Associated with Discontinuation of Treatment
Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3
depression studies discontinued treatment due to an adverse event. The more
common events ( ≥ 1%) associated with discontinuation and considered to be
drug-related (ie, those events associated with dropout at a rate approximately
twice or greater for venlafaxine compared to placebo) included:
CNS |
Venlafaxine |
Placebo |
Somnolence |
3% |
1% |
Insomnia |
3% |
1% |
Dizziness |
3% |
- |
Nervousness |
2% |
- |
Dry mouth |
2% |
- |
Anxiety |
2% |
1% |
Gastrointestinal |
|
Nausea |
6% |
1% |
Urogenital |
|
Abnormal ejaculation* |
3% |
- |
Other |
|
Headache |
3% |
1% |
Asthenia |
2% |
- |
Sweating |
2% |
- |
* Percentages based on the number of males.
- Less than 1% |
Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
The most commonly observed adverse events associated with the use of Effexor® (venlafaxine hydrochloride)
(incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated
patients (ie, incidence for Effexor (venlafaxine hydrochloride) at least twice that for placebo), derived
from the 1% incidence table below, were asthenia, sweating, nausea, constipation,
anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety,
tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence
in men.
Adverse Events Occurring at an Incidence of 1% or More Among Effexor (venlafaxine hydrochloride) -Treated
Patients The table that follows enumerates adverse events that occurred at an
incidence of 1% or more, and were more frequent than in the placebo group, among
Effexor (venlafaxine hydrochloride) -treated patients who participated in short-term (4- to 8-week) placebo-controlled
trials in which patients were administered doses in a range of 75 to 375 mg/day.
This table shows the percentage of patients in each group who had at least one
episode of an event at some time during their treatment. Reported adverse events
were classified using a standard COSTART-based Dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict
the incidence of side effects in the course of usual medical practice where
patient characteristics and other factors differ from those which prevailed
in the clinical trials. Similarly, the cited frequencies cannot be compared
with figures obtained from other clinical investigations involving different
treatments, uses and investigators. The cited figures, however, do provide the
prescribing physician with some basis for estimating the relative contribution
of drug and nondrug factors to the side effect incidence rate in the population
studied.
TABLE 2 : Treatment-Emergent Adverse Experience Incidence
in 4- to 8-Week Placebo-Controlled Clinical Trials1
Body System |
Preferred Term |
Effexor
(n=1033) |
Placebo
(n=609) |
Body as a Whole |
Headache |
25% |
24% |
Asthenia |
12% |
6% |
Infection |
6% |
5% |
Chills |
3% |
- |
Chest pain |
2% |
1% |
Trauma |
2% |
1% |
Cardiovascular |
Vasodilatation |
4% |
3% |
Increased blood pressure/hypertension |
2% |
- |
Tachycardia |
2% |
- |
Postural hypotension |
1% |
- |
Dermatological |
Sweating |
12% |
3% |
Rash |
3% |
2% |
Pruritus |
1% |
- |
Gastrointestinal |
Nausea |
37% |
11% |
Constipation |
15% |
7% |
Anorexia |
11% |
2% |
Diarrhea |
8% |
7% |
Vomiting |
6% |
2% |
Dyspepsia |
5% |
4% |
Flatulence |
3% |
2% |
Metabolic |
Weight loss |
1% |
- |
Nervous System |
Somnolence |
23% |
9% |
Dry mouth |
22% |
11% |
Dizziness |
19% |
7% |
Insomnia |
18% |
10% |
Nervousness |
13% |
6% |
Anxiety |
6% |
3% |
Tremor |
5% |
1% |
Abnormal dreams |
4% |
3% |
Hypertonia |
3% |
2% |
Paresthesia |
3% |
2% |
Libido decreased |
2% |
- |
Agitation |
2% |
- |
Confusion |
2% |
1% |
Thinking abnormal |
2% |
1% |
Depersonalization |
1% |
- |
Depression |
1% |
- |
Urinary retention |
1% |
- |
Twitching |
1% |
- |
Respiration |
Yawn |
3% |
- |
Special Senses |
Blurred vision |
6% |
2% |
Taste perversion |
2% |
- |
Tinnitus |
2% |
- |
Mydriasis |
2% |
- |
Urogenital System |
Abnormal ejaculation/ orgasm |
12%2 |
- 2 |
Impotence |
6%2 |
- 2 |
Urinary frequency |
3% |
2% |
Urination impaired |
2% |
- |
Orgasm disturbance |
2%3 |
- 3 |
1 Events reported
by at least 1% of patients treated with Effexor (venlafaxine hydrochloride)
are included, and are rounded to the nearest %. Events for which the Effexor (venlafaxine hydrochloride)
incidence was equal to or less than placebo are not listed in the table,
but included the following: abdominal pain, pain, back pain, flu syndrome,
fever, palpitation, increased appetite, myalgia, arthralgia, amnesia,
hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3.
- Incidence less than 1%.
2 Incidence based on number of male patients.
3 Incidence based on number of female patients. |
Dose Dependency of Adverse Events
A comparison of adverse event rates in a fixed-dose study comparing Effexor
(venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a
dose dependency for some of the more common adverse events associated with Effexor (venlafaxine hydrochloride)
use, as shown in the table that follows. 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 one Effexor (venlafaxine hydrochloride) 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.
TABLE 3 : Treatment-Emergent Adverse Experience Incidence
in a Dose Comparison Trial
Body System/ Preferred Term |
Placebo
(n=92) |
Effexor(mg/day) |
75
(n=89) |
225
(n=89) |
375
(n=88) |
Body as a Whole |
Abdominal pain |
3.3% |
3.4% |
2.2% |
8.0% |
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 System |
Hypertension |
1.1% |
1.1% |
2.2% |
4.5% |
Vasodilatation |
0.0% |
4.5% |
5.6% |
2.3% |
Digestive System |
Anorexia |
2.2% |
14.6% |
13.5% |
17.0% |
Dyspepsia |
2.2% |
6.7% |
6.7% |
4.5% |
Nausea |
14.1% |
32.6% |
38.2% |
58.0% |
Vomiting |
1.1% |
7.9% |
3.4% |
6.8% |
Nervous System |
Agitation |
0.0% |
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% |
18.0% |
26.1% |
Tremor |
0.0% |
1.1% |
2.2% |
10.2% |
Respiratory System |
Yawn |
0.0% |
4.5% |
5.6% |
8.0% |
Skin and Appendages |
Sweating |
5.4% |
6.7% |
12.4% |
19.3% |
Special Senses |
Abnormality of accommodation |
0.0% |
9.1% |
7.9% |
5.6% |
Urogenital System |
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) |
Adaptation to Certain Adverse Events
Over a 6-week period, there was evidence of adaptation to some adverse events
with continued therapy (eg, dizziness and nausea), but less to other effects
(eg, abnormal ejaculation and dry mouth).
Vital Sign Changes
Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups)
in clinical trials was associated with a mean increase in pulse rate of approximately
3 beats per minute, compared to no change for placebo. In a flexible-dose study,
with doses in the range of 200 to 375 mg/day and mean dose greater than 300
mg/day, the mean pulse was increased by about 2 beats per minute compared with
a decrease of about 1 beat per minute for placebo.
In controlled clinical trials, Effexor (venlafaxine hydrochloride) was associated with mean increases in
diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose
groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo.
However, there is a dose dependency for blood pressure increase (see WARNINGS).
Laboratory Changes
Of the serum chemistry and hematology parameters monitored during clinical
trials with Effexor (venlafaxine hydrochloride) , a statistically significant difference with placebo was
seen only for serum cholesterol. In premarketing trials, treatment with Effexor (venlafaxine hydrochloride)
tablets was associated with a mean final on-therapy increase in total cholesterol
of 3 mg/dL.
Patients treated with Effexor (venlafaxine hydrochloride) tablets 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 (see PRECAUTIONS General-Serum Cholesterol Elevation).
ECG Changes
In an analysis of ECGs obtained in 769 patients treated with Effexor (venlafaxine hydrochloride) and 450
patients treated with placebo in controlled clinical trials, the only statistically
significant difference observed was for heart rate, ie, a mean increase from
baseline of 4 beats per minute for Effexor (venlafaxine hydrochloride) . In a flexible-dose study, with doses
in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the
mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per
minute for placebo (see PRECAUTIONS, General, Use in Patients with Concomitant
Illness).
Other Events Observed During the Premarketing Evaluation of Venlafaxine
During its premarketing assessment, multiple doses of Effexor (venlafaxine hydrochloride) were administered
to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing
assessment of Effexor (venlafaxine hydrochloride) XR (the extended release form of venlafaxine), multiple
doses were administered to 705 patients in Phase 3 major depressive disorder
studies and Effexor (venlafaxine hydrochloride) was administered to 96 patients. During its premarketing
assessment, multiple doses of Effexor (venlafaxine hydrochloride) XR were also administered to 1381 patients
in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies.
The conditions and duration of exposure to venlafaxine in both development programs
varied greatly, and included (in overlapping categories) open and double-blind
studies, uncontrolled and controlled studies, inpatient (Effexor (venlafaxine hydrochloride) only) and outpatient
studies, fixed-dose and titration studies. Untoward events associated with this
exposure were recorded by clinical investigators using terminology of their
own choosing. Consequently, it is not possible to provide a meaningful estimate
of the proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event
categories.
In the tabulations that follow, reported adverse events were classified using
a standard COSTART-based Dictionary terminology. The frequencies presented,
therefore, represent the proportion of the 5356 patients exposed to multiple
doses of either formulation of venlafaxine who experienced an event of the type
cited on at least one occasion while receiving venlafaxine. All reported events
are included except those already listed in Table 2 and those events for which
a drug cause was remote. If the COSTART term for an event was so general as
to be uninformative, it was replaced with a more informative term. It is important
to emphasize that, although the events reported occurred during treatment with
venlafaxine, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing
frequency using the following definitions: frequent adverse events are
defined as those occurring on one or more occasions in at least 1/100 patients;
infrequent adverse events are those occurring in 1/100 to 1/1000 patients;
rare events are those occurring in fewer than 1/1000 patients.
Body as a whole - Frequent: accidental injury, chest pain substernal,
neck pain; Infrequent: face edema, intentional injury, malaise, moniliasis,
neck rigidity, pelvic pain, photosensitivity reaction, suicide attempt, withdrawal
syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis.
Cardiovascular system - Frequent: migraine; Infrequent: angina
pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder
(mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare:
aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy, bradycardia,
bundle branch block, capillary fragility, cardiovascular disorder (mitral valve
and circulatory disturbance), cerebral ischemia, coronary artery disease, congestive
heart failure, heart arrest, mucocutaneous hemorrhage, myocardial infarct, pallor.
Digestive system - Frequent: eructation; Infrequent: bruxism, colitis,
dysphagia, tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal
ulcer, gingivitis, glossitis, rectal hemorrhage, hemorrhoids, melena, oral moniliasis,
stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis,
duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum
hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis,
periodontitis, proctitis, increased salivation, soft stools, tongue discoloration.
Endocrine system - Rare: goiter, hyperthyroidism, hypothyroidism, thyroid
nodule, thyroiditis.
Hemic and lymphatic system - Frequent: ecchymosis; Infrequent:
anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia;
Rare: basophilia, bleeding time increased, cyanosis, eosinophilia, lymphocytosis,
multiple myeloma, purpura.
