Effexor® XR

Venlafaxine HCl

Antidepressant--Anxiolytic

Wyeth Canada

http://www.wyeth.com/

Effexor Monograph PDF download here.

 

CPS:PIS_m191600

Date of Preparation: July 18, 1994

Date of Revision: May 27, 2004

 

 

Pharmacology

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

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

     Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or 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 MAO inhibitory activity.

 

Pharmacokinetics

Effexor: Venlafaxine is well absorbed, with peak plasma concentrations with Effexor tablets 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.

Effexor XR: After administration of Effexor XR (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 an Effexor immediate release tablet.

Multiple-Dose Pharmacokinetic Profile (Tablets and Extended Release Capsules): Steady-state concentrations of both venlafaxine and ODV in plasma are attained within 3 days of oral multiple-dose therapy. The clearance of venlafaxine is slightly (15%) lower following multiple doses than following a single dose.

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

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

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

     When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended release capsule, the exposure (AUC, area under the concentration curve) to both venlafaxine and ODV was similar for the 2 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.

     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 i.v. 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.

     Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. 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 2 active species (venlafaxine and ODV, which have comparable activity) was similar in the 2 metabolizer groups.

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

Age and Gender: Population pharmacokinetic analyses of 547 venlafaxine-treated patients from 3 studies involving both venlafaxine immediate release tablets and venlafaxine extended release capsules showed that age and sex do 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 or gender is generally not necessary (see Dosage).

Extensive/Poor Metabolizers: 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 2 groups.

Hepatic Disease: In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV were significantly altered. Venlafaxine elimination half-life was prolonged by about 30%, and clearance was decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic patients compared to normal subjects.

     A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects. Dosage adjustment is necessary in patients with liver disease (see Dosage).

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

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

     Dosage adjustment is necessary in patients with renal disease (see Dosage).

Clinical Trials

Depression: Venlafaxine tablets (immediate release): The efficacy of  venlafaxine tablets in the treatment of depression was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-II or DSM-III-R category of major depressive disorder and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depressive disorder with melancholia.

     In one longer term study, outpatients meeting DSM-III-R criteria for major depressive disorder, recurrent type, who had “responded”{*For the purposes of this study: “Responded” was defined as HAM-D-21 total score ≤ 12 at the day 56 evaluation).  “Improved” was defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ≥ 20; (2) no more than 2 HAM-D-21 total scores >10, and (3) no single CGI Severity of Illness item score ≥ 4 (moderately ill). “Relapse” was defined as a CGI Severity of Illness item score ≥ 4 during the double-blind phase.} during an initial 26 weeks of treatment on venlafaxine tablets (100 to 200 mg/day, on a b.i.d. schedule) and continued to be “improved”,  were randomized to continuation of their same dose or to placebo. The follow-up period to observe patients for “relapse” was for up to 52 weeks. Patients receiving continued treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.

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

     In the 12-week study comparing venlafaxine immediate release tablets with Effexor XR capsules, once daily, Effexor XR was significantly more effective at weeks 8 and 12, compared with venlafaxine immediate release tablets given twice daily for treating major depression.

     In one longer term study, outpatients meeting DSM-IV criteria for major depressive disorder who had “responded”{*For the purposes of this study: “ Responded” during the open phase was defined as a CGI Severity of Illness item score 3 and a HAM-D-21 total score of ≤ 10 at the day 56 evaluation.  “Relapse” during the double-blind phase was defined as follows:  (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥ 4 (moderately ill),  (2) 2 consecutive CGI Severity of Illness item scores of ≥ 4, or  (3) a final CGI Severity of Illness item score of ≥ 4 for any patient who withdrew from the study for any reason.} during an 8-week open trial on Effexor XR capsules (75, 150, or 225 mg, in the morning (qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for “relapse”. Patients receiving continued Effexor XR treatment experienced significantly lower “relapse” rates  compared with those on placebo.

Generalized Anxiety Disorder (GAD): The efficacy of  venlafaxine extended release capsules in the treatment of GAD has been demonstrated in 3 fixed dose studies and 1 flexible dose study for time periods ranging from 8 to 28 weeks. In these studies, venlafaxine extended release was shown to have a statistically significant superiority over placebo on the following 3 measures: Hamilton Anxiety Rating Scale (total score), Hamilton anxious mood item, and Clinical Global Impression of Severity of Illness rating.

     In the 3 fixed dose studies, response rates at week 8 of treatment, as defined by the proportion of patients achieving Clinical Global Impression of Improvement Scores of “much” or “very much improved”, were as follows (last observation carried forward): see  Table 1.

CPS:Effexor_t1Click here for Table 1

Table 1: Effexor XR

Efficacy of Effexor XR in the Treatment of GAD

 

	Placebo			37.5 mg			75.0 mg				150 mg			225 mg
Study #	N	%	N		%	N		%	N	%		N	%
210 US	96	49				86		57	81	58		86	65
378 EU	130	45	138		59	130		69	131	78
214 US	98	39				87		62	87	49

 

     For the 2 long-term studies, response rates at month 6 were as follows for last observation carried forward (LOCF): see  Table 2.

CPS:Effexor_t2Click here for Table 2

Table 2: Effexor XR

Efficacy of Effexor XR in the Treatment of GAD

 

		Placebo			37.5 mg				75.0 mg			150 mg				75–225 mg
Study #		N	%	N		%	N	%		N	%		N	%
218 US	LOCF	123	33										115	67
378 EU	LOCF	130	48	138		66	130	75		131	81

 

Social Anxiety Disorder (Social Phobia): The efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in two 12-week, multicenter, placebo-controlled, flexible-dose studies 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.

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

 

Indications

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

     The short-term efficacy of Effexor Tablets (immediate release) has been demonstrated in placebo controlled  trials of up to 6 weeks.

     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 venlafaxine tablets (immediate release) in maintaining an antidepressant response in patients with recurrent depression was demonstrated in a 52 week placebo-controlled trial (see Pharmacology, Clinical Trials).

     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 (see Pharmacology, Clinical Trials).

Generalized Anxiety Disorder (GAD): Venlafaxine extended release capsules are indicated for the symptomatic relief of  anxiety causing clinically significant distress in patients with GAD. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of venlafaxine extended release 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 physician who elects to use Effexor XR for extended periods in the treatment of depression, GAD, or Social Anxiety Disorder should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Dosage).

 

Contraindications

Hypersensitivity: In patients with known hypersensitivity to venlafaxine or to any of the components of the formulations.

MAOIs: Venlafaxine should not be used in combination with MAOIs or within 2 weeks of terminating treatment with MAOIs. Treatment with MAOIs should not be started until 2 weeks after discontinuation of venlafaxine therapy.

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

 

Warnings

Potential Association with  Behavioural and Emotional Changes, Including Self-Harm:

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

     The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among the drugs in the class.

Adults and Pediatrics: Additional data: There are clinical trial and post-marketing reports with SSRIs and other newer 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, agitation, disinhibition, emotional lability, hostility, aggression,  depersonalization.  In some cases, the events occurred within several weeks of starting treatment.

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

Discontinuation: Patients currently taking Effexor XR should not be discontinued abruptly, due to risk of discontinuation symptoms (see Precautions).  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.

Sustained Hypertension: Venlafaxine Immediate Release Tablets: Sustained increases in blood pressure could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine have their blood pressure monitored regularly.  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 venlafaxine 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 mmHg and ≥ 10 mmHg above baseline for 3 consecutive visits, showed the following incidence and dose-relationship in  Table 3.

CPS:Effexor_t3Click here for Table 3

Table 3: Effexor XR

Probability of Sustained Elevation in SDBP (Pool of Premarketing Studies with Venlafaxine)

 

Treatment Group	(%) Incidence of Sustained Elevation in SDBP
Venlafaxine	Immediate Release	Extended Release
<100 mg/day	2	3
101–200 mg/day	5	2
201–300 mg/day	6	4
>300 mg/day	13	NEa
Placebo	2	0

 

 ^a Not evaluable.

 

 

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

Effexor XR Capsules: Depression: In placebo-controlled premarketing depression studies with venlafaxine extended release, a final on-therapy mean increase in supine diastolic pressure (SDBP) of <1.2 mmHg was observed for venlafaxine extended release-treated patients compared with a mean decrease of 0.2 mmHg for placebo-treated patients.

     Less than 3% of venlafaxine extended release patients treated with doses of 75 to 300 mg/day had sustained elevations in blood pressure (defined as treatment-emergent SDBP ≥ 90 mmHg and ≥ 10 mmHg above baseline for 3 consecutive on-therapy visits). An insufficient number of patients received doses of venlafaxine extended release >300 mg/day to evaluate systematically sustained blood pressure increases. Less than 1% of venlafaxine extended release-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 venlafaxine extended release 37.5 to 225 mg/day, a final on-drug mean increase in SDBP of 0.4 mmHg was observed for venlafaxine extended release-treated patients compared with a mean decrease of 0.8 mmHg for placebo-treated patients.

     Sustained increases in blood pressure could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine have their blood pressure monitored regularly. 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.

GAD: 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.

Social Anxiety Disorder (Social Phobia):  In 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 1.6 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 75-225 mg per day of Effexor XR in premarketing Social Anxiety Disorder studies, 1.4% (4/277) experienced sustained hypertension.

     In premarketing Social Anxiety Disorder studies up to 12 weeks with patients treated with 75-225 mg per day, 0.4% (1/277) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure.  In this patient, the blood pressure increase was modest (13 mm Hg, SDBP).

 

Precautions

General

Suicide: The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist until significant remission occurs. Close supervision of patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization of high risk patients. In order to reduce the risk of overdose, prescriptions for venlafaxine capsules should be written for the smallest quantity of tablets/capsules consistent with good patient management.

     The same precautions observed when treating patients with depression should be observed when treating patients with GAD or Social Anxiety Disorder (see Warnings, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

Seizures: Venlafaxine tablets and extended release capsules should be used cautiously in patients with a history of seizures, and should be promptly discontinued in any patient who develops seizures. Seizures have also been reported as a discontinuation symptom (see also Precautions, Discontinuation Symptoms; Adverse Effects, Discontinuation Symptoms; Dosage, Discontinuing Venlafaxine).

     During premarketing testing, seizures were reported in 8 out of 3082 venlafaxine tablet-treated patients (0.26%). In 5 of the 8 cases with immediate release tablets, patients were receiving doses of 150 mg/day or less. During premarketing depression studies no seizures were seen in 705 venlafaxine extended release 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. However, patients with a history of convulsive disorders were excluded from most of these studies. Venlafaxine should be used cautiously in patients with a history of seizures, and should be promptly discontinued in any patient who develops seizures.

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

     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).  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.

Abnormal Bleeding: There have been  reports of abnormal bleeding (most commonly ecchymosis) associated with venlafaxine treatment. While  a causal relationship to venlafaxine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences.   Skin and other mucous membrane bleedings have  been reported following treatment with venlafaxine. Venlafaxine should therefore be used with caution in patients concomitantly treated with drugs that give an increased risk for bleeding (e.g. anticoagulants, nonsteroidal anti-inflammatories and ASA) and in patients with a known tendency for bleeding or those with predisposing conditions.

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

     Reported symptoms include anorexia, anxiety, agitation, confusion,  convulsions, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headache, hypomania, insomnia, nausea, nervousness, nightmares, 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 (see Dosage).

Activation of Mania/Hypomania: During Phase II and III trials, mania or hypomania occurred in 0.5% of venlafaxine tablet-treated patients and in 0.3% and 0% of venlafaxine capsule-treated patients in depression and anxiety studies respectively. In premarketing Social Anxiety Disorder studies, no Effexor XR-treated patients and no placebo-treated patients experienced mania or hypomania. Mania or hypomania occurred in 0.5% of all venlafaxine-treated patients. Mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, venlafaxine should be used cautiously in patients with a history of mania.

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

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

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

Patients with Concomitant Illness: Clinical experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering venlafaxine to patients with diseases or conditions that could affect hemodynamic responses or metabolism. 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.

Cardiac Disease: Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's clinical trials. Therefore it should be used with caution in these patients. Evaluation of the ECGs 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 ECGs for 357 patients who received venlafaxine extended release and 285 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for venlafaxine extended release-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine extended release and decrease of 1.9 msec for placebo). The clinical significance of this change is unknown. Three of 705 venlafaxine extended release-treated patients in phase III studies experienced QTc prolongation to 500 msec during treatment. Baseline QTc was >450 msec for all 3 patients.

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

     Electrocardiograms were evaluated for 277 patients who received Effexor XR and 274 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder.  the mean change from baseline QTc for Effexor XR-treated patients in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 2.8 msec for Effexor XR and decrease of 2.0 msec for placebo).

     No case of sudden unexplained death or serious ventricular arrhythmia, which are possible clinical sequelae of QTc prolongation, was reported in venlafaxine extended release premarketing studies.

     The mean heart rate was increased by about 3-4 beats per minute during treatment with Effexor and Effexor XR 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).

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

     Venlafaxine treatment has been associated with sustained hypertension (see Warnings).

Hepatic and Renal Disease: In patients with hepatic or renal impairment (GFR=10 to 70 mL/min), the pharmacokinetic disposition of both venlafaxine and the active metabolite ODV are significantly altered. Dosage adjustment is necessary in these patients (see Dosage).

Insomnia and Nervousness: Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor and Effexor XR than with placebo (see Adverse Effects) in depression, GAD, and Social Anxiety Disorder studies, as shown in  Table 4.

CPS:Effexor_t4Click here for Table 4

Table 4: Effexor XR

Incidence of Insomnia and Nervousness in Placebo-Controlled Depression, GAD, and Social Anxiety Disorder Trials

 

	Depression			GAD			Social Anxiety Disorder
Symptom	Effexor XR n=357	Placebo n=285	Effexor XR n=1381		Placebo n=555	Effexor XR n=277		Placebo n=274
Insomnia	17%	11%	15%		10%	23%		7%
Nervousness	10%	5%	6%		4%	11%		3%

 

     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 3% and 0%, respectively, of the patients treated with Effexor XR up to 12 weeks.

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

Interference with Cognitive and Motor Performance: In healthy volunteers receiving venlafaxine 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.

Mydriasis: Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow-angle glaucoma be closely monitored.

 

Pregnancy

Pregnancy, Labour and Delivery: 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.

     If venlafaxine is used until or shortly before birth, discontinuation effects in the newborn should be considered.  There have been isolated reports of reactions such as tremors, jitteriness, restlessness, hypotonia, poor feeding, cyanosis, tonic-clonic seizures in neonates whose mother had been treated with sertraline during pregnancy.  However, causal relationship between venlafaxine treatment and the emergence of these events has not been established.

 

Lactation

Because venlafaxine and its active metabolite, ODV, 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.

 

Children

Safety and efficacy in children below the age of 18 have not been established.

Geriatrics

Of the 2897 patients in Phase II and III trials with venlafaxine 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 venlafaxine extended release capsules, were 65 years of age or older. Six (2%)  patients in placebo-controlled Social Anxiety 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.

 

Drug Interactions

As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Lithium: The steady-state pharmacokinetics of venlafaxine 150 mg administered as 50 mg every 8 hours was not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV was also unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium. (Also see Other CNS-Active Drugs.)

Diazepam: The steady-state pharmacokinetics of venlafaxine 150 mg administered as 50 mg every 8 hours was not affected when a single 10 mg oral dose of diazepam was administered to 18 healthy male subjects. ODV was also unaffected. Venlafaxine had no effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam. Additionally, venlafaxine administration did not affect the psychomotor and psychometric effects induced by diazepam.

Cimetidine: Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs in 18 healthy male subjects resulted in inhibition of first-pass metabolism of venlafaxine. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (C_max) of the drug were increased by about 60%. However, there was no effect on the pharmacokinetics of ODV. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults.

     However, for patients with pre-existing hypertension, for elderly patients and for patients with hepatic or renal dysfunction, the interaction associated with the concomitant use of cimetidine and venlafaxine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.

Haloperidol: Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol C_max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t_1/2) was unchanged. The mechanism explaining this finding is unknown.

Drugs Highly Bound to Plasma Proteins: Venlafaxine is not  highly bound to plasma proteins; therefore,  administration of  venlafaxine to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

Drugs that Inhibit Cytochrome P450 Isoenzymes: CYP2D6-Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of  many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6 mediated metabolism and venlafaxine.

     Drug interactions that reduce the metabolism of venlafaxine to ODV (see Imipramine below) potentially increase the plasma concentrations of venlafaxine and lower the concentrations of the active metabolite. However, the pharmacokinetic profile of venlafaxine in subjects concomitantly receiving a CYP2D6-inhibitor would not be substantially different than the pharmacokinetic profile in subjects who are CYP2D6 poor metabolizers, and no dosage adjustment is required.

CYP3A3/4 Inhibitors: Because the 2 primary metabolic pathways for venlafaxine are through CYP2D6 and, to a lesser extent, CYP3A3/4, concomitant intake of inhibitors of both of these isoenzymes is not recommended during treatment with venlafaxine. Interactions between concomitant intake of inhibitors of both CYP2D6 and CYP3A3/4 with venlafaxine have not been studied.

     In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A3/4. Because CYP3A3/4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A3/4-mediated metabolism and venlafaxine is small.

Drugs Metabolized by Cytochrome P450 Isoenzymes: CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in vivo by a clinical drug interaction study comparing the effect of venlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.

Imipramine: Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, AUC, C_max and C_min of desipramine (the active metabolite of imipramine) increased by approximately 35% in the presence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). The clinical significance of elevated 2-OH-desipramine levels is unknown.

     Imipramine partially inhibited the CYP2D6-mediated formation of ODV. However, the total concentration of active compounds (venlafaxine plus ODV) was not affected by coadministration with imipramine, and no dosage adjustment is required.

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

CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.

Indinavir: In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C_max. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.

CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.

CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of tolbutamide, a CYP2C9 substrate.

CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above).

MAOIs: See Contraindications.

Other CNS-Active Drugs: The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required.

Serotonergic Drugs: Based on the known mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is co-administered with other drugs that may affect the serotonergic neurotransmitter systems (such as triptans, selective serotonin reuptake inhibitors, or lithium).  Rare postmarketing reports describe patients with symptoms suggestive of, or diagnostic of, serotonin syndrome, following the combined use of a selective serotonin reuptake inhibitor (SSRI) with 5HT1-agonists (triptans) or lithium.

     If concomitant treatment with Effexor XR and a triptan (e.g., almotriptan, sumatriptan, rizatriptan, naratriptan, zolmitriptan), tricyclic antidepressants, or other drugs with serotonergic activity (including but not limited to fenfluramine, tryptophan and silbutramine) is clinically warranted, appropriate observation of the patient for acute and long-term adverse events is advised  (see also Precautions, Changes in Appetite and Weight.)

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

St. John’s Wort: 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.

Postmarketing Reports: There have been reports of elevated clozapine levels that were temporally associated with adverse events including seizures, following the addition of  venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.

Electroconvulsive Therapy: There are no clinical data on the use of electroconvulsive therapy combined with venlafaxine treatment.

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

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

 

Adverse Effects

Commonly Observed Adverse Reactions: During depression trials, the most commonly observed adverse events associated with the use of venlafaxine (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for venlafaxine at least twice that for placebo), derived from the 2% incidence  Table 6, were:

Venlafaxine Tablets: 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 venlafaxine extended release, derived from the 2% incidence  Table 8 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 two placebo-controlled trials for the Social Anxiety Disorder indication ( Table 10):  asthenia, nausea, anorexia, insomnia, dry mouth, somnolence, dizziness, nervousness, libido decreased, anxiety, yawn, sweating, abnormal vision, as well as abnormal ejaculation and impotence in men and anorgasmia in men and women.

Adverse Events that Led to Discontinuation of Treatment in Clinical Trials: Nineteen percent (537/2897) of venlafaxine tablet and 12% (88/705) of venlafaxine extended release capsule-treated patients in Phase II and III depression studies discontinued treatment due to an adverse reaction. Approximately 18% of the 1381 patients who received venlafaxine extended release capsules for up to 8 weeks in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. The more common events (≥ 1%) associated with discontinuation of treatment and considered to be drug-related (i.e., those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) are shown in  Table 5.

CPS:Effexor_t5Click here for Table 5

Table 5: Effexor XR

Adverse Reactions (Percentage) Leading to Discontinuation of Treatment

 

	Venlafaxine Tablets Depression Indication (n=2897)	Placebo Depression Indication (n=609)	Effexor XR Depression Indication (n=705)	Placebo Depression Indication (n=285)	Effexor XR Anxiety Indication (n=1381)	Placebo Anxiety Indication (n=555)
CNS
Somnolence	3	1	2	<1	3	<1
Insomnia	3	1	<1	<1	3	<1
Dizziness	3	<1	2	1	4	2
Nervousness	2	<1	<1	1	2	<1
Anxiety	2	1	<1	<1	1b	1
Tremor	<1	<1	<1	<1	1	0
Gastrointestinal
Dry Mouth	2	<1	<1	0	2	<1
Anorexia	1	<1	<1	<1	<1	<1
Nausea	6	1	4	<1	8	<1
Vomiting	<1	<1	1	0	1	<1
Urogenital
Abnormal Ejaculationa	3	0	<1	<1	<1	0
Other
Headache	3	1	2b	1	3	<1
Asthenia	2	<1	<1	1	3	<1
Sweating	2	<1	<1	0	2	<1

 

 ^a percentages based on the number of males.

 ^b greater than 1% but active drug rate not twice rate for placebo.

 

 

Incidence in Controlled Trials:  Table 6 enumerates adverse events that occurred at an incidence of 2% or more, and were more frequent than in the placebo group, among venlafaxine-treated depressed patients.

Venlafaxine Tablets: Patients participated in 4- to 8-week placebo-controlled trials in which doses in the range of 75 to 375 mg/day were administered.

Effexor XR: Patients participated in 8- to 12-week placebo-controlled trials in which doses in the range of 75 to 225 mg/day were administered.

     Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

     The prescriber should be aware that the cited frequencies for venlafaxine extended release cannot be compared with figures obtained from other clinical investigations of venlafaxine tablets which involved different treatments, uses and investigators. The cited figures for venlafaxine extended release, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.

CPS:Effexor_t6Click here for Table 6

Table 6: Effexor XR

Treatment-emergent Adverse Experience Incidence in Placebo-controlled Clinical Trials (Percentage)^a  in Depressed Patients

 

Body System/Preferred Term	Venlafaxine Tablets (n=1033)	Placebo (n=609)	Effexor XR (n=357)	Placebo (n=285)
Body as a Whole
Headache	25	24	26b	33
Asthenia	12	6	8	7
Infection	6	5	6b	9
Chills	3	<1	<1	1
Cardiovascular
Vasodilatation	4	3	4	2
Increased Blood Pressure/ Hypertension	2	<1	4	1
Tachycardia	2	<1	<1	<1
Dermatological
Sweating	12	3	14	3
Rash	3	2	1	1
Gastrointestinal
Nausea	37	11	31	12
Constipation	15	7	8	5
Anorexia	11	2	8	4
Diarrhea	8	7	8b	9
Vomiting	6	2	4	2
Dyspepsia	5	4	7b	9
Flatulence	3	2	4	3
Metabolic
Weight Loss	1	<1	3	0
Nervous
Somnolence	23	9	17	8
Dry Mouth	22	11	12	6
Dizziness	19	7	20	9
Insomnia	18	10	17	11
Nervousness	13	6	10	5
Anxiety	6	3	2b	5
Tremor	5	1	5	2
Abnormal Dreams	4	3	7	2
Hypertonia	3	2	1	0
Paresthesia	3	2	3	1
Libido Decreased	2	<1	3	<1
Agitation	2	<1	3	1
Depression	1	1	3	<1
Thinking Abnormal	2	<1	<1	1
Respiration
Pharyngitis	4	4	7	6
Yawn	3	0	3	0
Special Senses
Abnormal Vision	6	2	4	<1
Taste Perversion	2	<1	1	<1
Urogenital
Abnormal Ejaculation/Orgasm	12c	<1c	16c	<1c
Impotence	6c	<1c	4c	<1c
Anorgasmia	<1d	<1d	3d	<1d
Urinary Frequency	3	2	1	1
Urination Impaired	2	<1	<1	0

 

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

 ^b Incidence greater than 2%, but active drug incidence less than incidence for placebo.

 ^c Incidence based on number of male patients (For Effexor: n=439, Placebo: n=245; for Effexor XR: n=126, Placebo: n=108).

 ^d Incidence based on number of female patients (For Effexor: n=594, Placebo: n=364; for Effexor XR: n=231, Placebo: n=177).

 

fexor/Effexor XR are included, and are rounded to the nearest %. Events for which the Effexor/Effexor XR incidence was equal to or less than placebo included the following: abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis and sinusitis.

 ^b Incidence greater than 2%, but active drug incidence less than incidence for placebo.

 ^c Incidence based on number of male patients (For Effexor: n=439, Placebo: n=245; for Effexor XR: n=126, Placebo: n=108).

 ^d Incidence based on number of female patients (For Effexor: n=

Dose Dependency of Adverse Events: A comparison of adverse event rates in a fixed-dose study comparing venlafaxine tablets 75, 225, and 375 mg/day with placebo in depressed patients revealed a dose dependency for some of the more common adverse events associated with venlafaxine tablet use, as shown in  Table 7. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least 1 venlafaxine group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating and abnormal ejaculation.

