebo-controlled Social Anxiety Disorder trial had a mean final on-therapy increase in total serum cholesterol concentration of approximately 12.5 mg/dL (0.322 mmol/L), increase in HDL cholesterol of 1.0 mg/dL (0.026 mmol/L), and increase in LDL cholesterol of 8.2 mg/dL (0.213 mmol/L).

Patients treated with venlafaxine hydrochloride extended release capsules for up to 12 weeks in premarketing placebo-controlled Panic Disorder trials had a mean final on-therapy increases in total serum cholesterol concentration of approximately 5.8 mg/dL (0.149 mmol/L), increases in HDL cholesterol of 1.9 mg/dL (0.050 mmol/L), and increases in LDL cholesterol of 2.9 mg/dL (0.076 mmol/L). A dose-dependence effect in serum cholesterol concentration was noted in the 2 fixed-dose studies. In one study, a mean decrease of 2.9 mg/dL (0.07 mmol/L) was observed in the placebo group, and mean increases of 2.1 mg/dL (0.05 mmol/L) and 5.1 mg/dL (0.13 mmol/L) were observed in the venlafaxine hydrochloride extended release capsules 75 mg and 150 mg dosage groups, respectively. In another study, a mean decrease of 4.8 mg/dL (0.12 mmol/L) was observed in the placebo group, and mean increases of 2.3 mg/dL (0.06 mmol/L) and 11.5 mg/dL (0.30 mmol/L) were observed in the venlafaxine hydrochloride extended release capsules 75 mg and 225 mg dosage groups, respectively.

ECG Changes

The QT effect of venlafaxine was evaluated in a thorough QTc study. In healthy subjects, venlafaxine did not prolong the QTc interval at a dose of 450 mg/day (given as 225 mg twice a day).

An analysis of ECGs was obtained in 357 patients treated with venlafaxine hydrochloride extended release capsules and 285 patients treated with placebo in controlled clinical trials in depression, in 815 patients who received venlafaxine hydrochloride extended release capsules and 379 patients who received placebo for up to 6 months in double-blind, placebo-controlled trials in GAD, 593 patients who received venlafaxine hydrochloride extended release capsules and 534 patients who received placebo for up to 12 weeks in double-blind, placebo-controlled trials in Social Anxiety Disorder, and in 661 patients who received venlafaxine hydrochloride extended release capsules and 395 patients who received placebo for up to 12 weeks in double-blind, placebo-controlled trials in Panic Disorder were analyzed. The mean change from baseline in corrected QT interval (QTc) for venlafaxine hydrochloride extended release capsules -treated patients was increased relative to that for placebo-treated patients in the clinical trials for depression, Social Anxiety Disorder and Panic Disorder (see WARNINGS AND PRECAUTIONS, Cardiac Disease).

In North American clinical trials for Generalized Anxiety Disorder, mean reductions in PR interval (3-6 msec decrease) were reported during venlafaxine hydrochloride extended release capsules treatment which represented statistically significant differences from the corresponding placebo groups (1-3 msec increase). The clinical significance of these changes is not definitively known.

Other Events Observed During the Pre-marketing Evaluation of Venlafaxine

Multiple doses of venlafaxine hydrochloride extended release capsules were administered to 705 patients in phase III depression studies, to 1381 patients in phase III GAD studies, 819 patients in phase III Social Anxiety Disorder studies and 1314 patients in phase III Panic Disorder 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 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), 5A (GAD NA), 5B (GAD 378), 6A (SAD ST), 6B (SAD LT), and 7 (PD), 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: angioedema, face edema, intentional injury, malaise, moniliasis, neck rigidity, overdose, pelvic pain, photosensitivity reaction, suicide attempt.

Rare: anaphylaxis, appendicitis, bacteremia, body odour, carcinoma, cellulitis, granuloma, halitosis.

Cardiovascular system:

Common: palpitations

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, 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, gastrointestinal hemorrhage, 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 mellitis, 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/psychomotor restlessness, ataxia, circumoral paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesias, hypotonia, impaired coordination and balance, 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-Barré 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: pruritis.

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), stress cardiomyopathy (Takotsubo cardiomyopathy)

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

Injury, poisoning and procedural complications: bone fracture.

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: toxic epidermal necrolysis/Stevens-Johnson syndrome, erythema multiform, sweating including night sweats

Special senses: angle closure glaucoma, eye hemorrhage, tinnitus

Urogenital system: renal failure

DRUG INTERACTIONS

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, a potentially life threatening condition, 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, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI; see CONTRAINDICATIONS), amphetamines, lithium, sibutramine or fentanyl (and its analogues, dextromethorphan, tramadol, tapentadol, meperidine, methadone and pentazocine) 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 RIVA-VENLAFAXINE XR and an SSRI, an SNRI, 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; methylene blue (a surgical dye); 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.)

  Drugs that Prolong the QT Interval

  Pharmacokinetic and pharmacodynamic studies of venlafaxine combined with other medicinal products that prolong the QT interval have not been performed. An additive effect of venlafaxine and these medicinal products cannot be excluded. Therefore, co-administration of venlafaxine with medicinal products that have a clear QT interval prolonging effect is discouraged. Drugs that have been associated with QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QTc prolongation and/or torsade de pointes:

  • Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide);
  • Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide, dronedarone);
  • Class IC antiarrhythmics (e.g., flecainide, propafenone);
  • antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone);
  • antidepressants (e.g., citalopram, fluoxetine, sertraline, tricyclic/tetracyclic antidepressants e.g., amitriptyline, imipramine, maprotiline);
  • opioids (e.g., methadone);
  • macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, telithromycin, tacrolimus);
  • quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin);
  • antimalarials (e.g., quinine, chloroquine);
  • azole antifungals (e.g., ketoconazole, fluconazole, voriconazole);
  • domperidone;
  • 5-HT3 receptor antagonists (e.g., dolasetron, ondansetron);
  • tyrosine kinase inhibitors (e.g., vandetanib, sunitinib, nilotinib, lapatinib);
  • histone deacetylase inhibitors (e.g., vorinostat);
  • beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).

• Drugs that Affect Electrolytes

  The concomitant use of venlafaxine with drugs that can disrupt electrolyte levels is discouraged. Drugs that decrease electrolyte levels include, but are not limited to, the following: loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; high dose corticosteroids.

• 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. (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 C_max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t_1/2) was unchanged. The mechanism explaining this finding is unknown.

• Imipramine

  Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, AUC, C_max and C_min 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, α-hydroxymetoprolol. The clinical relevance of this finding is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, ODV. (see also WARNINGS AND PRECAUTIONS, General, Hypertension).

• Risperidone

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

• 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 C_max. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.

• 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 subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively. Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects. AUC values for ODV increased by 23% and 33% in EM and PM subjects, respectively.

• Drugs Affecting Platelet Function (e.g. NSAIDS, ASA and other anticoagulants)

  Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, ASA or other anticoagulants may potentiate the risk of bleeding.

  Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when RIVA-VENLAFAXINE XR is initiated or discontinued. (see WARNINGS AND PRECAUTIONS, Hematologic, Abnormal Bleeding.)

• 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 Metabolized by Cytochrome P450 Isoenzymes

  The metabolic pathways for venlafaxine include CYP2D6 and CYP3A4. Venlafaxine is primarily metabolized to its active metabolite, ODV, by the cytochrome P450 enzyme CYP2D6. CYP3A4 is a minor pathway relative to CYP2D6 in the metabolism of venlafaxine.

  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.

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 above) potentially increase the plasma concentrations of venlafaxine and lower the concentrations of the active metabolite. Concomitant use of CYP2D6 inhibitors and venlafaxine may reduce the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of ODV. As venlafaxine and ODV are both pharmacologically active, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.

• CYP3A3/4 Inhibitors:

  In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A3/4. Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV (see

  Ketoconazole, above). Therefore, caution is advised when combining venlafaxine with a CYP3A4 inhibitor.

• CYP2D6 and 3A4 Inhibitors:

  Interactions between concomitant intake of inhibitors of both CYP2D6 and CYP3A3/4 with venlafaxine have not been studied. However, this concomitant use would be expected to increase venlafaxine plasma concentrations. 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.

• 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.

• 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 hydrochloride extended release capsule-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 RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.

Drug-Laboratory Test Interactions

False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

Drug-Lifestyle Interactions

Interference with Cognitive and Motor Performance

Patients should be cautioned about operating hazardous machinery, including automobiles, or engaging in tasks requiring alertness until they have been able to assess the drug’s effect on their own psychomotor performance.

Drug Abuse and Dependence

Physical and Psychological Dependence

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

While venlafaxine has not been systematically studied in clinical trials for their potential for abuse, there was no indication of drug-seeking behaviour in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine (e.g., development of tolerance, incrementation of dose, drug-seeking behaviour).

DOSAGE AND ADMINISTRATION

Dosing Considerations

General

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

• Discontinuing Venlafaxine

  When discontinuing venlafaxine after more than 1 week of therapy, it is generally recommended that the dose be tapered gradually to minimize the risk of discontinuation symptoms.

  Discontinuation symptoms have been assessed both in patients with depression and in those with GAD. Abrupt discontinuation, dose reduction, or tapering of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with higher dose levels and with longer duration of treatment. Reported symptoms include but are not limited to the following: aggression, agitation, anorexia, anxiety, asthenia, confusion, convulsions, impaired coordination and balance, diarrhoea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, 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 RIVA-VENLAFAXINE XR be tapered gradually whenever possible and the patient monitored. The period required for tapering and the amount of dose reduction 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. In some patients, discontinuation may need to occur very gradually over periods of months or longer (see WARNINGS AND PRECAUTIONS, POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM, and also Discontinuation Symptoms; ADVERSE REACTIONS, Discontinuation Symptoms).

• Patients With Hepatic or Renal Impairment:

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

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

Patients with Generalized Anxiety Disorder (GAD)

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

Patients with Social Anxiety Disorder (Social Phobia)

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

Panic Disorder

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

Maintenance/Continuation/Extended Treatment

There is no body of evidence available to answer the question of how long a patient should continue to be treated with RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) for depression, GAD, Social Anxiety Disorder or Panic Disorder.

During long-term therapy for any indication, the RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) 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 of RIVA-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.

Social Anxiety Disorder

In patients with Social Anxiety Disorder, there are no efficacy data beyond 6 months of treatment with venlafaxine hydrochloride extended release capsules. The need for continuing medication in patients with Social Anxiety Disorder who improve with RIVA-VENLAFAXINE XR treatment should be periodically reassessed.

Panic Disorder

In one study in Panic Disorder, in which patients who were responders in the final 2 weeks of a 12-week acute treatment with 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) during 6 months of maintenance treatment, patients continuing venlafaxine hydrochloride extended release capsules treatment showed a significantly longer time to relapse than patients switched to placebo.

Special Patient Populations:

Treatment of Pregnant Women During the Third Trimester

Post-marketing reports indicate that some neonates exposed to venlafaxine hydrochloride 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 WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women). When treating a pregnant woman with RIVA-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 RIVA-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 or anxiolytic, drug for treatment of Social Anxiety Disorder, or Panic Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

Pediatrics

RIVA-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 should 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. Because of individual variability in clearance in these patients, individualization of dosage may be desirable. 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 should 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

Among the patients included in the premarketing evaluation of venlafaxine hydrochloride 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 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 capsules in anxiety trials. One patient took a combination of 0.75 g venlafaxine hydrochloride extended release capsules and 200 mg of paroxetine and 50 mg of zolpidem. This patient was described as being alert, able to communicate, and a little sleepy. This patient was hospitalized, treated with activated charcoal, and recovered without any untoward effects. The other patient took 1.2 g of venlafaxine hydrochloride extended release capsules. This patient recovered and no other specific problems were found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5 days after the overdose. There were no reports of acute overdose with venlafaxine hydrochloride extended release capsules in Social Anxiety Disorder trials. There were 2 reports of acute overdose with venlafaxine hydrochloride extended release capsules in Panic Disorder trials. One patient took 0.675 g of venlafaxine hydrochloride extended release capsules once and the other patient took 0.45 g of venlafaxine hydrochloride extended release capsules for 2 days. No signs or symptoms were associated with either overdose and no actions were taken to treat them.

Postmarketing Experience with Venlafaxine (Dosage Form Unknown)

In postmarketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other events reported include 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. Muscle enzymes should be monitored in patients with venlafaxine overdose to detect development of rhabdomyolysis at an early stage and to initiate appropriate treatment. According to post-marketing overdose reports with venlafaxine (where overdose amounts were provided) fatal acute overdoses have been reported with venlafaxine alone at doses as low as approximately 1 gram.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher burden of suicide risk factors than SSRI patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage as opposed to some characteristics of venlafaxine-treated patients is not clear. Prescriptions for venlafaxine should be written for the smallest quantity of drug consistent with good patient management, in order to reduce the risk of overdose.

