Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
| Table 1 |
|Age Range||Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated|
|Increases Compared to Placebo|
|<18||14 additional cases|
|18-24||5 additional cases|
|Decreases Compared to Placebo|
|25-64||1 fewer case|
|≥65||6 fewer cases|
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Effexor XR, for a description of the risks of discontinuation of Effexor XR).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Effexor XR should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use in treating bipolar depression.
Potential for Interaction with Monoamine Oxidase Inhibitors
Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. 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 hyperthermia 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. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, because venlafaxine is an inhibitor of both norepinephrine and serotonin reuptake, it is recommended that Effexor XR (venlafaxine hydrochloride) extended-release capsules not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting an MAOI.
The development of a potentially life-threatening serotonin syndrome may occur with Effexor XR treatment, particularly with concomitant use of serotonergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) (see PRECAUTIONS, Drug Interactions).
The concomitant use of Effexor XR with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS, Potential for Interaction with Monoamine Oxidase Inhibitors).
If concomitant treatment of Effexor XR with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions).
The concomitant use of Effexor XR with serotonin precursors (such as tryptophan supplements) is not recommended (see PRECAUTIONS, Drug Interactions).
Effexor XR treatment is associated with sustained hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits (see Table 2).
An analysis for patients in Effexor (immediate release) studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for Effexor (immediate release) (see Table 3).
An insufficient number of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.
Table 2 Number (%) of Sustained Elevations in SDBP in Effexor XR Premarketing Studies by Indication
|Social Anxiety Disorder|
|MDD = major depressive disorder|
GAD = generalized anxiety disorder
|19/705 (3)||5/1011 (0.5)||5/771 (0.6)||9/973 (0.9)|
Table 3 Incidence (%) of Sustained Elevations in SDBP in Effexor Immediate Release Studies
|>100 to ≤200||5%|
|>200 to ≤300||7%|
In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 6 months, 0.6% (5/771) of the Effexor XR‑treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1-24 mm Hg, SDBP). 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. In these patients, the blood pressure increases were in a modest range (7 to 19 mm Hg, SDBP).
Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered.
Elevations in Systolic and Diastolic Blood Pressure
In placebo-controlled premarketing studies, there were changes in mean blood pressure (see Table 4 for mean changes in supine systolic and supine diastolic blood pressure). Across most indications, a dose-related increase in supine systolic and diastolic blood pressure was evident in Effexor XR-treated patients.
Table 4 Final On-Therapy Mean Changes from Baseline in Supine Systolic and Diastolic Blood Pressure (mm Hg) Results by Indication, Study Duration, and Dose in Placebo-Controlled Trials
|Effexor XR mg/day||Placebo|
|1 Supine Systolic Blood Pressure|
2 Supine Diastolic Blood Pressure
|Major Depressive Disorder|
|Generalized Anxiety Disorder|
|Social Anxiety Disorder|
Across all clinical trials in MDD, GAD, Social Anxiety Disorder and panic disorder, 1.4% of patients in the Effexor XR-treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure with blood pressure ≥105 mm Hg compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Effexor XR-treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure with blood pressure ≥180 mm Hg compared to 0.3% of patients in the placebo groups.
Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients).
Discontinuation of Treatment with Effexor XR
Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospective surveys of trials in major depressive disorder, and Social Anxiety Disorder. Abrupt discontinuation or dose reduction 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. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock‑like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.
During marketing of Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).
Insomnia and Nervousness
Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder, GAD, Social Anxiety Disorder, and panic disorder studies, as shown in Table 5.
Table 5 Incidence of Insomnia and Nervousness in Placebo-Controlled Major Depressive Disorder, GAD, Social Anxiety Disorder, and Panic Disorder Trials
|Symptom ||Effexor XR|
n = 357
n = 285
n = 1381
n = 555
n = 819
n = 695
n = 1001
n = 662
Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with Effexor XR in major depressive disorder 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.
Changes in Weight
Adult Patients: A loss of 5% or more of body weight occurred in 7% of Effexor XR-treated and 2% of placebo-treated patients in the short-term placebo-controlled major depressive disorder trials. The discontinuation rate for weight loss associated with Effexor XR was 0.1% in major depressive disorder studies. In placebo-controlled GAD studies, a loss of 7% or more of body weight occurred in 3% of Effexor XR patients and 1% of placebo patients who received treatment for up to 6 months. The discontinuation rate for weight loss was 0.3% for patients receiving Effexor XR in GAD studies for up to eight weeks. In placebo-controlled Social Anxiety Disorder trials, 4% of the Effexor XR-treated and 1% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 6 months of treatment. None of the patients receiving Effexor XR in Social Anxiety Disorder studies discontinued for weight loss. In placebo-controlled panic disorder trials, 3% of the Effexor XR-treated and 2% of the placebo‑treated patients sustained a loss of 7% or more of body weight during up to 12 weeks of treatment. None of the patients receiving Effexor XR in panic disorder studies discontinued for weight loss.
The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of Effexor XR and weight loss agents is not recommended. Effexor XR is not indicated for weight loss alone or in combination with other products.
Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6-17) receiving Effexor XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated patients; p<0.001). In a 16-week, double-blind, placebo-controlled, flexible dose outpatient trial for Social Anxiety Disorder, Effexor XR-treated patients lost an average of 0.75 kg (n = 137), while placebo-treated patients gained an average of 0.76 kg (n = 148). More patients treated with Effexor XR than with placebo experienced a weight loss of at least 3.5% in the Social Anxiety Disorder study (47% of Effexor XR-treated patients vs. 14% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia (see PRECAUTIONS, General, Changes in Appetite).
The risks associated with longer-term Effexor XR use were assessed in an open-label MDD study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old).
Changes in Height
Pediatric Patients: During the eight-week, placebo-controlled GAD studies, Effexor XR-treated patients (ages 6-17) grew an average of 0.3 cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n = 132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). During the 16-week, placebo-controlled Social Anxiety Disorder study, both the Effexor XR-treated (n = 109) and the placebo-treated (n = 112) patients each grew an average of 1.0 cm. In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected based on data from age- and sex‑matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old).
Changes in Appetite
Adult Patients: Treatment-emergent anorexia was more commonly reported for Effexor XR‑treated (8%) than placebo-treated patients (4%) in the pool of short-term, double‑blind, placebo‑controlled major depressive disorder studies. The discontinuation rate for anorexia associated with Effexor XR was 1.0% in major depressive disorder studies. Treatment-emergent anorexia was more commonly reported for Effexor XR-treated (8%) than placebo‑treated patients (2%) in the pool of short-term, double-blind, placebo‑controlled GAD studies. The discontinuation rate for anorexia was 0.9% for patients receiving Effexor XR for up to 8 weeks in GAD studies. Treatment-emergent anorexia was more commonly reported for Effexor XR‑treated (17%) than placebo‑treated patients (2%) in the pool of short-term, double-blind, placebo-controlled Social Anxiety Disorder studies. The discontinuation rate for anorexia was 0.6% for patients receiving Effexor XR for up to 12 weeks in Social Anxiety Disorder studies; no patients discontinued for anorexia between week 12 and month 6. Treatment-emergent anorexia was more commonly reported for Effexor XR‑treated (8%) than placebo-treated patients (3%) in the pool of short-term, double-blind, placebo-controlled panic disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving Effexor XR for up to 12 weeks in panic disorder studies.
Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving Effexor XR. In the placebo-controlled trials for GAD and MDD, 10% of patients aged 6-17 treated with Effexor XR for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving Effexor XR discontinued for anorexia or weight loss. In the placebo-controlled trial for Social Anxiety Disorder, 22% and 3% of patients aged 8-17 treated for up to 16 weeks with Effexor XR and placebo, respectively, reported treatment-emergent anorexia (decreased appetite). The discontinuation rates for anorexia were 0.7% and 0.0% for patients receiving Effexor XR and placebo, respectively; the discontinuation rates for weight loss were 0.7% for patients receiving either Effexor XR or placebo.
Activation of Mania/Hypomania
During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of Effexor XR-treated patients and no placebo patients. In premarketing GAD studies, no Effexor XR-treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In premarketing Social Anxiety Disorder studies, 0.2% 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 no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with Effexor (immediate release), mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with no placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, Effexor XR should be used cautiously in patients with a history of mania.
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Effexor XR. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS, Geriatric Use). Discontinuation of Effexor XR should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
During premarketing experience, no seizures occurred among 705 Effexor XR-treated patients in the major depressive disorder studies, among 1381 Effexor XR-treated patients in GAD studies, or among 819 Effexor XR-treated patients in Social Anxiety Disorder studies. In panic disorder studies, 1 seizure occurred among 1,001 Effexor XR-treated patients. In all premarketing major depressive disorder trials with Effexor (immediate release), seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures.
SSRIs and SNRIs, including Effexor XR, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of Effexor XR and NSAIDs, aspirin, or other drugs that affect coagulation.
