Venlafaxine (Page 8 of 12)

Labor and Delivery

The effect of venlafaxine tablets on labor and delivery in humans is unknown.

Nursing Mothers

Venlafaxine and ODV have been reported to be excreted in humanmilk. Because of the potential for serious adverse reactions in nursing infants from venlafaxine tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have been conducted with venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support a claim for use in pediatric patients.

Anyone considering the use of venlafaxine tablets in a child or adolescent must balance the potential risks with the clinical need.

Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-release capsule’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that venlafaxine hydrochloride extended-release capsules may adversely affect weight and height (see PRECAUTIONS , General, Changes in Height and Changes in Weight). Should the decision be made to treat a pediatric patient with venlafaxine tablets, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of venlafaxine hydrochloride extended-release capsules treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration.

In the studies conducted in pediatric patients (ages 6 to 17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients (see WARNINGS, Sustained Hypertension, and PRECAUTIONS, General, Serum Cholesterol Elevation).

Geriatric Use

Of the 2,897 patients in Phase 2 and Phase 3 depression studies with venlafaxine tablets, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including venlafaxine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).

The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

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 (i.e., those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included:

CNS Venlafaxine Placebo

* Percentages based on the number of males.

— Less than 1%

Somnolence 3% 1%
Insomnia 3% 1%
Dizziness 3%
Nervousness 2%
Dry mouth 2%
Anxiety 2% 1%
Gastrointestinal
Nausea 6% 1%
Urogenital
Abnormal 3%
ejaculation *
Other
Headache 3% 1%
Asthenia 2%
Sweating 2%

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 Trials 1

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 dysmenorrhea 3.

— 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 $NoTableFooter $NoFootNote
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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