|
abdominal pain,
accidental injury,
anxiety,
back pain,
bronchitis,
diarrhea,
dysmenorrhea,
dyspepsia,
flu syndrome,
headache,
infection,
pain,
palpitation,
rhinitis,
sinusitis. 2 < 1 indicates an incidence greater than zero but less than 1 .
3 Mostly "hot flashes."
4 Mostly "vivid dreams," "nightmares," and "increased dreaming."
5 Mostly "blurred vision" and "difficulty focusing eyes."
6 Mostly "delayed ejaculation."
7 Incidence is based on the number of male patients.
8 Mostly "delayed orgasm" or "anorgasmia."
9 Incidence is based on the number of female patients. Table 4
Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled
Effexor XR Clinical Trials in GAD Patients 1,2
% % % % Reporting Event Body System
Preferred Term
Effexor XR
(n = 1381)
Placebo
(n = 555)
Body as a Whole Asthenia
12 8
Cardiovascular System Vasodilatation 3
4 2
Digestive System Nausea
35 12
Constipation 10 4
Anorexia 8 2
Vomiting 5% 3 % % % % Reporting Event Body System
Preferred Term
Effexor XR
(n = 1381)
Placebo
(n = 555)
Nervous System Dizziness
16 11
Dry Mouth 16 6
Insomnia 15 10
Somnolence 14 8
Nervousness 6 4
Libido Decreased 4 2
Tremor 4 < 1
Abnormal Dreams 4 3 2
Hypertonia 3 2
Paresthesia 2 1
Respiratory System Yawn
3 < 1
Skin Sweating
10 3
Special Senses Abnormal Vision 5
5 < 1
Urogenital System Abnormal Ejaculation 6,7
11 < 1
Impotence 7 5 < 1
Orgasmic Dysfunction (female) 8,9 2 0 1 Text Continues Below
Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, pain, palpitation,
pharyngitis, rhinitis, tinnitus, and urinary frequency. 2 < 1 means greater than zero but less than 1 .
3 Mostly "hot flashes."
4 Mostly "vivid dreams," "nightmares," and "increased dreaming."
5 Mostly "blurred vision" and "difficulty focusing eyes."
6 Includes "delayed ejaculation" and "anorgasmia."
7 Percentage based on the number of males (Effexor XR = 525, placebo = 220).
8 Includes "delayed orgasm," "abnormal orgasm," and "anorgasmia."
9 Percentage based on the number of females (Effexor XR = 856, placebo = 335). Table 5
Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled
Effexor XR Clinical Trials in Social Anxiety Disorder Patients 1,2
% % % % Reporting Event Body System Effexor XR Placebo
Preferred Term (n = 277) (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 3% 1%
Palpitation 3 1
Digestive System Nausea
29 9
Anorexia 4 20% 1%
Constipation 8 4
Diarrhea 6 5
Vomiting 3 2
Eructation 2 0
Metabolic/ Nutritional Weight Loss
4 0
Nervous System Insomnia
23 7
Dry Mouth 17 4%
Dizziness 16% 8
Somnolence 16 8
Nervousness 11 3
Libido Decreased 9 < 1
Anxiety 5 3
Agitation 4 1
Tremor 4% < 1
Abnormal Dreams 5 4 < 1
Paresthesia 3 < 1
Twitching 2 0
Respiratory System Yawn
5 < 1
Sinusitis 2 1
Skin Sweating
13 2 % % % % Reporting Event Body System Effexor XR Placebo
Preferred Term (n = 277) (n = 274)
Special Senses Abnormal Vision 6
6 3
Urogenital System Abnormal Ejaculation 7,8
16 1
Impotence 8 10 1
Orgasmic Dysfunction 9,10 8 0
1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placebo rate are not included. These events are: back pain, depression, dysmenorrhea, dyspepsia, infection, myalgia, pain, pharyngitis, rash, rhinitis, and upper respiratory infection. 2< 1 means greater than zero but less than 1 .
3 Mostly "hot flashes."
4 Mostly "decreased appetite" and "loss of appetite."
5 Mostly "vivid dreams," "nightmares," and "increased dreaming."
6 Mostly "blurred vision."
7 Includes "delayed ejaculation" and "anorgasmia."
8 Percentage based on the number of males (Effexor XR = 158, placebo = 153).
9 Includes "abnormal orgasm" and "anorgasmia."
10 Percentage based on the number of females (Effexor XR = 119, placebo = 121). Vital Sign Changes Effexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Effexor XR treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increase in pulse rate of approximately 4 beats per minute, compared with no change for placebo. (See the Sustained Hypertension section of WARNINGS for effects on blood pressure.) In a flexible-dose study, with Effexor 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. Laboratory Changes 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 in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 11.4 mg/ dL compared with a mean final decrease of 2.2 mg/ dL for placebo. Patients treated with Effexor tablets (the immediate-release form of venlafaxine) 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 a flexible-dose study, with Effexor 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 the Use in Patients with Concomitant Illness section of RECAUTIONS). Other Adverse Events Observed During the Premarketing Evaluation of Effexor and Effexor XR During its premarketing assessment, multiple doses of Effexor XR were administered to 705 patients in Phase 3 major depressive disorder studies and Effexor was administered to 96 patients. During its premarketing assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety
Disorder studies. In addition, in premarketing assessment of Effexor, multiple doses were administered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. 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 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 Tables 3, 4, and 5 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: chest pain substernal, chills, fever, 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, postural hypotension, tachycardia; 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, cerebral ischemia, coronary artery disease, congestive heart failure, heart arrest, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneous hemorrhage, myocardial infarct, pallor. Digestive system Frequent: increased appetite; 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, esophageal spasms, duodenitis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration. Nervous system Frequent: amnesia, confusion, depersonalization, hypesthesia, thinking
abnormal, 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, feeling drunk, loss of
consciousness, delusions, dementia, dystonia, facial paralysis, 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: cough increased, dyspnea;
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 increased, SGPT 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 Frequent: arthralgia; Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture. 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 Frequent: pruritus; 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, mydriasis, taste perversion; 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),* urination impaired, vaginitis*; Infrequent: albuminuria, amenorrhea,* cystitis, dysuria, hematuria, leukorrhea,* menorrhagia,* nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage*; Rare: abortion,* anuria, breast discharge, breast engorgement, balanitis,* breast enlargement, endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,* ovarian cyst,* prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney calculus, kidney pain, kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria, 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, aplastic anemia, catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; epidermal necrosis/ Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), 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), involuntary movements, LDH increased, neuroleptic malignant syndrome-like events (including a case of a 10-year-old who may have been taking methylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, pulmonary eosinophilia, renal failure, rhabdomyolysis, serotonin syndrome, shock-like electrical sensations (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 XR (venlafaxine hydrochloride) extended-release capsules 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 venlafaxine 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 venlafaxine (eg, development of tolerance, incrementation of dose, drug-seeking behavior).
Page: << Prev | 1 | 2 | 3 | 4 | 5
|
.gif)