Serum Cholesterol Elevation
Clinically relevant increases in 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 (see ADVERSE REACTIONS-Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment.
Interstitial Lung Disease and Eosinophilic Pneumonia
Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered.
Use in Patients With Concomitant Illness
Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering Effexor XR to patients with diseases or conditions that could affect hemodynamic responses or metabolism.
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 venlafaxine's premarketing testing. The electrocardiograms were analyzed for 275 patients who received Effexor XR and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major depressive disorder, for 610 patients who received Effexor XR and 298 patients who received placebo in 8-week double-blind, placebo-controlled trials in GAD, for 593 patients who received Effexor XR and 534 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder, and 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 corrected QT interval (QTc) for Effexor XR-treated patients in major depressive disorder 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 mean change from baseline in QTc interval for Effexor XR-treated patients in the GAD studies did not differ significantly from that with placebo. The mean change from baseline in QTc interval for Effexor XR‑treated patients in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 3.4 msec for Effexor XR and decrease of 1.6 msec for placebo). The mean change from baseline in QTc interval 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).
In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patients in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The mean change from baseline in heart rate for Effexor XR-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 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 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).
In a flexible-dose study, with Effexor (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group.
As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (eg, patients with hyperthyroidism, heart failure, or recent myocardial infarction).
Evaluation of the electrocardiograms for 769 patients who received Effexor (immediate release) in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo.
In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Effexor XR, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients.
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Effexor XR and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Effexor XR. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Effexor XR.
Clinical Worsening and Suicide Risk: 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 behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Interference with Cognitive and Motor Performance
Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely affect their ability to engage in such activities.
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Effexor XR and triptans, tramadol, tryptophan supplements or other serotonergic agents (see WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs).
Patients should be cautioned about the concomitant use of Effexor XR and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS, Abnormal Bleeding).
Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine.
Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breast-feeding an infant.
Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients should be advised to notify their physician if they have a history of glaucoma or a history of increased intraocular pressure (see WARNINGS).
There are no specific laboratory tests recommended.
As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O‑desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.
Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than venlafaxine. 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, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.
Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.
Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The mechanism explaining this finding is unknown.
The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below).
Drugs Highly Bound to Plasma Proteins
Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Effexor XR is initiated or discontinued.
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 of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers (see Metabolism and Excretion under CLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.
Ketoconazole: A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O‑desmethylvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively.
Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs - 2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM (range in PMs - 38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMs and 53% in PMs (range in PMs - 4% to 134%).
Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.
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 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, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC's increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2‑OH‑desipramine levels is unknown.
Metoprolol - Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α‑hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine.
Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with co-administration of venlafaxine and metoprolol.
Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure (see WARNINGS).
Risperidone - Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).
CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.
Indinavir - In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.
CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.
CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide.
CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19 (see Diazepam above).
Monoamine Oxidase Inhibitors
See CONTRAINDICATIONS and WARNINGS.
The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required.
Serotonergic Drugs: Based on the mechanism of action of Effexor XR and the potential for serotonin syndrome, caution is advised when Effexor XR is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS, Serotonin Syndrome). If concomitant treatment of Effexor XR with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome). The concomitant use of Effexor XR with tryptophan supplements is not recommended (see WARNINGS, Serotonin Syndrome).
Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Effexor XR with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).
There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment.
Postmarketing Spontaneous Drug Interaction Reports
See ADVERSE REACTIONS, Postmarketing Reports.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats.
Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow.
Impairment of Fertility
Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 2 times the maximum recommended human dose on a mg/m2 basis.
Teratogenic Effects - Pregnancy Category C
Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose on a mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate and well‑controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Neonates exposed to Effexor XR, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), 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 SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-Drug Interactions-CNS-Active Drugs). 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).
Labor and Delivery
The effect of venlafaxine on labor and delivery in humans is unknown.
Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Effexor XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo‑controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with Effexor XR, and the data were not sufficient to support a claim for use in pediatric patients.
Anyone considering the use of Effexor XR in a child or adolescent must balance the potential risks with the clinical need.
Although no studies have been designed to primarily assess Effexor XR's impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Effexor XR may adverselyaffect weight and height (see PRECAUTIONS, General, Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with Effexor XR, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Effexor XR treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration.
In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation).
Approximately 4% (14/357), 6% (77/1381), 1% (10/819), and 2% (16/1001) of Effexor XR‑treated patients in placebo-controlled premarketing major depressive disorder, GAD, Social Anxiety Disorder trials, and panic disorder trials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated (immediate release) patients in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Effexor XR have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).
The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION).