Generic Name: venlafaxine hydrochloride
Dosage Form: capsule, extended release
VENLAFAXINE HYDROCHLORIDE EXTENDED-RELEASE CAPSULES
7384
7385
7386
Rx only
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of venlafaxine hydrochloride extended-release capsules or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients (see WARNINGS, Clinical Worsening and Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS, Pediatric Use).
Venlafaxine ER Capsules Description
Venlafaxine hydrochloride extended-release capsules for oral administration contain venlafaxine hydrochloride, a structurally novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride. The structural formula is shown below.
C17H27NO2•HCl M.W. 313.87
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.
Venlafaxine hydrochloride extended-release capsules are formulated as an extended-release capsule for once-a-day oral administration. 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 black iron oxide, dibutyl sebacate, ethylcellulose, gelatin, polyethylene glycol, povidone, propylene glycol, shellac, sugar spheres (which contain sucrose and corn starch), sunset yellow FCF FD&C yellow 6, talc, and titanium dioxide. The 37.5 mg capsules also contain D&C yellow 10 and potassium hydroxide, the 75 mg capsules also contain D&C yellow 10 and may contain potassium hydroxide, and the 150 mg capsules also contain potassium hydroxide.
Venlafaxine ER Capsules - Clinical Pharmacology
Pharmacodynamics
The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity.
Pharmacokinetics
Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; apparent elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5 ± 3.7 and 5.7 ± 1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively).
Absorption
Venlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. 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 about 45%.
Administration of venlafaxine hydrochloride extended-release capsules (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than for venlafaxine hydrochloride tablets (immediate release) [Cmax's for immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax's were 2 hours for venlafaxine and 3 hours for ODV]. 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 venlafaxine hydrochloride extended-release capsule. Venlafaxine hydrochloride extended-release capsules, therefore, provide a slower rate of absorption, but the same extent of absorption compared with the immediate release tablet.
Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg venlafaxine hydrochloride extended-release capsule.
Metabolism and Excretion
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 ("extensive metabolizers"). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent.
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%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion.
Special Populations
Age and gender
A population pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION).
Extensive/poor metabolizers
Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups.
Liver disease
In 9 subjects with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic subjects compared to normal subjects. ODV elimination half-life was prolonged by about 60%, and clearance decreased by about 30% in cirrhotic subjects compared to normal subjects. A large degree of intersubject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects.
In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired, respectively). Venlafaxine oral bioavailability was increased 2 to 3 fold, oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half, compared to normal subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%, while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted.
Dosage adjustment is necessary in these hepatically impaired patients (see DOSAGE AND ADMINISTRATION).
Renal disease
In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR = 10 to 70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56% compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION).
Clinical Trials
Major Depressive Disorder
The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for major depressive disorder was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder.
A 12 week study utilizing venlafaxine hydrochloride extended-release capsule doses in a range 75 to 150 mg/day (mean dose for completers was 136 mg/day) and an 8 week study utilizing venlafaxine hydrochloride extended-release capsule doses in a range 75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of venlafaxine hydrochloride extended-release capsules over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global Improvement item. In both studies, venlafaxine hydrochloride extended-release capsules were also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score.
A 4 week study of inpatients meeting DSM-III-R criteria for major depressive disorder with melancholia utilizing venlafaxine hydrochloride tablets (immediate release) in a range of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of venlafaxine hydrochloride tablets over placebo. The mean dose in completers was 350 mg/day.
Examination of gender subsets of the population studied did not reveal any differential responsiveness on the basis of gender.
In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who had responded during an 8 week open trial on venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg, qAM) were randomized to continuation of their same venlafaxine hydrochloride extended-release capsule dose or to placebo, for up to 26 weeks of observation for relapse. Response during the open 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 venlafaxine hydrochloride extended-release capsule treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo.
In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depressive disorder, 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 venlafaxine hydrochloride tablets (immediate release) [100 to 200 mg/day, on a b.i.d. schedule] were randomized to continuation of their same venlafaxine hydrochloride tablet 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 venlafaxine hydrochloride tablet treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.
Indications and Usage for Venlafaxine ER Capsules
Major Depressive Disorder
Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of major depressive disorder.
The efficacy of venlafaxine hydrochloride extended-release capsules in the treatment of major depressive disorder was established in 8 and 12 week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials).
A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
The efficacy of venlafaxine hydrochloride tablets (immediate release) in the treatment of major depressive disorder in adult inpatients meeting diagnostic criteria for major depressive disorder with melancholia was established in a 4 week controlled trial (see Clinical Trials). The safety and efficacy of venlafaxine hydrochloride extended-release capsules in hospitalized depressed patients have not been adequately studied.
The efficacy of venlafaxine hydrochloride extended-release capsules in maintaining a response in major depressive disorder for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of venlafaxine hydrochloride tablets (immediate release) in maintaining a response in patients with recurrent major depressive disorder who had responded and continued to be improved during an initial 26 weeks of treatment and were then followed for a period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see Clinical Trials). Nevertheless, the physician who elects to use venlafaxine hydrochloride tablets/venlafaxine hydrochloride extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Contraindications
Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS).
Warnings
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
| Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
| Increases Compared to Placebo | |
| < 18 | 14 additional cases |
| 18 to 24 | 5 additional cases |
| Decreases Compared to Placebo | |
| 25 to 64 | 1 fewer case |
| ≥ 65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS, General, Discontinuation of Treatment With Venlafaxine Hydrochloride Extended-Release Capsules and DOSAGE AND ADMINISTRATION, Discontinuing Venlafaxine Hydrochloride Extended-Release Capsules, for a description of the risks of discontinuation of venlafaxine hydrochloride extended-release capsules).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for venlafaxine hydrochloride extended-release capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.
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 venlafaxine hydrochloride extended-release capsules are 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 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 venlafaxine hydrochloride extended-release capsule treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), 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 venlafaxine hydrochloride extended-release capsules with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS, Potential for Interaction With Monoamine Oxidase Inhibitors).
If concomitant treatment of venlafaxine hydrochloride extended-release capsules 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 venlafaxine hydrochloride extended-release capsules with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions).
Treatment with venlafaxine hydrochloride extended-release capsules 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
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 tablet (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.
MDD (75 to 375 mg/day)
19/705 (3)
MDD = major depressive disorder
| 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 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).
Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in postmarketing experience. Preexisting 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 capsule-treated patients.
| ||||||
| Venlafaxine Hydrochloride Extended-Release Capsules mg/day | Placebo | |||||
| ≤ 75 | > 75 | |||||
| SSBP* | SDBP† | SSBP | SDBP | SSBP | SDBP | |
| Major Depressive Disorder | ||||||
| 8 to 12 weeks | -0.28 | 0.37 | 2.93 | 3.56 | -1.08 | -0.10 |
Across all clinical trials in MDD, 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.
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, as shown in Table 5.
| Major Depressive Disorder | ||
| Venlafaxine Hydrochloride Extended-Release Capsules | Placebo | |
| Symptom | n = 357 | n = 285 |
| Insomnia | 17% | 11% |
| Nervousness | 10% | 5% |
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.
Changes in Weight
Adult patients
A loss of 5% or more of body weight occurred in 7% of venlafaxine hydrochloride extended-release capsule-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.
The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Coadministration 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 capsules. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials, venlafaxine hydrochloride extended-release capsule-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% (18% of venlafaxine hydrochloride extended-release capsule-treated patients vs. 3.6% of placebo-treated patients; p < 0.001) (see PRECAUTIONS, General, Changes in Appetite).
The risks associated with longer-term venlafaxine hydrochloride extended-release capsule 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).
Changes in Height
Pediatric patients
During the eight-week placebo-controlled MDD studies, venlafaxine hydrochloride extended-release capsule-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 capsule-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.
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.
Activation of Mania/Hypomania
During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of venlafaxine hydrochloride extended-release capsule-treated patients and no placebo patients. 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 capsule-treated patients in the major depressive disorder studies. 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 antidepre
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