VENLAFAXINE HYDROCHLORIDE (Page 4 of 12)

Sustained Hypertension

Venlafaxine hydrochloride extended-release capsules 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 tablets (immediate release) studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine hydrochloride tablets (immediate release) (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 Capsules Premarketing Studies by Indication

MDD = major depressive disorder

MDD(75 to 375 mg/day) Panic Disorder(75 to 225 mg/day)
19/705 (3) 9/973 (0.9)
Table 3 Incidence (%) of Sustained Elevations in SDBP in Venlafaxine Hydrochloride Tablets Immediate Release Studies
Venlafaxine Hydrochloride Tablets 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 capsules-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 panic disorder studies up to 12 weeks, 0.5% (5/1001) of the venlafaxine hydrochloride extended-release capsules-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 venlafaxine hydrochloride extended-release capsules 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 changes 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 capsules-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

1 Supine Systolic Blood Pressure

2 Supine Diastolic Blood Pressure

Venlafaxine HydrochlorideExtended-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 -0.10
Panic Disorder
10 to 12 weeks -1.15 0.97 -0.36 0.16 -1.29 -0.99

Across all clinical trials 1.4% of patients in the venlafaxine hydrochloride extended-release capsules-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 capsules-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.

Mydriasis

Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients).

PRECAUTIONS

General

Discontinuation of Treatment with venlafaxine hydrochloride extended-release capsules

Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include retrospective surveys of trials in major depressive disorder. 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.

During marketing of venlafaxine hydrochloride extended-release capsules, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

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 whenever possible. 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 physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).

Insomnia and Nervousness

Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with venlafaxine hydrochloride extended-release capsules than with placebo in pooled analyses of short-term major depressive disorder, and panic disorder studies, as shown in Table 5.

Table 5 Incidence of Insomnia and Nervousness in Placebo-Controlled Major Depressive Disorder, and Panic Disorder Trials
Major Depressive Disorder Panic Disorder
Venlafaxine HydrochlorideExtended-Release Capsules Placebo Venlafaxine HydrochlorideExtended-Release Capsules Placebo
Symptom n = 357 n = 285 n = 1001 n = 662
Insomnia 17% 11% 17% 9%
Nervousness 10% 5% 4% 6%

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with venlafaxine hydrochloride extended-release capsules in major depressive disorder studies.

In panic disorder trials, insomnia and nervousness led to drug discontinuation in 1% and 0.1%, respectively, of the patients treated with venlafaxine hydrochloride extended-release capsules up to 12 weeks.

Changes in Weight

Adult Patients: A loss of 5% or more of body weight occurred in 7% of venlafaxine hydrochloride extended-release capsules-treated and 2% of placebo-treated patients in the short-term placebo-controlled major depressive disorder trials. The discontinuation rate for weight loss associated with venlafaxine hydrochloride extended-release capsules was 0.1% in major depressive disorder studies. In placebo-controlled panic disorder trials, 3% of the venlafaxine hydrochloride extended-release capsules-treated and 2% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 12 weeks of treatment. None of the patients receiving venlafaxine hydrochloride extended-release capsules in panic disorder studies discontinued for weight loss.

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine hydrochloride extended-release capsules and weight loss agents is not recommended. Venlafaxine hydrochloride extended-release capsules are not indicated for weight loss alone or in combination with other products.

Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6 to 17) receiving venlafaxine hydrochloride extended-release capsule. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD), venlafaxine hydrochloride extended-release capsules-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with venlafaxine hydrochloride extended-release capsules than with placebo experienced a weight loss of at least 3.5% in the MDD studies (18% of venlafaxine hydrochloride extended-release capsules-treated patients vs. 3.6% of placebo-treated patients; p<0.001).

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 capsule 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).

Changes in Height

Pediatric Patients: During the eight-week placebo-controlled MDD studies, venlafaxine hydrochloride extended-release capsules-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147). 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 growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old).

Changes in Appetite

Adult Patients: Treatment-emergent anorexia was more commonly reported for venlafaxine hydrochloride extended-release capsules-treated (8%) than placebo-treated patients (4%) in the pool of short-term, double-blind, placebo-controlled major depressive disorder studies. The discontinuation rate for anorexia associated with venlafaxine hydrochloride extended-release capsules was 1.0% in major depressive disorder studies. Treatment-emergent anorexia was more commonly reported for venlafaxine hydrochloride extended-release capsules-treated (8%) than placebo-treated patients (3%) in the pool of short-term, double-blind, placebo-controlled panic disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving venlafaxine hydrochloride extended-release capsules for up to 12 weeks in panic disorder studies.

Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving venlafaxine hydrochloride extended-release capsules. In the placebo-controlled trials for MDD, 10% of patients aged 6 to 17 treated with venlafaxine hydrochloride extended-release capsules for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving venlafaxine hydrochloride extended-release capsules discontinued for anorexia or weight loss. The discontinuation rates for anorexia were 0.7% and 0.0% for patients receiving venlafaxine hydrochloride extended-release capsule and placebo, respectively; the discontinuation rates for weight loss were 0.7% for patients receiving either venlafaxine hydrochloride extended-release capsules or placebo.

Activation of Mania/Hypomania

During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of venlafaxine hydrochloride extended-release capsules-treated patients and no placebo patients. In premarketing panic disorder studies, 0.1% of venlafaxine hydrochloride extended-release capsules-treated patients and no placebo-treated patients experienced mania or hypomania. In all premarketing major depressive disorder trials with venlafaxine hydrochloride tablets (immediate release), mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with no placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, venlafaxine hydrochloride extended-release capsules should be used cautiously in patients with a history of mania.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including venlafaxine hydrochloride extended-release capsules. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS, Geriatric Use). Discontinuation of venlafaxine hydrochloride extended-release capsules should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

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.

Seizures

During premarketing experience, no seizures occurred among 705 venlafaxine hydrochloride extended-release capsules-treated patients in the major depressive disorder studies. In panic disorder studies, 1 seizure occurred among 1,001 venlafaxine hydrochloride extended-release capsules-treated patients. In all premarketing major depressive disorder trials with venlafaxine hydrochloride tablets (immediate release), seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Venlafaxine hydrochloride extended-release capsules, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures.

Abnormal Bleeding

SSRIs and SNRIs, including venlafaxine hydrochloride extended-release capsules, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants 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. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of venlafaxine hydrochloride extended-release capsules and NSAIDs, aspirin, or other drugs that affect coagulation.

Serum Cholesterol Elevation

Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials (see ADVERSE REACTIONS-Laboratory Changes). Measurement of serum cholesterol levels should be considered during long-term treatment.

Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered.

Use in Patients With Concomitant Illness

Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering venlafaxine hydrochloride extended-release capsules to patients with diseases or conditions that could affect hemodynamic responses or metabolism.

Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine’s premarketing testing. The electrocardiograms were analyzed for 275 patients who received venlafaxine hydrochloride extended-release capsules and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major depressive disorder, and for 661 patients who received venlafaxine hydrochloride extended-release capsules and 395 patients who received placebo in three 10- to 12-week double-blind, placebo-controlled trials in panic disorder. The mean change from baseline in corrected QT interval (QTc) for venlafaxine hydrochloride extended-release capsules-treated patients in major depressive disorder studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine hydrochloride extended-release capsules and decrease of 1.9 msec for placebo). The mean change from baseline in QTc interval for venlafaxine hydrochloride extended-release capsules-treated patients in the panic disorder studies was increased relative to that for placebo-treated patients (increase of 1.5 msec for venlafaxine hydrochloride extended-release capsules and decrease of 0.7 msec for placebo).

In these same trials, the mean change from baseline in heart rate for venlafaxine hydrochloride extended-release capsules-treated patients in the major depressive disorder studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for venlafaxine hydrochloride extended-release capsules and 1 beat per minute for placebo). The mean change from baseline in heart rate for venlafaxine hydrochloride extended-release capsules-treated patients in the panic disorder studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for venlafaxine hydrochloride extended-release capsules and a mean decrease of less than 1 beat per minute for placebo).

In a flexible-dose study, with venlafaxine hydrochloride tablets (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, venlafaxine hydrochloride tablets-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group.

As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction).

Evaluation of the electrocardiograms for 769 patients who received venlafaxine hydrochloride tablets (immediate release) in 4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial- emergent conduction abnormalities did not differ from that with placebo.

In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see DOSAGE AND ADMINISTRATION). Venlafaxine hydrochloride extended-release capsules, like all drugs effective in the treatment of major depressive disorder, should be used with caution in such patients.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.