Effexor XR

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

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.

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

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.

Monoamine Oxidase Inhibitors: See Contraindications and Dosage and Administration, Switching Patients to or from a Monoamine Oxidase Inhibitor.

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

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).

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.

Dosage adjustments are required (see Dosage and Administration, Special Patients Populations).

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

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.

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

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

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 EFFEXOR XR be tapered gradually whenever possible and the patient monitored. The period required for tapering may depend on the dose, duration of therapy and the individual patient. If venlafaxine has been used for more than 6 weeks, tapering over at least a two week period is recommended (see Warnings and Precautions, Potential Association with Behavioral and Emotional Changes, Including Self-harm) and also Discontinuation Symptoms; Adverse Reactions, Discontinuation Symptoms).

EFFEXOR 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).

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

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

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

EFFEXOR 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).

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

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

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.

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.

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

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.

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

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

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

It is not known whether or not the dose of EFFEXOR XR needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.

Post-marketing reports indicate that some neonates exposed to immediate release venlafaxine or EFFEXOR XR, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. (See Warnings and Precautions, Special Populations, Pregnant Women). When treating a pregnant woman with EFFEXOR XR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Due to the potential for discontinuation symptoms, if a decision is taken to discontinue EFFEXOR XR treatment, a gradual reduction in the dose rather than an abrupt cessation is recommended (see Warnings and Precautions, Discontinuation Symptoms).

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.

Treatment with venlafaxine immediate release tablets (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. It was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see Warnings and Precautions, Sustained Hypertension for effects on blood pressure).

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

EFFEXOR XR 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. EFFEXOR XR 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).

EFFEXOR XR 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 EFFEXOR XR 75 mg dosage groups, and a mean increase of 1 beat/min was observed in the EFFEXOR XR 150 group. In another study, there was a mean increase of less than 1 beat/min in both placebo and EFFEXOR XR 75 mg groups, and a mean increase of 3 beats/min in the EFFEXOR XR 225 mg group.

Mean changes in supine diastolic blood pressure and sustained hypertension were also associated with EFFEXOR XR treatment in the Panic Disorder trials (see Warnings and Precautions, Sustained Hypertension).

angle closure glaucoma, eye hemorrhage, tinnitus.

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

In an analysis of ECGs obtained in 769 patients treated with venlafaxine immediate release tablets and 450 patients treated with placebo in controlled clinical trials in depression, the only statistically significant difference observed was for heart rate, i.e., a mean increase from baseline of 4 beats per minute for venlafaxine immediate release tablets.

An analysis of ECGs was obtained in 357 patients treated with EFFEXOR XR and 285 patients treated with placebo in controlled clinical trials in depression, in 815 patients who received EFFEXOR XR and 379 patients who received placebo for up to 6 months in double-blind, placebo-controlled trials in GAD, 593 patients who received EFFEXOR XR 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 EFFEXOR XR 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 EFFEXOR XR-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 EFFEXOR XR 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.

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.

Patients treated with venlafaxine immediate release tablets for at least 3 months in placebo-controlled 12-month extension trials for Major Depressive Disorders had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL (0.2364 mmol/L) compared with a decrease of 7.1 mg/dL (0.1835 mmol/L) among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL (1.2930 mmol/L) from baseline and to a value ≥261 mg/dL (6.7495 mmol/L) or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL (1.2930 mmol/L) from baseline and to a value ≥261 mg/dL (6.7495 mmol/L), were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients.

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).

Treatment-emergent Adverse Event Incidence (%) in Short-term, Placebo-controlled EFFEXOR XR Clinical Trials (391-CA/EU, 353-US/CA, 398-EU and 399-AC) in Panic Disorder Patients^{a , b} (10-12 Weeks, Dosage Range 37.5-225 mg)

prolactin increased.

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:

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.

Clinically and statistically relevant increases in cholesterol levels have been noted in studies using venlafaxine immediate release tablets and EFFEXOR XR Capsules (see Warnings and Precautions, Serum Cholesterol Elevation).

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.

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, 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.

Patients should be monitored for these or any other symptoms when discontinuing treatment, regardless of the indication for which EFFEXOR 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, General, Discontinuing Venlafaxine for details).

During depression trials, the most commonly observed adverse events associated with the use of venlafaxine immediate release tablets and EFFEXOR XR (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for immediate release formulation/EFFEXOR XR at least twice that for placebo), derived from the 2% incidence Table 4, were:

Venlafaxine Immediate Release: asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, blurred vision, and abnormal ejaculation/orgasm and impotence in men.

EFFEXOR XR: 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 EFFEXOR XR, derived from the 2% incidence Table 6 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 EFFEXOR XR 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 8): 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 EFFEXOR XR and at a rate at least twice that of the placebo group (Table 9): 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 EFFEXOR XR patients and at a rate at least twice that of the placebo group for the placebo-controlled trials for the Panic Disorder indication (Table 10): anorexia, constipation, dry mouth, somnolence, tremor, abnormal ejaculation in men, and sweating.

agranulocytosis, aplastic anemia, neutropenia, pancytopenia.

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.

rhabdomyolysis.

During the premarketing assessment of venlafaxine immediate release tablets, multiple doses were administered to 2897 patients in phase II-III depression studies. Multiple doses of EFFEXOR XR were administered to 705 patients in phase III depression studies (as well as 96 patients on venlafaxine immediate release tablets), 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, inpatient (venlafaxine immediate release tablets only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 7212 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in Table 4 (MDD), Table 5 (MDD dose related), Table 6 (GAD NA), Table 7 (GAD 378), Table 8 (SAD ST), Table 9 (SAD LT), and Table 10 (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.

renal failure.

interstitial lung disease (including pulmonary eosinophilia).

CPK increased, dehydration, hepatitis, LDH increased, syndrome of inappropriate antidiuretic hormone secretion, weight loss.

EFFEXOR XR (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.

EFFEXOR XR 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 EFFEXOR XR 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 EFFEXOR XR 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 EFFEXOR XR 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 EFFEXOR XR 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 EFFEXOR XR 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 EFFEXOR XR 75 mg and 225 mg dosage groups, respectively.

In premarketing experience with venlafaxine immediate release Tablets over a 6-week period, and EFFEXOR XR 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 EFFEXOR XR-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 EFFEXOR XR-treated patients and 4% and 4% for placebo-treated patients, respectively.

Infrequent: anemia, gastrointestinal hemorrhage, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, mucous membrane bleeding. Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura, thrombocytopenia.

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).

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).

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 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 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 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.

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 postmarketing 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.

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

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

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

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

Each extended release, hard gelatin capsule, with dark orange cap and body, with “W” and “Effexor XR” on the cap and “150” on the body, in white ink, contains: venlafaxine HCl equivalent to venlafaxine base 150 mg. Nonmedicinal ingredients: ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, microcrystalline cellulose, talc, titanium dioxide and White Tek SB-0007. Gluten-free. Bottles of 15, 90 and 100.

Each extended release, hard gelatin capsule, with gray cap and peach body, with “W” and “Effexor XR” on the cap and “37.5” on the body, in red ink, contains: venlafaxine HCl equivalent to venlafaxine base 37.5 mg. Nonmedicinal ingredients: ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, microcrystalline cellulose, Opacode Red S-1-15034 ink, talc and titanium dioxide. Gluten-free. Bottles of 15, 90 and 100.

Each extended release, hard gelatin capsule, with peach cap and body, with “W” and “Effexor XR” on the cap and “75” on the body, in red ink, contains: venlafaxine HCl equivalent to venlafaxine base 75 mg. Nonmedicinal ingredients: ethylcellulose, gelatin, hydroxypropyl methylcellulose, iron oxide, microcrystalline cellulose, Opacode Red S-1-15034 ink, talc and titanium dioxide. Gluten-free. Bottles of 15, 90 and 100.

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, General, Patients with Hepatic or Renal Impairment and Recommended Dose and Dosage Adjustment, Patients with Renal Impairment).

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

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. 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.

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.

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

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.

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.

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

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. The risk of skin and mucous membrane bleeding, including gastrointestinal hemorrhage, may be increased in patients taking venlafaxine.

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

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

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.

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

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).

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 behavioral changes (see Warnings and Precautions, Potential Association with Behavioral and Emotional Changes, Including Self-harm).

Of the 2897 patients in Phase II and III trials with venlafaxine immediate release tablets, 357 (12%) were 65 years of age or older. Forty three (4%) of the patients in premarketing depression and 77 (6%) in GAD trials respectively, with EFFEXOR XR Capsules, were 65 years of age or older. Ten (1%) patients in placebo-controlled Social Anxiety Disorder studies were 65 years or older. Sixteen (2%) patients in placebo-controlled Panic Disorder studies were 65 years or older. No overall differences in effectiveness and safety were observed between these geriatric patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

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).

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).

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

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.)

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

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.

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).

See Warnings and Precautions, General, Hypertension.

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.

See Adverse Reactions.

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.

There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, 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 behavioral changes.

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

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.

During Phase II and III trials, mania or hypomania occurred in 0.5% of venlafaxine immediate release tablet-treated patients and in 0.3% and 0% of EFFEXOR XR Capsule-treated patients in depression and anxiety studies respectively. In premarketing Social Anxiety Disorder studies, 0.2% of EFFEXOR XR-treated patients and no placebo-treated patients experienced mania or hypomania. In premarketing Panic Disorder studies, 0.1% of EFFEXOR XR-treated patients and 0.0% placebo-treated patients experienced mania or hypomania. Mania or hypomania occurred in 0.4% of all venlafaxine-treated patients. Mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, EFFEXOR XR should be used cautiously in patients with a history or family history of bipolar disorder.

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

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with EFFEXOR XR in depression studies.

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

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, 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 also Adverse Reactions, Discontinuation Symptoms; Dosage and Administration, Discontinuing Venlafaxine.)

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.

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

Venlafaxine 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.)

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.

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.

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.

EFFEXOR XR should be used cautiously in patients with a history of seizures, and should be promptly discontinued in any patient who develops seizures. Seizures have also been reported as a discontinuation symptom (see also Warnings and Precautions, Discontinuation Symptoms; Adverse Reactions, Discontinuation Symptoms; Dosage and Administration, Discontinuing Venlafaxine).

During premarketing testing, seizures were reported in 8 out of 3082 immediate release tablet-treated patients (0.3%). In 5 of the 8 cases with immediate release tablets, patients were receiving doses of 150 mg/day or less. During premarketing depression studies no seizures were seen in 705 EFFEXOR XR Capsule-treated patients. Premarketing, no seizures occurred among 1381 EFFEXOR XR-treated patients in Generalized Anxiety Disorder studies or among 277 EFFEXOR XR-treated patients in Social Anxiety Disorder Studies. In Panic Disorder studies, 1 seizure occurred among 1001 EFFEXOR XR-treated patients (0.1%). However, patients with a history of convulsive disorders were excluded from most of these studies. EFFEXOR XR should be used cautiously in patients with a history of seizures, and should be promptly discontinued in any patient who develops seizures.

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.

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, and 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 Behavioral and Emotional Changes, Including Self-harm.)

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.

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

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 Patients Populations).

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

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.

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

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

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

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

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

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.

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 Patients Populations).

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

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.

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.

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.

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

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

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

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

The mean±SD steady-state plasma clearances of venlafaxine and ODV are 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively.

Venlafaxine and ODV renal clearances are 49±27 and 94±56 mL/h/kg, respectively, which correspond to 5±3.0% and 25±13% of an administered venlafaxine dose recovered in urine as venlafaxine and ODV, respectively.

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

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

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