Metabolic and nutritional - Frequent: edema, weight gain; Infrequent:
alkaline phosphatase increased, dehydration, hypercholesteremia, hyperglycemia,
hyperlipemia, hypokalemia, SGOT (AST) increased, SGPT (ALT) increased, thirst;
Rare: alcohol intolerance, bilirubinemia, BUN increased, creatinine increased,
diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis, hypercalcinuria,
hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia, hypoglycemia,
hyponatremia, hypophosphatemia, hypoproteinemia, uremia.
Musculoskeletal system - Infrequent: arthritis, arthrosis, bone pain,
bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological
fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid
arthritis, tendon rupture.
Nervous system - Frequent: trismus, vertigo; Infrequent: akathisia,
apathy, ataxia, circumoral paresthesia, CNS stimulation, emotional lability,
euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypotonia,
incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy,
psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol
abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident,
loss of consciousness, delusions, dementia, dystonia, facial paralysis, feeling
drunk, abnormal gait, Guillain-Barre Syndrome, hyperchlorhydria, hypokinesia,
impulse control difficulties, neuritis, nystagmus, paranoid reaction, paresis,
psychotic depression, reflexes decreased, reflexes increased, suicidal ideation,
torticollis.
Respiratory system - Frequent: bronchitis, dyspnea; Infrequent:
asthma, chest congestion, epistaxis, hyperventilation, laryngismus, laryngitis,
pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoventilation,
hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea.
Skin and appendages - Infrequent: acne, alopecia, brittle nails, contact
dermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis,
urticaria; Rare: erythema nodosum, exfoliative dermatitis, lichenoid
dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism,
leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea,
skin atrophy, skin striae.
Special senses - Frequent: abnormality of accommodation, abnormal vision;
Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes,
eye pain, hyperacusis, otitis media, parosmia, photophobia, taste loss, visual
field defect; Rare: blepharitis, chromatopsia, conjunctival edema, deafness,
exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis,
labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa,
scleritis, uveitis.
Urogenital system - Frequent: metrorrhagia*, prostatic disorder (prostatitis
and enlarged prostate)*, vaginitis*; Infrequent: albuminuria, amenorrhea*,
cystitis, dysuria, hematuria, leukorrhea*, menorrhagia*, nocturia, bladder pain,
breast pain, polyuria, pyuria, urinary incontinence, urinary urgency, vaginal
hemorrhage*; Rare: abortion*, anuria, balanitis*, breast discharge, breast
engorgement, breast enlargement, endometriosis*, fibrocystic breast, calcium
crystalluria, cervicitis*, ovarian cyst*, prolonged erection*, gynecomastia
(male)*, hypomenorrhea*, kidney calculus, kidney pain, kidney function abnormal,
female lactation*, mastitis, menopause*, oliguria, orchitis*, pyelonephritis,
salpingitis*, urolithiasis, uterine hemorrhage*, uterine spasm*, vaginal dryness*.
* Based on the number of men and women as appropriate.
Postmarketing Reports
Voluntary reports of other adverse events temporally associated with the use
of venlafaxine that have been received since market introduction and that may
have no causal relationship with the use of venlafaxine include the following:
agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital
anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis,
delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including
atrial fibrillation, supraventricular tachycardia, ventricular extrasystole,
and rare reports of ventricular fibrillation and ventricular tachycardia, including
torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema
multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia),
angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding),
hepatic events (including GGT elevation; abnormalities of unspecified liver
function tests; liver damage, necrosis, or failure; and fatty liver), interstitial
lung disease, involuntary movements, LDH increased, neutropenia, night sweats,
pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis,
shock-like electrical sensations or tinnitus (in some cases, subsequent to the
discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate
antidiuretic hormone secretion (usually in the elderly).
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.
Drug Abuse And Dependence
Controlled Substance Class
Effexor (venlafaxine hydrochloride) is not a controlled substance.
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.
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).
While Effexor (venlafaxine hydrochloride) has not been systematically studied in clinical trials for its
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 Effexor (venlafaxine hydrochloride) (eg, development of tolerance,
incrementation of dose, drug-seeking behavior).