Effexor Xr (Venlafaxine Hydrochloride)

Warnings and Precautions (

Effexor XR is indicated in adults for the treatment of:

• •Major Depressive Disorder (MDD)
  [see

  14.1 Major Depressive Disorder

  The efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for Major Depressive Disorder (MDD) was established in two placebo-controlled, short-term (8 weeks for study 1; 12 weeks for study 2), flexible-dose studies, with doses starting at 75 mg per day and ranging to 225 mg per day in adult outpatients meeting DSM-III-R or DSM-IV criteria for MDD. In moderately depressed outpatients, the initial dose of venlafaxine was 75 mg per day. In both studies, Effexor XR demonstrated superiority over placebo on the primary efficacy measure defined as change from baseline in the HAM-D-21 total score to the endpoint visit, Effexor XR also demonstrated superiority over placebo on the key secondary efficacy endpoint, the Clinical Global Impressions (CGI) Severity of Illness scale. Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

  A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizing Effexor in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule) demonstrated superiority of Effexor over placebo based on the HAM-D-21 total score. The mean dose in completers was 350 mg per day (study 3).

  In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label study on Effexor XR (75, 150, or 225 mg, once daily every morning) 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-label 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 ≥4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illness item score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving continued Effexor XR treatment experienced statistically significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo (study 4).

  In a second longer term trial, adult outpatients with MDD, 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 ≥20; (2) no more than 2 HAM-D-21 total scores >10, and (3) no single CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks of treatment on Effexor [100 to 200 mg per day, on a twice daily 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 ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment experienced statistically significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo (study 5).

  Table 18: Primary Efficacy Results for Studies in Major Depressive Disorder in Adults (Studies 1, 2, 3)

  Study Number	Treatment Group		Primary Efficacy Measure: HAM-D Score
  		Mean Baseline Score (SD)	LS Mean Change from Baseline	Placebo Subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95%CI)
  SD=standard deviation; LS Mean=least-squares mean; CI=confidence interval.
  Study 1	Effexor (XR 75-225 mg/day)Doses statistically significantly superior to placebo.	24.5	-11.7	-4.45 (-6.66, -2.25)
  	Placebo	23.6	-7.24	-
  Study 2	Effexor (XR 75-225 mg/day)	24.5	-15.11	-6.40 (-8.45, -4.34)
  	Placebo	24.9	-8.71
  Study 3	Effexor (IR 150-375 mg/day)	28.2 (0.5)	-14.9	-10.2 (-14.4, -6.0)
  	Placebo	28.6 (0.6)	-4.7	-

  ]
• •Generalized Anxiety Disorder (GAD)
  [see

  14.2 Generalized Anxiety Disorder

  The efficacy of Effexor XR as a treatment for Generalized Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one 6-month, placebo-controlled, fixed-dose study (37.5, 75, and 150 mg per day) in adult outpatients meeting DSM-IV criteria for GAD.

  In one 8-week study, Effexor XR demonstrated superiority over placebo for the 75, 150, and 225 mg per day doses as measured by the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global Impressions (CGI) scale. However, the 75 and 150 mg per day doses were not as consistently effective as the highest dose (study 1). A second 8-week study evaluating doses of 75 and 150 mg per day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg per day dose was more consistently effective than the 150 mg per day dose (study 2). A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225 mg per day dose range studied.

  Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg per day (study 3) and the other evaluating Effexor XR doses of 75 to 225 mg per day (study 4), showed that daily doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo for the 37.5 mg per day dose, this dose was not as consistently effective as the higher doses.

  Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.

  Table 19: Primary Efficacy Results for Studies in Generalized Anxiety Disorder in Adults (Studies 1, 2, 3, 4)

  Study Number	Treatment Group	Primary Efficacy Measure: HAM-A Score
  		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE) Doses statistically significantly superior to placebo.	Placebo Subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI)
  SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval.
  Study 1	Ven XR 75 mg	24.7	-11.1 (0.95)	-1.5 (-3.8, 0.8)
  	Ven XR 150 mg	24.5	-11.7 (0.87)	-2.2 (-4.5, 0.1)
  	Ven XR 225 mg	23.6	-12.1 (0.81)	-2.6 (-4.9, -0.3)
  	Placebo	24.1	-9.5 (0.85)
  Study 2	Ven XR 75 mg	23.7	-10.6 (0.82)	-2.6 (-4.6, -0.5)
  	Ven XR 150 mg	23.0	-9.8 (0.86)	-1.7 (-3.8, 0.3)
  	Placebo	23.7	-8.0 (0.73)
  Study 3	Ven XR 37.5 mg	26.6 (0.4)	-13.8	-2.8 (-5.1, -0.6)
  	Ven XR 75 mg	26.3 (0.4)	-15.5	-4.6 (-6.9, -2.3)
  	Ven XR150 mg	26.3 (0.4)	-16.4	-5.5 (-7.8, -3.1)
  	Placebo	26.7 (0.5)	-11.0
  Study 4	Ven XR 75-225 mg	25.0	-13.4 (0.79)	-4.7 (-6.6, -2.9)
  	Placebo	24.9	-8.7 (0.70)

  ]
• •Social Anxiety Disorder (SAD)
  [see

  14.3 Social Anxiety Disorder (Also Known as Social Phobia)

  The efficacy of Effexor XR as a treatment for Social Anxiety Disorder (SAD) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies (studies 1-4) and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study, which included doses in a range of 75 to 225 mg per day in adult outpatients meeting DSM-IV criteria for SAD (study 5).

  In these five studies, Effexor XR was statistically significantly more effective than placebo on change from baseline to endpoint on the Liebowitz Social Anxiety Scale (LSAS) total score. There was no evidence for any greater effectiveness of the 150 to 225 mg per day group compared to the 75 mg per day group in the 6-month study.

  Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.

  Table 20: Primary Efficacy Results for Studies in Social Anxiety Disorder in Adults (Studies 1, 2, 3, 4, 5)

  Study Number	Treatment Group	Primary Efficacy Measure: LSAS Score
  		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo Subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI)
  SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=confidence interval.
  Study 1	Ven XR (75-225 mg)Doses statistically significantly superior to placebo.	91.1	-31.0 (2.22)	11.2 (-5.3, -17.1)
  	Placebo	86.7	-19.9 (2.22)	-
  Study 2	Ven XR (75-225 mg)	90.8	-32.8 (2.69)	-10.7 (-3.7, -17.6)
  	Placebo	87.4	-22.1 (2.66)	-
  Study 3	Ven XR (75-225 mg)	83.2	-36.0 (2.35)	-16.9 (-22.6, -11.2)
  	Placebo	83.6	-19.1 (2.40)	-12.7 (-6.5, -19.0)
  Study 4	Ven XR (75-225 mg)	86.2	-35.0 (2.64)	-14.6 (-21.8, -7.4)
  	Placebo	86.1	-22.2 (2.47)
  Study 5	Ven XR 75 mg	91.8	-38.1 (3.16)	-14.6 (-21.8, -7.4)
  	Ven XR (150-225 mg)	86.2	-37.6 (3.05)	-14.1 (-21.3, -6.9)
  	Placebo	89.3	-23.5 (3.08)

  ]
• •Panic Disorder (PD)
  [see

  14.4 Panic Disorder

  The efficacy of Effexor XR as a treatment for Panic Disorder (PD) was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients meeting DSM-IV criteria for PD, with or without agoraphobia. Patients received fixed doses of 75 or 150 mg per day in one study (study 1) and 75 or 225 mg per day in the other study (study 2).

  Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of patients rated as responders (much improved or very much improved) on the Clinical Global Impressions (CGI) Improvement scale. In these two studies, Effexor XR was statistically significantly more effective than placebo (for each fixed dose) on all three endpoints, but a dose-response relationship was not clearly established.

  Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.

  In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD who had responded during a 12-week open phase with Effexor XR (75 to 225 mg per day) were randomly assigned to continue the same Effexor XR dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as determined by the investigators during the study. Randomized patients were in response status for a mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-label period, patients receiving continued Effexor XR experienced a statistically significantly longer time to relapse.

  Table 21: Primary Efficacy Results for Studies in Panic Disorder in Adults (Studies 1 and 2)

  Study Treatment Group Number		Primary Efficacy Measure: Whether Free of Full-symptom Panic Attacks
  		Percent of Patients Free of Full Symptom Panic Attack	Adjusted Odds Ratio Odds ratio (drug to placebo) in terms of probability of free of full-symptom panic attacks based on logistic regression model. 95% CI: 95% confidence interval without adjusting for multiple dose arms. to Placebo	Adjusted Odds Ratio 95% Confidence Interval
  Study 1	Ven XR 75 mgDoses statistically significantly superior to placebo. Ven XR 150 mg Placebo	54.1% (85/157) 61.4% (97/158) 34.4% (53/154)	2.268 3.035 --	(1.43, 3.59) (1.91, 4.82) --
  Study 2	Ven XR 75 mg Ven XR 225 mg Placebo	64.1% (100/156) 70.0% (112/160) 46.5% (73/157)	2.350 2.890 --	(1.46, 3.78) (1.80, 4.64) --

  ]

• •Take once daily with food. Capsules should be taken whole; do not divide, crush, chew, or dissolve (
  2.1 General Administration Information

  Administer Effexor XR as a single dose with food, either in the morning or in the evening at approximately the same time each day

  [see Clinical Pharmacology (12.3)]

  . Swallow capsules whole with fluid. Do not divide, crush, chew, or place in water.

  The capsule may also be administered by carefully opening the capsule and sprinkling the entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately without chewing and followed with a glass of water to ensure complete swallowing of the pellets (spheroids).
  ).
• •When discontinuing treatment, reduce the dose gradually (
  2.10 Discontinuing Treatment with Effexor XR

  A gradual reduction in the dose, rather than abrupt cessation, is recommended when discontinuing therapy with Effexor XR. In clinical studies with Effexor XR, tapering was achieved by reducing the daily dose by 75 mg at one-week intervals. Individualization of tapering may be necessary. In some patients, discontinuation may need to occur over a period of several months

  [see

  Warnings and Precautions (5.7)

  ]

  .
  ,
  5.7 Discontinuation Syndrome

  Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD and SAD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock‑like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.

  There have been postmarketing reports of serious discontinuation symptoms which can be protracted and severe. Completed suicide, suicidal thoughts, aggression and violent behavior have been observed in patients during reduction in Effexor XR dosage, including during discontinuation. Other postmarketing reports describe visual changes (such as blurred vision or trouble focusing) and increased blood pressure after stopping or reducing the dose of Effexor XR.

  During marketing of Effexor XR, other SNRIs, and SSRIs, there have been reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: irritability, lethargy, emotional lability, tinnitus, and seizures.

  Patients should be monitored for these symptoms when discontinuing treatment with Effexor XR. A gradual reduction in the dose, rather than abrupt cessation, is recommended. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months

  [see Dosage and Administration (2.10)]

  .
  ).
• •Renal impairment: reduce the total daily dose by 25% to 50% in patients with renal impairment. Reduce the total daily dose by 50% or more in patients undergoing dialysis or with severe renal impairment (
  2.9 Dosage Recommendations for Patients with Renal Impairment

  Reduce the Effexor XR total daily dose by 25% to 50% in patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. Reduce the total daily dose by 50% or more in patients undergoing hemodialysis or with severe renal impairment (CLcr <30 mL/min). Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage is recommended in some patients

  [see Use in Specific Populations (8.7)]

  .
  ).
• •Hepatic impairment: reduce the daily dose by 50% in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment or hepatic cirrhosis, it may be necessary to reduce the dose by more than 50% (
  2.8 Dosage Recommendations for Patients with Hepatic Impairment

  Reduce the Effexor XR total daily dose by 50% in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. Reduce the total daily dose by 50% or more in patients with severe hepatic impairment (Child-Pugh Class C) or hepatic cirrhosis

  [see Use in Specific Populations (8.6)]

  .
  ).

Effexor XR^® is available in the following strengths:

• •37.5 mg extended-release capsule: grey cap and peach body with “W” and “Effexor XR” on the cap and “37.5” on the body
• •75 mg extended-release capsule: peach cap and body with “W” and “Effexor XR” on the cap and “75” on the body
• •150 mg extended-release capsule: dark orange cap and body with “W” and “Effexor XR” on the cap and “150” on the body