Venlafaxine Hydrochloride (Page 5 of 12)

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 venlafaxine 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 0.2

Common Adverse Reactions in Placebo-controlled Studies The number of patients receiving multiple doses of venlafaxine hydrochloride extended-release capsuels 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 hydrochloride only) and outpatient studies, fixed-dose, and titration studies.

T able 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 hydrochloride, 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

B ody System Adverse Reaction Venlafaxine Hydrochloride Extended-Release Capsules n = 3,558 P l acebo n = 2,197
Body as a whole
Asthenia 12.6 7.8
Cardiovascular system
Hypertension 3.4 2.6
Palpitation 2.2 2
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 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
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 0.2
Impotence (men)a 5.3 1

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

B ody as a whole – Photosensitivity reaction, chills

C ardiovascular system – Postural hypotension, syncope, hypotension, tachycardia

D i gestive 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

S kin and appendages – Urticaria, pruritus, rash, alopecia

S pecial senses – Mydriasis, abnormality of accommodation, tinnitus, taste perversion

U rogenital 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 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 were 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 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 extended-release Premarketing Studies

Indication D ose Range (mg per day) Incidence (%)
MDD 75 to 375 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)

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

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

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