Prescription Drug Information: Venlafaxine Hydrochloride (Page 3 of 9)

5.11 Appetite Changes in Pediatric Patients

Decreased appetite (reported as anorexia) was more commonly observed in venlafaxine hydrochloride extended-release capsules treated patients versus placebo-treated patients in the premarketing evaluation of venlafaxine hydrochloride extended-release capsules for MDD, GAD, and SAD (see Table 6). Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

Table 6: Incidence (%) of Decreased Appetite and Associated Discontinuation Ratesa (%) in Pediatric Patientsb in Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release Capsules

Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Incidence Discontinuation Placebo Incidence Discontinuation
MDD and GAD (pooled, 8 weeks) 10 0.0 3
SAD(16 weeks) 22 0.7 3 0.0

a The discontinuation rates for weight loss were 0.7% for patients receiving either venlafaxine hydrochloride extended-release capsules or placebo.

b Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients.

5.12 Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these events should be considered in venlafaxine hydrochloride extended-release capsules-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine hydrochloride extended-release capsules should be considered.

5.13 Sexual Dysfunction

Use of SNRIs, including venlafaxine hydrochloride extended-release capsules, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of venlafaxine hydrochloride extended-release capsules and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling:
• Hypersensitivity [see Contraindications (4)]
• Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (5.1)]
• Serotonin Syndrome [see Warnings and Precautions (5.2)]
• Elevated Blood Pressure [see Warnings and Precautions (5.3)]
• Increased Risk of 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)]
• Sexual Dysfunction [see Warnings and Precautions (5.13)]

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
Most Common Adverse Reactions
The most commonly observed adverse reactions in the clinical study database in venlafaxine hydrochloride extended-release capsules 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 venlafaxine hydrochloride extended-release capsules (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 venlafaxine hydrochloride extended-release capsules 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 Venlafaxine Hydrochloride Extended-Release Capsules 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 venlafaxine hydrochloride extended-release capsules 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 (venlafaxine tablets only) and outpatient studies, fixed-dose, and titration studies.

Table 8: Patients Receiving Venlafaxine Hydrochloride Extended-Release Capsules in Premarketing Clinical Studies

Indication Venlafaxine Hydrochloride Extended-Release Capsules
MDD 705a
GAD 1,381
SAD 819
PD 1,314

a In addition, in the premarketing assessment of venlafaxine tablets, multiple doses were administered to 2,897 patients in studies for MDD.

The incidences of common adverse reactions (those that occurred in ≥2% of venlafaxine hydrochloride extended-release capsules treated patients [357 MDD patients, 1,381 GAD patients, 819 SAD patients, and 1,001 PD patients] and more frequently than placebo) in venlafaxine hydrochloride extended-release capsules 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 Venlafaxine Hydrochloride Extended-Release Capsules n = 3,558 Placebo n = 2,197
Body as a wholeAsthenia 12.6 7.8
Cardiovascular systemHypertension 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)a 9.9 0.5
Anorgasmia (men)a 3.6 0.1
Anorgasmia (women)b 2.0 0.2
Impotence (men)a 5.3 1.0

a Percentages based on the number of men (venlafaxine hydrochloride extended-release capsules, n = 1,440; placebo, n = 923)

b Percentages based on the number of women (venlafaxine hydrochloride extended-release capsules, n = 2,118; placebo, n = 1,274)

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)
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 venlafaxine hydrochloride extended-release capsules. Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the venlafaxine hydrochloride extended-release capsules 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 venlafaxine hydrochloride extended-release capsules 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

Venlafaxine Hydrochloride Extended-Release Capsules Placebo
Indication ≤75 mg per day >75 mg per day
(Duration) SSBP SDBP SSBP SDBP SSBP SDBP
MDD
(8 to 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 to 12 weeks) -1.15 0.97 -0.36 0.16 -1.29 -0.99

Venlafaxine hydrochloride extended-release capsules treatment was associated with sustained hypertension (defined as 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 venlafaxine hydrochloride extended-release capsules 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 Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies

Indication Dose Range (mg per day) Incidence (%)
MDD 75 to 375a 19/705 (3)
GAD 37.5 to 225 5/1011 (0.5)
SAD 75 to 225 5/771 (0.6)
PD 75 to 225 9/973 (0.9)

a Maximum recommended dosage for venlafaxine hydrochloride extended-release capsules is 225 mg once daily.

Venlafaxine hydrochloride extended-release capsules were 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 Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Placebo-controlled Studies (up to 12 Weeks Duration)

Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo
MDD (12 weeks) 2 1
GAD (8 weeks) 2 <1
SAD (12 weeks) 3 1
PD (12 weeks) 1 <1

Laboratory Changes
Serum Cholesterol Venlafaxine hydrochloride extended-release capsules were 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 Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies

Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo
MDD (12 weeks) +1.5 -7.4
GAD (8 weeks) (6 months) +1.0+2.3 -4.9-7.7
SAD (12 weeks) (6 months) +7.9+5.6 -2.9-4.2
PD (12 weeks) +5.8 -3.7

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. Venlafaxine hydrochloride extended-release capsules 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. Venlafaxine hydrochloride extended-release capsules 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. Venlafaxine hydrochloride extended-release capsules 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 venlafaxine tablets (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 Venlafaxine hydrochloride extended-release capsules were 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 Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies

Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules 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

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