"The U.S. Food and Drug Administration today approved Brintellix (vortioxetine) to treat adults with major depressive disorder.
Major depressive disorder (MDD), commonly referred to as depression, is a mental disorder characterized by mo"...
The following adverse reactions are discussed in greater detail in other sections of the label:
- Hypersensitivity [see CONTRAINDICATIONS]
- Suicidal Thoughts and Behaviors in Children, Adolescents, and Adults [see WARNINGS AND PRECAUTIONS]
- Serotonin Syndrome [see WARNINGS AND PRECAUTIONS]
- Elevations in Blood Pressure [see WARNINGS AND PRECAUTIONS]
- Abnormal Bleeding [see WARNINGS AND PRECAUTIONS]
- Angle Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
- Activation of Mania/Hypomania [see WARNINGS AND PRECAUTIONS]
- Discontinuation Syndrome [see WARNINGS AND PRECAUTIONS]
- Renal Impairment [see WARNINGS AND PRECAUTIONS]
- Hepatic Impairment [see WARNINGS AND PRECAUTIONS]
- Seizure [see WARNINGS AND PRECAUTIONS]
- Hyponatremia [see WARNINGS AND PRECAUTIONS]
- Weight and Height changes in Pediatric Patients [see WARNINGS AND PRECAUTIONS]
- Appetite Changes in Pediatric Patients [see WARNINGS AND PRECAUTIONS]
- Interstitial Lung Disease and Eosinophilic Pneumonia [see WARNINGS AND PRECAUTIONS]
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Most Common Adverse Reactions
The most commonly observed adverse reactions in the clinical study database in Effexor XR treated patients in MDD, GAD, SAD, and PD (incidence ≥ 5% and at least twice the rate of placebo) were: nausea (30.0%), somnolence (15.3%), dry mouth (14.8%), sweating (11.4%), abnormal ejaculation (9.9%), anorexia (9.8%), constipation (9.3%), impotence (5.3%) and decreased libido (5.1%).
Adverse Reactions Reported as Reasons for Discontinuation of Treatment
Combined across short-term, placebo-controlled premarketing studies for all indications, 12% of the 3,558 patients who received Effexor XR (37.5-225 mg) discontinued treatment due to an adverse experience, compared with 4% of the 2,197 placebo-treated patients in those studies.
The most common adverse reactions leading to discontinuation in ≥ 1% of the Effexor XR treated patients in the short-term studies (up to 12 weeks) across indications are shown in Table 7.
Table 7: Incidence (%) of Patients Reporting Adverse
Reactions Leading to Discontinuation in Placebo-controlled Clinical Studies (up
to 12 Weeks Duration)
|Body System Adverse Reaction||Effexor XR
n = 3,558
n = 2,197
|Body as a whole|
|Skin and appendages||1.5||0.6|
Common Adverse Reactions in Placebo-controlled Studies
The number of patients receiving multiple doses of Effexor XR during the premarketing assessment for each approved indication is shown in Table 8. The conditions and duration of exposure to venlafaxine in all development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titration studies.
Table 8: Patients Receiving
Effexor XR in Premarketing Clinical Studies
|aIn addition, in the premarketing assessment of Effexor, multiple doses were administered to 2,897 patients in studies for MDD.|
The incidences of common adverse reactions (those that occurred in ≥ 2% of Effexor XR treated patients [357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and more frequently than placebo) in Effexor XR treated patients in short-term, placebo-controlled, fixed-and flexible-dose clinical studies (doses 37.5 to 225 mg per day) are shown in Table 9.
The adverse reaction profile did not differ substantially between the different patient populations.
Table 9: Common Adverse Reactions: Percentage of
Patients Reporting Adverse Reactions ( ≥ 2% and > placebo) in
Placebo-controlled Studies (up to 12 Weeks Duration) across All Indications
n = 3,558
n = 2,197
|Body as a whole|
|Skin and appendages|
|Sweating (including night sweats)||11.4||2.9|
|Abnormal ejaculation/orgasm (men)a||9.9||0.5|
|aPercentages based on the number of men (Effexor XR, n =
1,440; placebo, n = 923)
bPercentages based on the number of women (Effexor XR, n = 2,118; placebo, n = 1,274)
Other Adverse Reactions Observed in Clinical Studies
Body as a whole – Photosensitivity reaction
Nervous system – Seizures [see WARNINGS AND PRECAUTIONS], manic reaction [see WARNINGS AND PRECAUTIONS], agitation, confusion, akathisia, hallucinations, hypertonia, myoclonus, depersonalization, apathy
Urogenital system – Urinary retention, urination impaired, urinary incontinence, urinary frequency increased, menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g., menorrhagia, metrorrhagia)
Vital Sign Changes
In placebo-controlled premarketing studies, there were increases in mean blood pressure (see Table 10). Across most indications, a dose-related increase in mean supine systolic and diastolic blood pressure was evident in patients treated with Effexor XRs. Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the Effexor XR groups experienced an increase in SDBP of ≥ 15 mm Hg along with a blood pressure ≥ 105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Effexor XR groups experienced an increase in SSBP of ≥ 20 mm Hg with a blood pressure ≥ 180 mm Hg, compared to 0.3% of patients in the placebo groups.
Table 10: Final On-therapy
Mean Changes From Baseline in Supine Systolic (SSBP) and Diastolic (SDBP) Blood
Pressure (mm Hg) in Placebo-controlled Studies
|Indication (Duration)||Effexor XR||Placebo|
|≤ 75 mg per day||> 75 mg per day|
Effexor XR treatment was associated with sustained hypertension (defined as treatment-emergent Supine Diastolic Blood Pressure [SDBP] ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for three consecutive on-therapy visits (see Table 11). An insufficient number of patients received mean doses of Effexor XR over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.
Table 11: Sustained
Elevations in SDBP in Effexor XR Premarketing Studies
|Indication||Dose Range (mg per day)||Incidence (%)|
Effexor XR was associated with mean increases in pulse rate compared with placebo in premarketing placebo-controlled studies (see Table 12) [see WARNINGS AND PRECAUTIONS].
Table 12: Approximate Mean
Final On-therapy Increase in Pulse Rate (beats/min) in Effexor XR Premarketing
Placebo-controlled Studies (up to 12 Weeks Duration)
|Indication (Duration)||Effexor XR||Placebo|
|(8 weeks)||2||< 1|
|(12 weeks)||1||< 1|
Effexor XR was associated with mean final increases in serum cholesterol concentrations compared with mean final decreases for placebo in premarketing MDD, GAD, SAD and PD clinical studies (Table 13).
Table 13: Mean Final On-therapy Changes in Cholesterol
Concentrations (mg/dL) in Effexor XR Premarketing Studies
|Indication (Duration)||Effexor XR||Placebo|
Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo.
Patients treated with Effexor (immediate release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥ 50 mg/dL from baseline and to a value ≥ 261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥ 50 mg/dL from baseline and to a value ≥ 261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients.
Effexor XR was associated with mean final on-therapy increases in fasting serum triglycerides compared with placebo in premarketing clinical studies of SAD and PD up to 12 weeks (pooled data) and 6 months duration (Table 14).
Table 14: Mean Final On-therapy Increases in
Triglyceride Concentrations (mg/dL) in Effexor XR Premarketing Studies
|Indication (Duration)||Effexor XR||Placebo|
In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical studies) in children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed.
Adverse Reactions Identified During Postapproval Use
The following adverse reactions have been identified during postapproval use of Effexor XR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
Digestive system – Pancreatitis
Hemic/Lymphatic system – Mucous membrane bleeding [see WARNINGS AND PRECAUTIONS], blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia
Metabolic/Nutritional – Hyponatremia [see WARNINGS AND PRECAUTIONS], Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [see WARNINGS AND PRECAUTIONS], abnormal liver function tests, hepatitis, prolactin increased
Musculoskeletal – Rhabdomyolysis
Nervous system – Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS], serotonergic syndrome [see WARNINGS AND PRECAUTIONS], delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia
Respiratory system – Pulmonary eosinophilia
Special senses – Angle-closure glaucoma [see WARNINGS AND PRECAUTIONS]
Read the Effexor XR (venlafaxine hydrochloride extended-release) Side Effects Center for a complete guide to possible side effects
Central Nervous System (CNS)-Active Drugs
The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when Effexor XR is taken in combination with other CNS-active drugs.
Monoamine Oxidase Inhibitors
Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from an MAOI and started on antidepressants with pharmacological properties similar to Effexor XR (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Based on the mechanism of action of Effexor XR and the potential for serotonin syndrome, caution is advised when Effexor XR is coadministered 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. If concomitant treatment with Effexor XR and these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Effexor XR with tryptophan supplements is not recommended [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS].
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, And Warfarin)
Serotonin release by platelets plays an important role in hemostasis. The use of psychotropic drugs that interfere with serotonin reuptake is associated with the occurrence of upper gastrointestinal bleeding and concurrent use of an NSAID or aspirin may potentiate this risk of bleeding [see WARNINGS AND PRECAUTIONS]. 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.
Weight Loss Agents
The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration 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.
Effects Of Other Drugs On Effexor XR
Figure 1: Effect of interacting drugs on the
pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine
Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; Cmax, peak plasma concentrations; EM's, extensive metabolizers; PM's, poor metabolizers
* No dose adjustment on co-administration with CYP2D6 inhibitors (Fig 3 and Metabolism Section 12.3)
Effects Of Effexor XR On Other Drugs
Figure 2: Effect of
venlafaxine on the pharmacokinetics interacting drugs and their active
Abbreviations: AUC, area under the curve; Cmax, peak plasma concentrations; OH, hydroxyl
* Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for Cmax and AUC of 2-OH desipramine were 6.6 (5.5, 7.9) and 4.4 (3.8, 5.0), respectively.
Note: *: 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.
Drug-Laboratory Test Interactions
False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.
Drug Abuse And Dependence
Effexor XR is not a controlled substance.
While venlafaxine has not been systematically studied in clinical studies for its potential for abuse, there was no indication of drug-seeking behavior in the clinical studies. 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).
Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Discontinuation effects have been reported in patients receiving venlafaxine [see DOSAGE AND ADMINISTRATION].
Read the Effexor XR Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/12/2015
This monograph has been modified to include the generic and brand name in many instances.
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