EFFEXOR XR Venlafaxine Hydrochloride Extended Release Capsules is indicated for:

• Depression: EFFEXOR XR Capsules (extended release) are indicated for the symptomatic relief of major depressive disorder.

  
  

  The short-term efficacy of EFFEXOR XR Capsules (extended release) has been demonstrated in placebo-controlled trials of up to 12 weeks.

  
  

  The efficacy of EFFEXOR XR Capsules (extended release) 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.

  
  

• Generalized Anxiety Disorder (GAD): EFFEXOR 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 EFFEXOR XR in long-term use has been evaluated for up to 6 months in controlled clinical trials.

  
  

• Social Anxiety Disorder (Social Phobia): EFFEXOR XR 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 EFFEXOR XR 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 EFFEXOR XR doses in a range of 75-225 mg/day demonstrated that EFFEXOR XR was significantly more effective than placebo for the Liebowitz Social Anxiety Scale Total score, Clinical Global Impressions of Severity of Illness rating, and Social Phobia Inventory.

  
  

• Panic Disorder: EFFEXOR 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 behavior 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, lightheaded, 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 EFFEXOR XR 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 EFFEXOR XR 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.

  
  

The physician who elects to use EFFEXOR 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).

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.

EFFEXOR XR (venlafaxine) is not indicated for use in children under 18 years of age (see Warnings and Precautions, Potential Association with Behavioral and Emotional Changes, Including Self-harm).

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

  
  

• Monoamine Oxidase Inhibitors (MAOIs): EFFEXOR XR should not be used in combination with MAOIs or within two weeks of terminating treatment with MAOIs. Treatment with MAOIs should not be started until 2 weeks after discontinuation of EFFEXOR XR therapy.

  
  

  Adverse reactions, some serious, have been reported when EFFEXOR XR therapy is initiated soon after discontinuing an MAOI and when an MAOI is initiated soon after discontinuation of EFFEXOR XR. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hypothermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI.

  
  

• 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.

  
  

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

  
  

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

  
  

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

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

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).

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

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

Treatment with immediate release venlafaxine HCl tablets was associated with modest but sustained increases in blood pressure during premarketing studies. Sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive visits, showed the following incidence and dose-relationship (see Table 1).

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

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

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

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

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

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

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

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

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

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

Reported symptoms include aggression, agitation, anorexia, anxiety, asthenia, confusion, convulsions, coordination impaired, diarrhoea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headache, hypomania, insomnia, nausea, nightmares, nervousness, paresthesia, electric shock sensations, sensory disturbances (including shock like electrical sensations), sleep disturbances, somnolence, sweating, tinnitus, vertigo, and vomiting. Where such symptoms occurred they were usually self-limiting but in a few patients continued for several weeks.

Discontinuation effects are well known to occur with antidepressants, and, therefore, it is recommended that the dosage be tapered gradually and the patient monitored. Time to event onset after dose reduction or discontinuation can vary in individual patients and range from the same day to several weeks. (See also Adverse Reactions, Discontinuation Symptoms and Dosage and Administration, Discontinuing Venlafaxine.)

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

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

The following additional precautions are listed alphabetically.

See Warnings and Precautions, General, Hypertension.

Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's clinical trials. Therefore it should be used with caution in these patients.

Evaluation of the electrocardiograms for 769 patients who received venlafaxine immediate release tablets in 4- to 6-week double-blind trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo.

The electrocardiograms for 357 patients who received EFFEXOR XR and 285 patients who received placebo in 8 to 12 week double-blind, placebo-controlled trials in depression were analyzed. The mean change from baseline in corrected QT interval (QTc) for EFFEXOR XR-treated patients in depression studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for EFFEXOR XR and decrease of 1.9 msec for placebo). The clinical significance of this change is unknown. Three of 705 EFFEXOR XR-treated patients in phase III studies experienced QTc prolongation to 500 msec during treatment. Baseline QTc was >450 msec for all 3 patients.

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

Electrocardiograms were evaluated for 401 patients who received EFFEXOR XR and 444 patients who received placebo in four 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline in QTc for EFFEXOR XR-treated patients in the 12-week Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 4.1 msec for EFFEXOR XR and decrease of 1.4 msec for placebo). Electrocardiograms were evaluated for 101 patients who received EFFEXOR XR 75 mg/day, 96 patients who received 150-225 mg/day, and 90 patients who received placebo in one 6-month double-blind, placebo-controlled trial in Social Anxiety Disorder. A mean decrease from baseline in QTc of 0.05 ms was observed for patients treated with EFFEXOR XR 75 mg/day, a mean increase from baseline in QTc of 3.4 ms was observed for patients treated with EFFEXOR XR 150-225 mg/day, and a mean increase from baseline in QTc of 0.5 ms was observed for patients treated with placebo in the 6-month Social Anxiety Disorder study.

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

No case of sudden unexplained death or serious ventricular arrhythmia, which are possible clinical sequelae of QTc prolongation, was reported in EFFEXOR XR pre-marketing studies.

The mean heart rate was increased by about 3-4 beats per minute during treatment with venlafaxine in clinical trials of depression and GAD. The mean change from baseline in heart rate for EFFEXOR XR-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for EFFEXOR XR and no change for placebo).

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

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

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

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

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

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

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

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

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 coadministration includes the possibility of serotonin syndrome. (See Drug Interactions, Drug-Drug Interactions, Serotonergic Drugs.)

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

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

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

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

There have been reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences.

Skin and other mucous membrane bleedings have been reported following treatment with venlafaxine. Venlafaxine should therefore be used with caution in patients concomitantly treated with drugs that give an increased risk for bleeding (e.g. anticoagulants, nonsteroidal anti-inflammatories and ASA) and in patients with a known tendency for bleeding or those with predisposing conditions.

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

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