CPS:Effexor_t7Click here for Table 7

Table 7: Effexor

Treatment-emergent Adverse Experience Incidence (Percentage) in a Dose Comparison Trial in Depressed Patients

 

		Venlafaxine Immediate Release Tablets (mg/day)
Body System/Preferred Term	Placebo (n=92)	75 (n=89)	225 (n=89)	375 (n=88)
Body as a Whole
Abdominal Pain	3.3	3.4	2.2	8
Asthenia	3.3	16.9	14.6	14.8
Chills	1.1	2.2	5.6	6.8
Infection	2.2	2.2	5.6	2.3
Cardiovascular
Hypertension	1.1	1.1	2.2	4.5
Vasodilatation	0	4.5	5.6	2.3
Digestive
Anorexia	2.2	14.6	13.5	17
Dyspepsia	2.2	6.7	6.7	4.5
Nausea	14.1	32.6	38.2	58
Vomiting	1.1	7.9	3.4	6.8
Nervous
Agitation	0	1.1	2.2	4.5
Anxiety	4.3	11.2	4.5	2.3
Dizziness	4.3	19.1	22.5	23.9
Insomnia	9.8	22.5	20.2	13.6
Libido Decreased	1.1	2.2	1.1	5.7
Nervousness	4.3	21.3	13.5	12.5
Somnolence	4.3	16.9	18	26.1
Tremor	0.0	1.1	2.2	10.2
Respiratory
Yawn	0	4.5	5.6	8
Skin and Appendages
Sweating	5.4	6.7	12.4	19.3
Special Senses
Abnormality of Accommodation	0	9.1	7.9	5.6
Urogenital
Abnormal Ejaculation/Orgasm	0.0	4.5	2.2	12.5
Impotence	0.0	5.8	2.1	3.6
(Number of men)	(n=63)	(n=52)	(n=48)	(n=56)

 

 

      Table 8 and  Table 9 enumerate adverse events that occurred at an incidence of 2% or more, and at a higher rate than the placebo group, among venlafaxine extended release-treated anxious patients.

CPS:Effexor_t8Click here for Table 8

Table 8: Effexor XR

Treatment-emergent Adverse Event Incidence (%) in Placebo-controlled Effexor XR North American Clinical Trials (210 US, 214 US and 218 US) in GAD Patients^{a ,b}  (8–28 Weeks, Dosage Range 75–225 mg)

 

Body System/Preferred Term	Effexor XR (n=600)	Placebo (n=328)
Body as a Whole
Asthenia	16	10
Accidental Injury	5	4
Fever	3	2
Chills	3	<1
Cardiovascular
Vasodilatation	8	3
Hypertension	4	3
Tachycardia	3	2
Digestive
Nausea	46	18
Dry Mouth	24	9
Diarrhea	16	13
Anorexia	13	3
Constipation	12	6
Vomiting	7	4
Flatulence	3	2
Nervous
Dizziness	27	13
Somnolence	24	11
Insomnia	24	15
Nervousness	13	8
Libido Decreased	6	3
Abnormal Dreams	6	3
Tremor	5	2
Hypertonia	4	3
Paresthesia	3	2
Thinking Abnormal	3	2
Twitching	3	<1
Trismus	2	<1
Confusion	2	<1
Respiratory
Yawn	5	<1
Cough Increased	4	3
Skin and Appendages
Sweating	12	2
Special Senses
Abnormal Vision	8	1
Urogenital
Abnormal Ejaculation/Orgasm (male)c	15	0
Anorgasmia	4	<1
(male)c	5	<1
(female)d	3	0
Urinary Frequency	4	2
Impotence (male)c	6	<1
Urination Impaired	2	0
Menstrual Disorder (female)d	3	2

 

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

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

 ^c Incidence is based on number of male patients (For Effexor XR: n=242, Placebo: n=131).

 ^d Incidence is based on number of female patients (For Effexor XR: n=358, Placebo: n=197).

