CLINICAL TRIALS

The efficacy of Effexor (venlafaxine hydrochloride) tablets as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score),Hamilton depressed mood item, and Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day.

While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open phase was defined as a CGI Severity of Illness item score of <3 and a HAM-D-21 total score of £10 at the day 56 evaluation. Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ³4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ³4, or (3) a final CGI Severity of Illness item score of ³4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo.

In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression, recurrent type, who had responded (HAM-D-21 total score £12 at the day 56 evaluation) and continued to be improved [defined as the following criteria being met for days 56 through 180: (1) no HAM-D-21 total score ³20; (2) no more than 2 HAM-D-21 total scores >10; and (3) no single CGI Severity of Illness item score ³4 (moderately ill)] during an initial 26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ³4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.

SIDE EFFECTS

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 ³1%) associated with discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included: