Effexor XR (Page 4 of 15)

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use in treating bipolar depression.

Potential for Interaction with Monoamine Oxidase Inhibitors

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, because venlafaxine is an inhibitor of both norepinephrine and serotonin reuptake, it is recommended that Effexor XR (venlafaxine hydrochloride) extended-release capsules not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting an MAOI.

Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions

The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Effexor XR treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs, eg, methylene blue), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms [e.g., nausea, vomiting, diarrhea] (see PRECAUTIONS, Drug Interactions). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

The concomitant use of Effexor XR with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS, Potential for Interaction with Monoamine Oxidase Inhibitors).

If concomitant treatment of Effexor XR with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions).

The concomitant use of Effexor XR with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions).

Treatment with Effexor XR and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Sustained Hypertension

Effexor XR treatment is associated with sustained hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits (see Table 2).

An analysis for patients in Effexor (immediate release) studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for Effexor (immediate release) (see Table 3).

An insufficient number of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

Table 2 Number (%) of Sustained Elevations in SDBP in Effexor XR Premarketing Studies by Indication
MDD = major depressive disorder

GAD = generalized anxiety disorder

MDD(75-375 mg/day) GAD(37.5-225 mg/day) Social Anxiety Disorder(75-225 mg/day) Panic Disorder(75-225 mg/day)
19/705 (3) 5/1011 (0.5) 5/771 (0.6) 9/973 (0.9)
Table 3 Incidence (%) of Sustained Elevations in SDBP in Effexor Immediate Release Studies
Effexor mg/day Incidence
<100 3%
>100 to ≤200 5%
>200 to ≤300 7%
>300 13%

In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 6 months, 0.6% (5/771) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1-24 mm Hg, SDBP). In premarketing panic disorder studies up to 12 weeks, 0.5% (5/1001) of the Effexor XR-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were in a modest range (7 to 19 mm Hg, SDBP).

Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving Effexor XR have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered.

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