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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Hypersensitivity [see Contraindications (4.1) ] Suicidal Thoughts and Behaviors in Children, Adolescents, and Adults [see Warnings and Precautions (5.1) ] Serotonin Syndrome [see Warnings and Precautions (5.2) ] Elevations in Blood Pressure [see Warnings and Precautions (5.3) ] Abnormal Bleeding [see Warnings and Precautions (5.4) ] Angle Closure Glaucoma [see Warnings and Precautions (5.5) ] Activation of Mania/Hypomania [see Warnings and Precautions (5.6) ] Discontinuation Syndrome [see Warnings and Precautions (5.7) ] Seizure [see Warnings and Precautions (5.8) ] Hyponatremia [see Warnings and Precautions (5.9) ] Weight and Height changes in Pediatric Patients [see Warnings and Precautions (5.10) ] Appetite Changes in Pediatric Patients [see Warnings and Precautions (5.11) ] Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions (5.12) ] Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): nausea, somnolence, dry mouth, sweating, abnormal ejaculation, anorexia, constipation, erectile dysfunction, and libido decreased ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Wyeth Pharmaceuticals Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 Placebo n = 2,197 Body as a whole Asthenia 1.7 0.5 Headache 1.5 0.8 Digestive system Nausea 4.3 0.4 Nervous system Dizziness 2.2 0.8 Insomnia 2.1 0.6 Somnolence 1.7 0.3 Skin and appendages 1.5 0.6 Sweating 1.0 0.2 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 Indication Effexor XR MDD 705 In addition, in the premarketing assessment of Effexor, multiple doses were administered to 2,897 patients in studies for MDD. GAD 1,381 SAD 819 PD 1,314 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 Body System Adverse Reaction Effexor XR n = 3,558 Placebo n = 2,197 Body as a whole Asthenia 12.6 7.8 Cardiovascular system Hypertension 3.4 2.6 Palpitation 2.2 2.0 Vasodilatation 3.7 1.9 Digestive system Anorexia 9.8 2.6 Constipation 9.3 3.4 Diarrhea 7.7 7.2 Dry mouth 14.8 5.3 Nausea 30.0 11.8 Vomiting 4.3 2.7 Nervous system Abnormal dreams 2.9 1.4 Dizziness 15.8 9.5 Insomnia 17.8 9.5 Libido decreased 5.1 1.6 Nervousness 7.1 5.0 Paresthesia 2.4 1.4 Somnolence 15.3 7.5 Tremor 4.7 1.6 Respiratory system Yawn 3.7 0.2 Skin and appendages Sweating (including night sweats) 11.4 2.9 Special senses Abnormal vision 4.2 1.6 Urogenital system Abnormal ejaculation/orgasm (men) Percentages based on the number of men (Effexor XR, n = 1,440; placebo, n = 923) 9.9 0.5 Anorgasmia (men) 3.6 0.1 Anorgasmia (women) Percentages based on the number of women (Effexor XR, n = 2,118; placebo, n = 1,274) 2.0 0.2 Impotence (men) 5.3 1.0 Other Adverse Reactions Observed in Clinical Studies Body as a whole – Photosensitivity reaction, chills Cardiovascular system – Postural hypotension, syncope, hypotension, tachycardia Digestive system – Gastrointestinal hemorrhage [see Warnings and Precautions (5.4) ] , bruxism Hemic/Lymphatic system – Ecchymosis [see Warnings and Precautions (5.4) ] Metabolic/Nutritional – Hypercholesterolemia, weight gain [see Warnings and Precautions (5.10) ] , weight loss [see Warnings and Precautions (5.10) ] Nervous system – Seizures [see Warnings and Precautions (5.8) ] , manic reaction [see Warnings and Precautions (5.6) ] , agitation, confusion, akathisia, hallucinations, hypertonia, myoclonus, depersonalization, apathy Skin and appendages – Urticaria, pruritus, rash, alopecia Special senses – Mydriasis, abnormality of accommodation, tinnitus, taste perversion 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) 6.2 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 Effexor XR Placebo Indication ≤ 75 mg per day > 75 mg per day (Duration) SSBP SDBP SSBP SDBP SSBP SDBP MDD (8–12 weeks) -0.28 0.37 2.93 3.56 -1.08 -0.10 GAD (8 weeks) -0.28 0.02 2.40 1.68 -1.26 -0.92 (6 months) 1.27 -0.69 2.06 1.28 -1.29 -0.74 SAD (12 weeks) -0.29 -1.26 1.18 1.34 -1.96 -1.22 (6 months) -0.98 -0.49 2.51 1.96 -1.84 -0.65 PD (10–12 weeks) -1.15 0.97 -0.36 0.16 -1.29 -0.99 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 (%) MDD 75–375 19/705 (3) GAD 37.5–225 5/1011 (0.5) SAD 75–225 5/771 (0.6) PD 75–225 9/973 (0.9) 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 (5.3 , 5.4) ] . 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 MDD (12 weeks) 2 1 GAD (8 weeks) 2 < 1 SAD (12 weeks) 3 1 PD (12 weeks) 1 < 1 6.3 Laboratory Changes Serum Cholesterol 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 MDD (12 weeks) +1.5 -7.4 GAD (8 weeks) +1.0 -4.9 (6 months) +2.3 -7.7 SAD (12 weeks) +7.9 -2.9 (6 months) +5.6 -4.2 PD (12 weeks) 5.8 -3.7 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. Serum Triglycerides 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 SAD (12 weeks) 8.2 0.4 SAD (6 months) 11.8 1.8 PD (12 weeks) 5.9 0.9 PD (6 months) 9.3 0.3 6.4 Pediatric Patients 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 (5.3 , 5.10 , 5.11) and Use in Specific Populations (8.4) ] . In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed. Particularly, the following adverse reactions were observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia. 6.5 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: Body as a whole – Anaphylaxis, angioedema Cardiovascular system – QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathy Digestive system – Pancreatitis Hemic/Lymphatic system – Mucous membrane bleeding [see Warnings and Precautions (5.4 ) ] , blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia Metabolic/Nutritional – Hyponatremia [see Warnings and Precautions (5.9) ] , Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion [see Warnings and Precautions (5.9) ] , abnormal liver function tests, hepatitis, prolactin increased Musculoskeletal – Rhabdomyolysis Nervous system – Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.2) ] , serotonergic syndrome [see Warnings and Precautions (5.2) ] , delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia Respiratory system – Dyspnea, interstitial lung disease, pulmonary eosinophilia [see Warnings and Precautions (5.12) ] Skin and appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Special senses – Angle-closure glaucoma [see Warnings and Precautions (5.5) ]