Overdosage Management

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

In managing overdosage, consider the possibility of multiple drug involvement.

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 α₁- 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

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.

Multiple-Dose Pharmacokinetic Profile (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 an 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. Venlafaxine hydrochloride extended release capsules provides a slower rate of absorption, but the same extent of absorption (i.e., AUC).

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.

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

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

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

A large degree of inter-subject variability was noted.

Dosage adjustment is necessary in patients with renal impairment (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 (15-30ºC), in a dry place.

SPECIAL HANDLING INSTRUCTIONS

None.

DOSAGE FORMS, COMPOSITION AND PACKAGING

RIVA-VENLAFAXINE XR 37.5 mg Capsule (venlafaxine as venlafaxine hydrochloride)

Non-medicinal ingredients:

Black iron oxide, D&C yellow 10, dibutyl sebacate, ethylcellulose, FD&C yellow 6, gelatine, polyethylene glycol, potassium hydroxide, povidone, propylene glycol, red iron oxide, shellac, starch, strong ammonia solution, sucrose, talc, and titanium dioxide.

RIVA-VENLAFAXINE XR 75 mg Capsule (venlafaxine as venlafaxine hydrochloride)

Non-medicinal ingredients:

Dibutyl sebacate, D&C yellow 10, ethylcellulose, FD&C yellow 6, gelatin, polyethylene glycol, potassium hydroxide, povidone, propylene glycol, red iron oxide, shellac, starch, strong ammonia solution, sucrose, talc, and titanium dioxide.

RIVA-VENLAFAXINE XR 150 mg Capsule (venlafaxine as venlafaxine hydrochloride)

Non-medicinal ingredients:

Dibutyl sebacate, ethylcellulose, FD&C yellow 6, gelatin, polyethylene glycol, povidone, propylene glycol, Shellac Glaze ~ 45% (20% esterified) in Ethanol, starch, sucrose, talc, and titanium dioxide.

RIVA-VENLAFAXINE XR 37.5 mg is supplied as a hard gelatin capsule, with a grey cap and peach body, filled with white to off-white pellets. Imprinting on Body: 37.5 Cap: N. They are available in white HDPE bottles of 100 capsules.

RIVA-VENLAFAXINE XR 75 mg is supplied as a hard gelatin capsule, with peach cap and peach body, filled with white to off-white pellets. Imprinting on Body: 75 Cap: N. They are available in white HDPE bottles of 100 or 500 capsules.

RIVA-VENLAFAXINE XR 150 mg is supplied as a hard gelatin capsule, with a dark orange cap and dark orange body, filled with white to off-white pellets. Imprinting on Body: 150 Cap: N. They are available in white HDPE bottles of 100 or 500 capsules.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Venlafaxine Hydrochloride

Chemical name: (±)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol hydrochloride

or N,N-dimethyl-2-(1-hydroxycyclohexyl)-2-(4-methyloxyphenyl) ethylamine hydrochloride

Molecular formula and molecular mass: C₁₇H₂₇NO₂*HCl 313.87 g/mol

Structural formula:

Physicochemical properties:

Description: Venlafaxine Hydrochloride is a white to off-white powder.

Melting range: 210°C - 218°C

pKa: 9.4

pH: 6.3 to 6.4. (2 % venlafaxine hydrochloride solution)

CLINICAL TRIALS

The objective of this study was to evaluate the comparative bioavailability between RIVA-VENLAFAXINE XR 150 mg Capsules (Laboratoire Riva Inc.) and Effexor^® XR Capsules 150 mg (Wyeth-Ayerst Canada Inc., Canada) after a single-dose in 24 healthy males under fasting conditions.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) 150 mg Capsules (Laboratoire Riva Inc.)

† Effexor^® XR Capsules 150 mg (Wyeth-Ayerst Canada Inc., Canada, purchased in Canada)

§ Expressed as the arithmetic mean (CV%) only

The objective of this study was to evaluate the comparative bioavailability between RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) 150 mg Capsules (Laboratoire Riva Inc.) and EFFEXOR^® XR Capsules 150 mg (Wyeth-Ayerst Canada, Canada), after a single-dose in 32 healthy males under fed conditions.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) 150 mg Capsules (Laboratoire Riva Inc.)

^† EFFEXOR^® XR 150 mg Capsules (Wyeth-Ayerst Canada, Canada, purchased in Canada)

§ Expressed as the arithmetic mean (CV%) only

The objective of this study is to evaluate the comparative bioavailability between RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) 150 mg Capsules (Laboratoire Riva Inc.) and Effexor^® XR Capsules 150 mg (Wyeth-Ayerst Canada Inc., Canada), after a multiple doses in 24 healthy males under fasting conditions.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* RIVA-VENLAFAXINE XR (venlafaxine hydrochloride) 150 mg Capsules (Laboratoire Riva Inc.)

† Effexor^® XR Capsules 150 mg (Wyeth-Ayerst Canada Inc., Canada, purchased in Canada)

§ Expressed as the arithmetic mean (CV%) only

DEPRESSION

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

In the 12-week study comparing immediate release tablets with 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.

In one longer term study, outpatients meeting DSM-IV criteria for major depressive disorder who had “responded”* during an 8-week open trial on venlafaxine hydrochloride extended release capsules (75, 150, or 225 mg, in the morning (qAM) were randomized to continuation of their same venlafaxine hydrochloride extended release capsules dose or to placebo, for up to 26 weeks of observation for “relapse”*. Patients receiving continued venlafaxine hydrochloride extended release capsules treatment experienced significantly lower “relapse”* rates compared with those on placebo.

*For the purposes of this study:

“Responded” during the open phase was defined as a CGI Severity of Illness item score < 3 and a HAM-D-21 total score of < 10 at the day 56 evaluation.

“Relapse” during the double-blind phase was defined as follows:

(1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of > 4 (moderately ill),

(2) 2 consecutive CGI Severity of Illness item scores of > 4, or

(3) a final CGI Severity of Illness item score of > 4 for any patient who withdrew from the study for any reason.

Generalized Anxiety Disorder (GAD)

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

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

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

Social Anxiety Disorder (Social Phobia)

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

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

Panic Disorder

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

In one flexible-dose study (75 mg to 225 mg daily doses), the primary outcome, the percentage of patients free of full-symptom panic attacks, approached significance (p=0.056). In this study, venlafaxine hydrochloride extended release capsules was significantly more effective than placebo for the two key secondary outcomes, (1) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score, and (2) percentage of patients rated as responders (much improved or very much improved) in the Clinical Global Impressions (CGI) Improvement scale.

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

Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.

In a longer-term study, adult outpatients meeting DSM-IV criteria for Panic Disorder who had responded at the end of a 12-week open phase with venlafaxine hydrochloride extended release capsules (75 to 225 mg/day) were randomly assigned to continue the same venlafaxine hydrochloride extended release capsules dose (75, 150, or 225 mg) or switch to placebo for observation for relapse during a 6-month double-blind phase. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved) during that same 2-week period. Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigator. Patients receiving continued venlafaxine hydrochloride extended release capsules treatment experienced significantly longer time to relapse over the subsequent 6 months compared with those receiving placebo.

DETAILED PHARMACOLOGY

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

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

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

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

TOXICOLOGY

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

Acute Toxicity

Venlafaxine showed low acute toxicity with LD_50s ≥405 mg/kg in mice and ≥ 336 mg/kg in rats; i.v. LD_50s in mice were ≥ 48 mg/kg. No drug-related macroscopic lesions were observed; microscopic examinations were not performed.

Long Term Toxicity/Carcinogenicity

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

Mice

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

Rats

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

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

Dogs

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

Monkeys

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

Mutagenicity

Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vivo Chinese hamster ovary cell chromosomal aberration assay, or in the in vivo chromosomal aberration assay in rat bone marrow.

Reproductive Toxicity

The reproductive toxicology of venlafaxine was studied in rats and rabbits. No teratogenic effect was observed and no deaths occurred.

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

Reproductive Toxicity with the Major Metabolite of Venlafaxine

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

In this study, administration of ODV as the succinate salt in male and female rats resulted in disrupted estrous cycles and increased time-to-mating at ≥30 mg/kg/day; decreased fertility rates at ≥100 mg/kg/day; and increased preimplantation loss and decreased fetal weight at 300 mg/kg/day. There was decreased prostate weight at ≥30 mg/kg/day associated with prostate atrophy at ≥100 mg/kg/day; however, there were no compound-related macroscopic or microscopic findings in the epididymides, seminal vesicles, or testes. The no-observed-adverse- effect level (NOAEL) for effects on fertility was 30 mg/kg/day and the developmental NOAEL was 100 mg/kg/day.

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