 

 

CPS:Effexor_t9Click here for Table 9

Table 9: Effexor XR

Treatment-emergent Adverse Event Incidence (%) in a Dose Comparison Trial (378 EU, 24 Weeks) with GAD Patients^{a ,c}

 

		Effexor XR
Body System/Preferred Term	Placebo (n=130)	37.5 mg (n=140)	75 mg (n=134)	150 mg (n=137)
Body as a Whole
Accidental Injury	4	5	5	7
Asthenia	9	11	13	12
Back Pain	5	7	5	5
Chest Pain	2	5	2	2b
Cyst	0	<1	2	0
Flu Syndrome	6	6	5	7
Headache	26	28	24	25
Infection	4	9	5	12
Withdrawal Syndrome	0	0	0	2
Cardiovascular
Hypertension	2	1	2	5
Migraine	<1	4	2b	2b
Tachycardia	0	0	2b	2
Vasodilation	2b	4	2b	4
Digestive
Anorexia	2b	4	2b	3
Constipation	5	8	13	15
Diarrhea	8	8	7	10
Dry Mouth	4	6	13	17
Dyspepsia	5	4	6	3
Nausea	14	22	34	42
Vomiting	6	5	8	7
Musculoskeletal
Arthralgia	4	4	5	2b
Myalgia	2b	1	<1	3
Tenosynovitis	<1	2	0	0
Nervous
Abnormal Dreams	2b	4	6	3
Anxiety	6	5	2b	7
Depersonalization	<1	<1	<1	2
Depression	2b	4	2	<1
Dizziness	14	15	22	31
Hypertonia	<1	3	2b	3
Insomnia	10	7	12	15
Libido Decreased	<1	3	2b	4
Nervousness	2b	4	3	3
Paresthesia	2	1	2	10
Somnolence	4	1	6	7
Thinking Abnormal	0	2	0	0
Tremor	0	2	4	4
Vertigo	<1	2	2	0
Respiratory
Bronchitis	<1	3	2b	4
Cough Increased	2b	3	3	2
Dyspnea	2b	1	2	0
Rhinitis	2b	4	4	3
Sinusitis	<1	4	5	4
Yawn	0	0	2	5
Skin and Appendages
Eczema	<1	2	2b	2b
Rash	2b	<1	3	2
Sweating	5	9	11	18
Special Senses
Abnormal Vision	2b	<1	8	4
Conjunctivitis	0	4	2b	2b
Mydriasis	0	<1	<1	2
Tinnitus	<1	4	4	3
Urogenital
Abnormal Ejaculation/Orgasm (male)d	0	1	0	2
Anorgasmia (male)d	0	2	0	8
(female)e	0	0	0	2
Dysmenorrhea (female)e	3	4	1	1
Dysuria	0	<1	2	2b
Impotence (male)d	0	2	2	3
Menorrhagia (female)e	0	3	1	2
Urinary Frequency	2b	2	<1	2b

 

 ^a Incidence rounded to the nearest %, for events reported by at least 2% of patients in any Effexor XR treatment group and at an incidence greater than the respective placebo incidence.

 ^b Incidence is less than 2% but rounds to 2%.

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

 ^d Incidence is based on number of male patients (For Effexor XR: n=60 (37.5 mg), 51 (75 mg), 48 (150 mg); Placebo: n=54).

 ^e Incidence is based on number of female patients (For Effexor XR: n=80 (37.5 mg), 83 (75 mg), 89 (150 mg); Placebo: n=76).

 

 

      Table 10 enumerates adverse events that occurred at an incidence of 2% or more, and were more frequent than in the placebo group, among venlafaxine-treated patients with Social Anxiety Disorder.

CPS:Effexor_t10Click here for Table 10

Table 10: Effexor XR

Treatment-emergent Adverse Event Incidence (%) In Short-Term, Placebo-controlled Effexor XR Clinical Trials (387EU/CA And 393 US) in Social Anxiety Disorder Patients^{a ,c}  (12 Weeks, Dosage Range 75–225 Mg)

 

Body System/ Preferred term	Effexor XR (n=277)	Placebo  (n=274)
Body as a Whole
Headache	34	33
Asthenia	17	8
Flu syndrome	6	5
Accidental injury	5	3
Abdominal pain	4	3
Cardiovascular System
Hypertension	5	4
Vasodilatation	3	1
Palpitation	3	1
Digestive System
Nausea	29	9
Anorexia	20	1
Constipation	8	4
Diarrhea	6	5
Vomiting	3	2b
Eructation	2	0
Metabolic and Nutritional
Weight loss	4	0
Nervous System
Insomnia	23	7
Dry mouth	17	4
Dizziness	16	8
Somnolence	16	8
Nervousness