Venlafaxine Hydrochloride (Page 3 of 12)

5.2 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including venlafaxine hydrochloride extended-release tablets, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, busipirone, amphetamines, and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of venlafaxine hydrochloride extended-release tablets with MAOIs intended to treat psychiatric disorders is contraindicated. Venlafaxine hydrochloride extended-release tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking venlafaxine hydrochloride extended-release tablets. Venlafaxine hydrochloride extended-release tablets should be discontinued before initiating treatment with the MAOI. [see CONTRAINDICATIONS (4.1) and DOSAGE AND ADMINISTRATION (2.6 and 2.7)].

If concomitant use of venlafaxine hydrochloride extended-release tablets with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort is clinically warranted, patients should be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with venlafaxine hydrochloride extended-release tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.3 Sustained Hypertension

Venlafaxine hydrochloride extended-release capsule 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 venlafaxine hydrochloride immediate-release tablet studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for immediate-release venlafaxine hydrochloride (see Table 3).

An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsules 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 Venlafaxine Hydrochloride Extended-Release Capsule Premarketing Studies by Indication

Major Depressive Disorder (75 to 375 mg/day) Other Clinical Trials (75 to 225 mg/day)
19/705 (3) 5/771 (0.6)

Table 3: Incidence (%) of Sustained Elevations in SDBP in Venlafaxine Hydrochloride Immediate-Release Tablet Studies

Venlafaxine 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 venlafaxine hydrochloride extended-release capsule-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 other clinical studies, 0.6% (5/771) of the venlafaxine hydrochloride extended-release capsule-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1 to 24 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. Preexisting hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine hydrochloride extended-release tablets 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.

Elevations in Systolic and Diastolic Blood Pressure

In placebo-controlled premarketing studies, there were changes in mean blood pressure (see Table 4 for mean change in supine systolic and supine diastolic blood pressure). Across most indications, a dose-related increase in supine systolic and diastolic blood pressure was evident in venlafaxine hydrochloride extended-release capsule-treated patients.

Table 4: Final On-Therapy Mean Changes from Baseline in Supine Systolic and Diastolic Blood Pressure (mm Hg) Results by Indication, Study Duration, and Dose in Placebo-Controlled Trials

Venlafaxine Hydrochloride Extended-Release Capsules mg/day Placebo
≤75 >75
SSBP1 SDBP2 SSBP SDBP SSBP SDBP
Major Depressive Disorder 8 to 12 weeks -0.28 0.37 2.93 3.56 -1.08 -0.1
Other Clinical Trials 12 weeks -0.29 -1.26 1.18 1.34 -1.96 -1.22

1 Supine Systolic Blood Pressure

2 Supine Diastolic Blood Pressure

Across all clinical trials, 1.4% of patients in the venlafaxine hydrochloride extended-release capsule-treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure with blood pressure ≥105 mm Hg compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine hydrochloride extended-release capsule-treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure with blood pressure ≥180 mm Hg compared to 0.3% of patients in the placebo groups.

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