Venlafaxine (Page 8 of 12)

Incidence in Controlled Trials

Commonly Observed Adverse Events in Controlled Clinical Trials

The most commonly observed adverse events associated with the use of venlafaxine tablets (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for venlafaxine tablets 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 Venlafaxine Tablets -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 venlafaxine tablets-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
1 Events reported by at least 1% of patients treated with venlafaxine tablets are included, and are rounded to the nearest %. Events for which the venlafaxine tablets 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.

Body System

Preferred Term

Venlafaxine Tablets

Placebo

(n=1033)

(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

Dose Dependency of Adverse Events

A comparison of adverse event rates in a fixed-dose study comparing venlafaxine tablets 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine tablets 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 venlafaxine tablets 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

Venlafaxine Tablets (mg/day)

Body System/

Preferred Term

Placebo

75

225

375

(n=92)

(n=89)

(n=89)

(n=88)

Body as a Whole

Abdominal pain

3.3%

3.4%

2.2%

8%

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%

4.5%

5.6%

2.3%

Digestive System

Anorexia

2.2%

14.6%

13.5%

17%

Dyspepsia

2.2%

6.7%

6.7%

4.5%

Nausea

14.1%

32.6%

38.2%

58%

Vomiting

1.1%

7.9%

3.4%

6.8%

Nervous System

Agitation

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%

26.1%

Tremor

0%

1.1%

2.2%

10.2%

Respiratory System

Yawn

0%

4.5%

5.6%

8%

Skin and Appendages

Sweating

5.4%

6.7%

12.4%

19.3%

Special Senses

Abnormality of

accommodation

0%

9.1%

7.9%

5.6%

Urogenital System

Abnormal

ejaculation/orgasm

0%

4.5%

2.2%

12.5%

Impotence

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 (e.g., dizziness and nausea), but less to other effects (e.g., abnormal ejaculation and dry mouth).

Vital Sign Changes

Venlafaxine tablets 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, venlafaxine tablets were 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 venlafaxine tablets, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with venlafaxine tablets was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL.

Patients treated with venlafaxine 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% of placebo-treated patients (see PRECAUTIONS General Serum Cholesterol Elevation).

ECG Changes

In an analysis of ECGs obtained in 769 patients treated with venlafaxine tablets and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, i.e., a mean increase from baseline of 4 beats per minute for venlafaxine tablets. 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).

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