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EFFEXOR® XR (venlafaxine HCl) Adverse Reactions

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

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
*
In addition, in the premarketing assessment of Effexor, multiple doses were administered to 2,897 patients in studies for MDD.
MDD 705*
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
*
Percentages based on the number of men (Effexor XR, n = 1,440; placebo, n = 923)
Percentages based on the number of women (Effexor XR, n = 2,118; placebo, n = 1,274)
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)* 9.9 0.5
  Anorgasmia (men)* 3.6 0.1
  Anorgasmia (women) 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)]

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