Get your patient on 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

  [seeClinical 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

  [seeDosage 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

  [seeUse 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

  [seeUse 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

Effexor XR is contraindicated in patients:

• •with known hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation
  [see

  6.2 Postmarketing Experience

  The following adverse reactions have been identified during post-approval use of Effexor XR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  Body as a Whole

  – Anaphylaxis, angioedema

  Cardiovascular System

  – QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), takotsubo cardiomyopathy

  Digestive System

  – Pancreatitis

  Hemic/Lymphatic System

  – Mucous membrane bleeding

  [see

  Warnings and Precautions (5.4)

  ]

  , blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged bleeding time, thrombocytopenia

  Metabolic/Nutritional

  – Hyponatremia

  [see

  Warnings and Precautions (5.9)

  ]

  , Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion

  [see

  Warnings and Precautions (5.9)

  ]

  , abnormal liver function tests, hepatitis, prolactin increased

  Musculoskeletal

  – Rhabdomyolysis

  Nervous System

  – Neuroleptic Malignant Syndrome (NMS)

  [seeWarnings and Precautions (5.2)]

  , serotonergic syndrome

  [seeWarnings and Precautions (5.2)]

  , delirium, extrapyramidal reactions (including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia

  Respiratory, Thoracic and Mediastinal Disorders –

  Anosmia, dyspnea, hyposmia, interstitial lung disease, pulmonary eosinophilia

  [see

  Warnings and Precautions (5.12)

  ]

  Skin and Appendages

  – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

  Special Senses

  – Angle-closure glaucoma

  [see

  Warnings and Precautions (5.5)

  ]

  ]
  .
• •taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of the risk of serotonin syndrome
  [see

  2.11 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

  At least 14 days must elapse between discontinuation of an MAOI antidepressant and initiation of Effexor XR. In addition, at least 7 days must elapse after stopping Effexor XR before starting an MAOI antidepressant

  [seeContraindications (4),Warnings and Precautions (5.2), andDrug Interactions (7.1)]

  .

  ,

  5.2 Serotonin Syndrome

  Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Effexor XR, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs

  [seeContraindications (4),Drug Interactions (7.1)]

  . Serotonin syndrome can also occur when these drugs are used alone.

  Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

  The concomitant use of Effexor XR with MAOIs is contraindicated. In addition, do not initiate Effexor XR in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor XR, discontinue Effexor XR before initiating treatment with the MAOI

  [seeContraindications (4),Drug Interactions (7.1)]

  .

  Monitor all patients taking Effexor XR for the emergence of serotonin syndrome. Discontinue treatment with Effexor XR and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Effexor XR with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

  , and

  7.1 Drugs Having Clinically Important Interactions with Effexor XR

  Table 15: Clinically Important Drug Interactions with Effexor XR

  Monoamine Oxidase Inhibitors (MAOI)
  Clinical Impact	The concomitant use of SNRIs, including Effexor XR, with MAOIs increases the risk of serotonin syndrome.
  Intervention	Concomitant use of Effexor XR is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [seeDosage and Administration (2.11),Contraindications (4)andWarnings and Precautions (5.2)].
  Other Serotonergic Drugs
  Clinical Impact	Concomitant use of Effexor XR with other serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome.
  Intervention	Monitor for symptoms of serotonin syndrome when Effexor XR is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of Effexor XR and/or concomitant serotonergic drugs [seeDosage and Administration (2.11)andWarnings and Precautions (5.2)].
  Drugs that Interfere with Hemostasis
  Clinical Impact	Concomitant use of Effexor XR with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of Effexor XR on the release of serotonin by platelets.
  Intervention	Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when Effexor XR is initiated or discontinued [see Warnings and Precautions (5.4) ] .
  Effect of CYP3A Inhibitors
  Clinical Impact	Concomitant use of a CYP3A inhibitor increases the Cmaxand AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [seeClinical Pharmacology (12.3)] , which may increase the risk of toxicity of Effexor XR.
  Intervention	Consider reducing the dose of Effexor XR.
  CYP2D6 Substrates
  Clinical Impact	Concomitant use of Effexor XR increases Cmaxand AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [seeClinical Pharmacology (12.3)] .
  Intervention	Consider reduction in dose of concomitant CYP2D6 substrates.

  ]
  .

• •
  Serotonin Syndrome:
   Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue Effexor XR and serotonergic agents and initiate supportive treatment (
  4 CONTRAINDICATIONS

  Effexor XR is contraindicated in patients:

  • •with known hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation
    [seeAdverse Reactions (6.2)]
    .
  • •taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of the risk of serotonin syndrome
    [seeDosage and Administration (2.11),Warnings and Precautions (5.2), andDrug Interactions (7.1)]
    .

  • •Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in the Effexor XR formulation (4).
  • •Concomitant use of monoaminoxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI (4,5.2,7.1).
  ,
  5.2 Serotonin Syndrome

  Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Effexor XR, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs

  [seeContraindications (4),Drug Interactions (7.1)]

  . Serotonin syndrome can also occur when these drugs are used alone.

  Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

  The concomitant use of Effexor XR with MAOIs is contraindicated. In addition, do not initiate Effexor XR in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor XR, discontinue Effexor XR before initiating treatment with the MAOI

  [seeContraindications (4),Drug Interactions (7.1)]

  .

  Monitor all patients taking Effexor XR for the emergence of serotonin syndrome. Discontinue treatment with Effexor XR and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Effexor XR with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
  ,
  7.1 Drugs Having Clinically Important Interactions with Effexor XR

  Table 15: Clinically Important Drug Interactions with Effexor XR

  Monoamine Oxidase Inhibitors (MAOI)
  Clinical Impact	The concomitant use of SNRIs, including Effexor XR, with MAOIs increases the risk of serotonin syndrome.
  Intervention	Concomitant use of Effexor XR is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [seeDosage and Administration (2.11),Contraindications (4)andWarnings and Precautions (5.2)].
  Other Serotonergic Drugs
  Clinical Impact	Concomitant use of Effexor XR with other serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome.
  Intervention	Monitor for symptoms of serotonin syndrome when Effexor XR is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of Effexor XR and/or concomitant serotonergic drugs [seeDosage and Administration (2.11)andWarnings and Precautions (5.2)].
  Drugs that Interfere with Hemostasis
  Clinical Impact	Concomitant use of Effexor XR with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of Effexor XR on the release of serotonin by platelets.
  Intervention	Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when Effexor XR is initiated or discontinued [see Warnings and Precautions (5.4) ] .
  Effect of CYP3A Inhibitors
  Clinical Impact	Concomitant use of a CYP3A inhibitor increases the Cmaxand AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [seeClinical Pharmacology (12.3)] , which may increase the risk of toxicity of Effexor XR.
  Intervention	Consider reducing the dose of Effexor XR.
  CYP2D6 Substrates
  Clinical Impact	Concomitant use of Effexor XR increases Cmaxand AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [seeClinical Pharmacology (12.3)] .
  Intervention	Consider reduction in dose of concomitant CYP2D6 substrates.
  ).
• •
  Elevated Blood Pressure:
   Control hypertension before initiating treatment. Monitor blood pressure regularly during treatment (
  5.3 Elevated Blood Pressure

  In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension

  [seeAdverse Reactions (6.1)].

  Monitor blood pressure before initiating treatment with Effexor XR and regularly during treatment. Control pre-existing hypertension before initiating treatment with Effexor XR. Use caution in treating patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of elevated blood pressure requiring immediate treatment have been reported with Effexor XR. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure.

  Across all clinical studies with Effexor, 1.4% of patients in the Effexor XR treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure (SDBP) ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Effexor XR treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups

  [seeAdverse Reactions (6.1)]

  . Treatment with Effexor XR was associated with sustained hypertension defined as SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits

  [seeAdverse Reactions (6.1)]

  . An insufficient number of patients received mean doses of Effexor XR over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.
  ).
• •
  Increased Risk of Bleeding:
   Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other anticoagulants may increase risk (
  5.4 Increased Risk of Bleeding

  Drugs that interfere with serotonin reuptake inhibition, including Effexor XR, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti‑coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case‑control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage

  [seeUse in Specific Populations (8.1)]

  .

  Inform patients about the increased risk of bleeding associated with the concomitant use of Effexor XR and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Effexor XR

  .
  ).
• •
  Angle‑Closure Glaucoma:
   
  Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles, treated with antidepressants (
  5.5 Angle-Closure Glaucoma

  The pupillary dilation that occurs following use of many antidepressant drugs including Effexor XR may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Effexor XR, in patients with untreated anatomically narrow angles.
  ).
• •
  Activation of Mania or Hypomania:
   Screen patients for bipolar disorder (
  5.6 Activation of Mania or Hypomania

  In patients with bipolar disorder, treating a depressive episode with Effexor XR or another antidepressant may precipitate a mixed/manic episode. Mania or hypomania was reported in Effexor XR treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Prior to initiating treatment with Effexor XR, screen for any personal or family history of bipolar disorder, mania, or hypomania.

  Table 2: Incidence (%) of Mania or Hypomania Reported in Effexor XR Treated Patients in the Premarketing Studies

  Indication	Effexor XR	Placebo
  MDD	0.3	0.0
  GAD	0.0	0.2
  SAD	0.2	0.0
  PD	0.1	0.0
  ).
• •
  Discontinuation Syndrome:
   Taper dose and monitor for discontinuation symptoms (
  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

  [seeDosage and Administration (2.10)]

  .
  ).
• •
  Seizures:
   
  Can occur. Use cautiously in patients with seizure disorder (
  5.8 Seizures

  Cases of seizure have been reported with venlafaxine therapy. Effexor XR has not been systematically evaluated in patients with seizure disorder. Effexor XR should be prescribed with caution in patients with a seizure disorder.
  ).
• •
  Hyponatremia:
   
  Can occur in association with SIADH (
  5.9 Hyponatremia

  Hyponatremia can occur as a result of treatment with SNRIs, including Effexor XR. In many cases, the hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk

  [seeUse in Specific Populations (8.5)andClinical Pharmacology (12.3)]

  . Consider discontinuation of Effexor XR in patients with symptomatic hyponatremia, and institute appropriate medical intervention.

  Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
  ).
• •
  Interstitial Lung Disease and Eosinophilic Pneumonia:
   
  Can occur (
  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 Effexor XR‑treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of Effexor XR should be considered.
  ).
• •
  Sexual Dysfunction:
   Effexor XR may cause symptoms of sexual dysfunction (
  5.13 Sexual Dysfunction

  Use of SNRIs, including Effexor XR, may cause symptoms of sexual dysfunction

  [seeAdverse 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 Effexor XR 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.
  ).

The following adverse reactions are discussed in more detail in other sections of the labeling:

• •Hypersensitivity
  [see

  4 CONTRAINDICATIONS

  Effexor XR is contraindicated in patients:

  • •with known hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation
    [seeAdverse Reactions (6.2)]
    .
  • •taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of the risk of serotonin syndrome
    [seeDosage and Administration (2.11),Warnings and Precautions (5.2), andDrug Interactions (7.1)]
    .

  • •Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in the Effexor XR formulation (4).
  • •Concomitant use of monoaminoxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI (4,5.2,7.1).

  ]
• •Suicidal Thoughts and Behaviors in Adolescents and Young Adults
  [see

  5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

  In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.

  Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in PediatricEffexor XR is not approved in pediatric patients.and Adult Patients

  Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated
  	Increases Compared to Placebo
  <18 years old	14 additional patients
  18-24 years old	5 additional patients
  	Decreases Compared to Placebo
  25-64 years old	1 fewer patient
  ≥65 years old	6 fewer patients

  It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

  Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Effexor XR, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

  ]
• •Serotonin Syndrome
  [see

  5.2 Serotonin Syndrome

  Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Effexor XR, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs

  [seeContraindications (4),Drug Interactions (7.1)]

  . Serotonin syndrome can also occur when these drugs are used alone.

  Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

  The concomitant use of Effexor XR with MAOIs is contraindicated. In addition, do not initiate Effexor XR in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor XR, discontinue Effexor XR before initiating treatment with the MAOI

  [seeContraindications (4),Drug Interactions (7.1)]

  .

  Monitor all patients taking Effexor XR for the emergence of serotonin syndrome. Discontinue treatment with Effexor XR and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Effexor XR with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

  ]
• •Elevated Blood Pressure
  [see
  5.3 Elevated Blood Pressure

  In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well as cases of sustained hypertension

  [seeAdverse Reactions (6.1)].

  Monitor blood pressure before initiating treatment with Effexor XR and regularly during treatment. Control pre-existing hypertension before initiating treatment with Effexor XR. Use caution in treating patients with pre-existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of elevated blood pressure requiring immediate treatment have been reported with Effexor XR. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure.

  Across all clinical studies with Effexor, 1.4% of patients in the Effexor XR treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure (SDBP) ≥105 mm Hg, compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the Effexor XR treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥180 mm Hg, compared to 0.3% of patients in the placebo groups

  [seeAdverse Reactions (6.1)]

  . Treatment with Effexor XR was associated with sustained hypertension defined as SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits

  [seeAdverse Reactions (6.1)]

  . An insufficient number of patients received mean doses of Effexor XR over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.
  ]
• •Increased Risk of Bleeding
  [see
  5.4 Increased Risk of Bleeding

  Drugs that interfere with serotonin reuptake inhibition, including Effexor XR, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti‑coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case‑control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage

  [seeUse in Specific Populations (8.1)]

  .

  Inform patients about the increased risk of bleeding associated with the concomitant use of Effexor XR and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Effexor XR

  .
  ]
• •Angle-Closure Glaucoma
  [see
  5.5 Angle-Closure Glaucoma

  The pupillary dilation that occurs following use of many antidepressant drugs including Effexor XR may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Effexor XR, in patients with untreated anatomically narrow angles.
  ]
• •Activation of Mania/Hypomania
  [see
  5.6 Activation of Mania or Hypomania

  In patients with bipolar disorder, treating a depressive episode with Effexor XR or another antidepressant may precipitate a mixed/manic episode. Mania or hypomania was reported in Effexor XR treated patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Prior to initiating treatment with Effexor XR, screen for any personal or family history of bipolar disorder, mania, or hypomania.

  Table 2: Incidence (%) of Mania or Hypomania Reported in Effexor XR Treated Patients in the Premarketing Studies

  Indication	Effexor XR	Placebo
  MDD	0.3	0.0
  GAD	0.0	0.2
  SAD	0.2	0.0
  PD	0.1	0.0
  ]
• •Discontinuation Syndrome
  [see
  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

  [seeDosage and Administration (2.10)]

  .
  ]
• •Seizure
  [see
  5.8 Seizures

  Cases of seizure have been reported with venlafaxine therapy. Effexor XR has not been systematically evaluated in patients with seizure disorder. Effexor XR should be prescribed with caution in patients with a seizure disorder.
  ]
• •Hyponatremia
  [see
  5.9 Hyponatremia

  Hyponatremia can occur as a result of treatment with SNRIs, including Effexor XR. In many cases, the hyponatremia appears to be the result of the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs. Also, patients taking diuretics, or those who are otherwise volume-depleted, may be at greater risk

  [seeUse in Specific Populations (8.5)andClinical Pharmacology (12.3)]

  . Consider discontinuation of Effexor XR in patients with symptomatic hyponatremia, and institute appropriate medical intervention.

  Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
  ]
• •Weight and Height Changes in Pediatric Patients
  [see
  5.10 Weight and Height Changes in Pediatric Patients

  Weight Changes

  The average change in body weight and incidence of weight loss (percentage of patients who lost 3.5% or more) in the placebo-controlled pediatric studies in MDD, GAD, and SAD are shown in Tables 3 and 4.

  Table 3: Average Change in Body Weight (kg) From Beginning of Treatment in Pediatric PatientsEffexor XR is not approved for use in pediatric patients.in Double-blind, Placebo-controlled Studies of Effexor XR

  Indication (Duration)	Effexor XR	Placebo
  MDD and GAD (4 pooled studies, 8 weeks)	-0.45 (n = 333)	+0.77 (n = 333)
  SAD (16 weeks)	-0.75 (n = 137)	+0.76 (n = 148)

  Table 4: Incidence (%) of Pediatric PatientsEffexor XR is not approved for use in pediatric patients.Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Effexor XR

  Indication (Duration)	Effexor XR	Placebo
  MDD and GAD (4 pooled studies, 8 weeks)	18p <0.001 versus placebo(n = 333)	3.6 (n = 333)
  SAD (16 weeks)	47 (n = 137)	14 (n = 148)

  Weight loss was not limited to patients with anorexia

  [see

  Warnings and Precautions (5.11)

  ]

  .

  The risks associated with longer term Effexor XR use were assessed in an open-label MDD study of children and adolescents who received Effexor XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected, based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old).

  Effexor XR is not approved for use in pediatric patients

  [Use in Specific Populations (8.4)]

  .

  Height Changes

  Table 5 shows the average height increase in pediatric patients in the short‑term, placebo-controlled MDD, GAD, and SAD studies. The differences in height increases in GAD and MDD studies were most notable in patients younger than 12 years old.

  Table 5: Average Height Increases (cm) in Pediatric PatientsEffexor XR is not approved for use in pediatric patients.in Placebo-controlled Studies of Effexor XR

  Indication (Duration)	Effexor XR	Placebo
  MDD (8 weeks)	0.8 (n = 146)	0.7 (n = 147)
  GAD (8 weeks)	0.3p = 0.041(n = 122)	1.0 (n = 132)
  SAD (16 weeks)	1.0 (n = 109)	1.0 (n = 112)

  In the six-month, open-label MDD study, children and adolescents had height increases that were less than expected, based on data from age- and sex-matched peers. The difference between observed and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old)

  [seeUse in Specific Populations (8.4)]

  .
  ]
• •Appetite Changes in Pediatric Patients
  [see
  5.11 Appetite Changes in Pediatric Patients

  Decreased appetite (reported as anorexia) was more commonly observed in Effexor XR treated patients versus placebo-treated patients in the premarketing evaluation of Effexor XR for MDD, GAD, and SAD (see Table 6).

  Effexor XR is not approved for use in pediatric patients

  [

  seeUse in Specific Populations (8.4)]

  .

  Table 6: Incidence (%) of Decreased Appetite and Associated Discontinuation RatesThe discontinuation rates for weight loss were 0.7% for patients receiving either Effexor XR or placebo.(%) in Pediatric PatientsEffexor XR is not approved for use in pediatric patients.in Placebo-controlled Studies of Effexor XR

  Indication	Effexor XR		Placebo
  (Duration)	Incidence	Discontinuation	Incidence	Discontinuation
  MDD and GAD (pooled, 8 weeks)	10	0.0	3	–
  SAD (16 weeks)	22	0.7	3	0.0
  ]
• •Interstitial Lung Disease and Eosinophilic Pneumonia
  [see
  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 Effexor XR‑treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of Effexor XR should be considered.
  ]
• •Sexual Dysfunction
  [see
  5.13 Sexual Dysfunction

  Use of SNRIs, including Effexor XR, may cause symptoms of sexual dysfunction

  [seeAdverse 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 Effexor XR 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.
  ]

ODV=O-desmethylvenlafaxine; AUC=area under the curve; C_max=peak plasma concentrations.

^*Similar effect is expected with strong CYP2D6 inhibitors.

Drug Interaction Studies

Clinical Studies

Effect of Other Drugs on Effexor XR and Active Metabolite ODV

The effects of other drugs on the exposure of venlafaxine and ODV are summarized in Figure 2.

ODV=O-desmethylvenlafaxine; AUC=area under the curve; C_max=peak plasma concentrations; EM’s=extensive metabolizers; PM’s=poor metabolizers.

The effects of Effexor XR on the exposure of other drugs are summarized in Figure 3.

AUC=area under the curve; C_max=peak plasma concentrations; OH=hydroxyl.

^*Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for C_maxand AUC of 2-OH desipramine were 6.6 (5.5, 7.9) and 4.4 (3.8, 5.0), respectively.

ODV=O-desmethylvenlafaxine; AUC=area under the curve; C_max=peak plasma concentrations.

^*Similar effect is expected with strong CYP2D6 inhibitors.

Drug Interaction Studies

Clinical Studies

Effect of Other Drugs on Effexor XR and Active Metabolite ODV

The effects of other drugs on the exposure of venlafaxine and ODV are summarized in Figure 2.

ODV=O-desmethylvenlafaxine; AUC=area under the curve; C_max=peak plasma concentrations; EM’s=extensive metabolizers; PM’s=poor metabolizers.

The effects of Effexor XR on the exposure of other drugs are summarized in Figure 3.

AUC=area under the curve; C_max=peak plasma concentrations; OH=hydroxyl.

^*Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for C_maxand AUC of 2-OH desipramine were 6.6 (5.5, 7.9) and 4.4 (3.8, 5.0), respectively.

Table 15: Clinically Important Drug Interactions with Effexor XR

•

•

•

•

Figure 1: Pharmacokinetics of Venlafaxine and Active Metabolite O-desmethylvenlafaxine (ODV) in Special Populations

Figure 2: Effect of Other Drugs on the Pharmacokinetics of Venlafaxine and Active Metabolite O‑desmethylvenlafaxine (ODV)

Figure 3: Effect of Venlafaxine on the Pharmacokinetics of Interacting Drugs and their Active Metabolites

Figure 1: Pharmacokinetics of Venlafaxine and Active Metabolite O-desmethylvenlafaxine (ODV) in Special Populations

Figure 2: Effect of Other Drugs on the Pharmacokinetics of Venlafaxine and Active Metabolite O‑desmethylvenlafaxine (ODV)

Figure 3: Effect of Venlafaxine on the Pharmacokinetics of Interacting Drugs and their Active Metabolites

Monoamine Oxidase Inhibitors (MAOI)
Clinical Impact	The concomitant use of SNRIs, including Effexor XR, with MAOIs increases the risk of serotonin syndrome.
Intervention	Concomitant use of Effexor XR is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see 2.11 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days must elapse between discontinuation of an MAOI antidepressant and initiation of Effexor XR. In addition, at least 7 days must elapse after stopping Effexor XR before starting an MAOI antidepressant [seeContraindications (4),Warnings and Precautions (5.2), andDrug Interactions (7.1)] . , 4 CONTRAINDICATIONS Effexor XR is contraindicated in patients:
Other Serotonergic Drugs
Clinical Impact	Concomitant use of Effexor XR with other serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome.
Intervention	Monitor for symptoms of serotonin syndrome when Effexor XR is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of Effexor XR and/or concomitant serotonergic drugs [see 2.11 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days must elapse between discontinuation of an MAOI antidepressant and initiation of Effexor XR. In addition, at least 7 days must elapse after stopping Effexor XR before starting an MAOI antidepressant [seeContraindications (4),Warnings and Precautions (5.2), andDrug Interactions (7.1)] . and 5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Effexor XR, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [seeContraindications (4),Drug Interactions (7.1)] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Effexor XR with MAOIs is contraindicated. In addition, do not initiate Effexor XR in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Effexor XR, discontinue Effexor XR before initiating treatment with the MAOI [seeContraindications (4),Drug Interactions (7.1)] . Monitor all patients taking Effexor XR for the emergence of serotonin syndrome. Discontinue treatment with Effexor XR and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Effexor XR with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. ].
Drugs that Interfere with Hemostasis
Clinical Impact	Concomitant use of Effexor XR with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of Effexor XR on the release of serotonin by platelets.
Intervention	Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when Effexor XR is initiated or discontinued [see 5.4 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including Effexor XR, may increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), warfarin, and other anti‑coagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case‑control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [seeUse in Specific Populations (8.1)] . Inform patients about the increased risk of bleeding associated with the concomitant use of Effexor XR and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing Effexor XR . ] .
Effect of CYP3A Inhibitors
Clinical Impact	Concomitant use of a CYP3A inhibitor increases the Cmax and AUC of venlafaxine and O-desmethylvenlafaxine (ODV) [see 12.3 Pharmacokinetics Venlafaxine and ODV steady-state concentrations are reached within 3 days. Venlafaxine and ODV exhibited linear kinetics over the dosage range of 75 to 450 mg per day (0.33 to 2 times the maximum recommended dosage). Time of administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. Absorption Venlafaxine is well absorbed. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is approximately 45%. Administration of Effexor XR (150 mg once daily) generally resulted in lower Cmaxand later Tmaxvalues than for Effexor administered twice daily (Table 17). When equal daily doses of venlafaxine were administered as either an immediate-release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Therefore, Effexor XR provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Table 17: Comparison of Cmaxand TmaxValues for Venlafaxine and ODV Following Oral Administration of Effexor XR and Effexor (Immediate-Release) Venlafaxine ODV Cmax (ng/mL) Tmax (h) Cmax (ng/mL) Tmax (h) Effexor XR (150 mg once daily) 150 5.5 260 9 Effexor (75 mg twice daily) 225 2 290 3 Effect of Food Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Distribution Venlafaxine is 27% and ODV is 30% bound to plasma proteins. The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV. Elimination Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV. The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. Metabolism Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (poor metabolizers) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 levels (extensive metabolizers) (see Figure 1). Excretion Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of venlafaxine and its active metabolite ODV is presented in Figure 1.
Intervention	Consider reducing the dose of Effexor XR.
CYP2D6 Substrates
Clinical Impact	Concomitant use of Effexor XR increases Cmax and AUC of a CYP2D6 substrate, which may increase the risk of toxicity of the CYP2D6 substrate [see 12.3 Pharmacokinetics Venlafaxine and ODV steady-state concentrations are reached within 3 days. Venlafaxine and ODV exhibited linear kinetics over the dosage range of 75 to 450 mg per day (0.33 to 2 times the maximum recommended dosage). Time of administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg Effexor XR capsule. Absorption Venlafaxine is well absorbed. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is approximately 45%. Administration of Effexor XR (150 mg once daily) generally resulted in lower Cmaxand later Tmaxvalues than for Effexor administered twice daily (Table 17). When equal daily doses of venlafaxine were administered as either an immediate-release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with the Effexor XR capsule. Therefore, Effexor XR provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Table 17: Comparison of Cmaxand TmaxValues for Venlafaxine and ODV Following Oral Administration of Effexor XR and Effexor (Immediate-Release) Venlafaxine ODV Cmax (ng/mL) Tmax (h) Cmax (ng/mL) Tmax (h) Effexor XR (150 mg once daily) 150 5.5 260 9 Effexor (75 mg twice daily) 225 2 290 3 Effect of Food Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Distribution Venlafaxine is 27% and ODV is 30% bound to plasma proteins. The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV. Elimination Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV. The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV. Metabolism Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (poor metabolizers) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 levels (extensive metabolizers) (see Figure 1). Excretion Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Specific Populations The effect of intrinsic patient factors on the pharmacokinetics of venlafaxine and its active metabolite ODV is presented in Figure 1.
Intervention	Consider reduction in dose of concomitant CYP2D6 substrates.

Effexor XR is an extended-release capsule for once-a-day oral administration that contains venlafaxine hydrochloride, a serotonin and norepinephrine reuptake inhibitor (SNRI).

Venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C₁₇H₂₇NO₂ HCl. Its molecular weight is 313.86. The structural formula is shown as follows:

Venlafaxine hydrochloride is a white to off-white crystalline solid, with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium chloride) partition coefficient is 0.43.

Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH-dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or 150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

The mechanism of action of venlafaxine in the treatment of MDD, GAD, SAD, and PD is unclear, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake.

Tumors were not increased by venlafaxine treatment in mice or rats. Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose on a mg/m² basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of the ODV were lower in rats than in patients receiving the maximum recommended dose. ODV, the major human metabolite of venlafaxine, administered by oral gavage to mice and rats for 2 years did not increase the incidence of tumors in either study. Mice received ODV at dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The exposure at the 300 mg/kg/day dose is 9 times that of a human dose of 225 mg/day. Rats received ODV at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The exposure at the highest dose is approximately 8 (males) or 11 (females) times that of a human dose of 225 mg/day.

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).

Effexor XR^® is available as:

• •37.5 mg, grey cap/peach body with “W” and “Effexor XR” on the cap and “37.5” on the body.
  
  NDC 58151-125-93, bottle of 30 capsules in unit-of-use package.
  
   
  
  NDC 58151-125-77, bottle of 90 capsules in unit-of-use package.
• •75 mg, peach cap and body with “W” and “Effexor XR” on the cap and “75” on the body.
  
  NDC 58151-126-93, bottle of 30 capsules in unit-of-use package.
  
   
  
  NDC 58151-126-77, bottle of 90 capsules in unit-of-use package.
• •150 mg, dark orange cap and body with “W” and “Effexor XR” on the cap and “150” on the body.
  
  NDC 58151-127-93, bottle of 30 capsules in unit-of-use package.
  
   
  
  NDC 58151-127-77, bottle of 90 capsules in unit-of-use package.

Store at controlled room temperature, 20° to 25°C (68° to 77°F).

The mechanism of action of venlafaxine in the treatment of MDD, GAD, SAD, and PD is unclear, but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake.