Prescription Drug Information: Venlafaxine Hydrochloride (Page 2 of 9)

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 [see Adverse Reactions (6.1)].
Monitor blood pressure before initiating treatment with venlafaxine hydrochloride extended-release capsules and regularly during treatment. Control pre-existing hypertension before initiating treatment with venlafaxine hydrochloride extended-release capsules. 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 venlafaxine hydrochloride extended-release capsules. Consider dose reduction or discontinuation of treatment for patients who experience a sustained increase in blood pressure. Across all clinical studies with venlafaxine tablets, 1.4% of patients in the venlafaxine hydrochloride extended-release capsules 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 venlafaxine hydrochloride extended-release capsules 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 [see Adverse Reactions (6.1)]. Treatment with venlafaxine hydrochloride extended-release capsules was associated with sustained hypertension defined as SDBP ≥90 mm Hg and ≥10 mm Hg above baseline for three consecutive on-therapy visits [see Adverse Reactions (6.1)]. An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release capsules over 300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

5.4 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including venlafaxine hydrochloride extended-release capsules, 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 [see Use in Specific Populations (8.1)]. Inform patients about the increased risk of bleeding associated with the concomitant use of venlafaxine hydrochloride extended-release capsules 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 venlafaxine hydrochloride extended-release capsules.

5.5 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including venlafaxine hydrochloride extended-release capsules 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 venlafaxine hydrochloride extended-release capsules, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania or Hypomania

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

Table 2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine Hydrochloride Extended-Release Capsules Treated Patients in the Premarketing Studies

Indication Venlafaxine Hydrochloride Extended-Release Capsules Placebo
MDD 0.3 0.0
GAD 0.0 0.2
SAD 0.2 0.0
PD 0.1 0.0

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 venlafaxine hydrochloride extended-release capsules 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 venlafaxine hydrochloride extended-release capsules.

During marketing of venlafaxine hydrochloride extended-release capsules, 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 venlafaxine hydrochloride extended-release capsules. A gradual reduction in the dose, rather than abrupt cessation, is recommended. If intolerable symptoms occur following a decrease in the dose or upon

discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose, but at a more gradual rate. In some patients, discontinuation may need to occur over a period of several months [see Dosage and Administration (2.10)].

5.8 Seizures

Cases of seizure have been reported with venlafaxine therapy. Venlafaxine hydrochloride extended-release capsules have not been systematically evaluated in patients with seizure disorder. Venlafaxine hydrochloride extended-release capsules should be prescribed with caution in patients with a seizure disorder.

5.9 Hyponatremia

Hyponatremia can occur as a result of treatment with SNRIs, including venlafaxine hydrochloride extended-release capsules. 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 [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Consider discontinuation of venlafaxine hydrochloride extended-release capsules 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.

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 Patientsa in Double-blind, Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release Capsules

Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules 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)

a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients.

Table 4: Incidence (%) of Pediatric Patientsa Experiencing Weight Loss (3.5% or more) in Double-blind, Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release Capsules

Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo
MDD and GAD(4 pooled studies, 8 weeks) 18b (n = 333) 3.6 (n = 333)
SAD(16 weeks) 47b (n = 137) 14 (n = 148)

a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients.

b p <0.001 versus placebo

Weight loss was not limited to patients with anorexia [see Warnings and Precautions (5.11)].
The risks associated with longer term venlafaxine hydrochloride extended-release capsules use were assessed in an open-label MDD study of children and adolescents who received venlafaxine hydrochloride extended-release capsules 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).
Venlafaxine hydrochloride extended-release capsules are 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 Patientsa in Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release Capsules

Indication (Duration) Venlafaxine Hydrochloride Extended-Release Capsules Placebo
MDD (8 weeks) 0.8 (n = 146) 0.7 (n = 147)
GAD (8 weeks) 0.3b (n = 122) 1.0 (n = 132)
SAD (16 weeks) 1.0 (n = 109) 1.0 (n = 112)

a Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients.

b p = 0.041

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) [see Use in Specific Populations (8.4)].

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