Venlafaxine Information
Venlafaxine ()
Venlafaxine () Indications And Usage
Venlafaxine () Extended Release Tablets (Venlafaxine () hydrochloride) are indicated for the treatment of major depressive disorder (MDD).
Efficacy of Venlafaxine () in MDD was shown in both short-term trials and a longer-term trial in MDD [].
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.
Venlafaxine () Extended Release Tablets are indicated for the treatment of Social Anxiety Disorder (SAD), also known as Social Phobia, as defined in DSM-IV.
Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
Efficacy of Venlafaxine () extended release in the treatment of SAD was established in short-term SAD trials [].
Venlafaxine () Dosage And Administration
Venlafaxine () Extended Release Tablets should be administered in a single dose with food either in the morning or in the evening at approximately the same time each day. Each tablet should be swallowed whole with fluid and not divided, crushed, chewed, or placed in water.
There is no body of evidence available from controlled trials to indicate how long patients with major depressive disorder should be treated with Venlafaxine () Extended Release Tablets.
It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in which patients responding during 8 weeks of acute treatment with Venlafaxine () hydrochloride extended-release capsules were assigned randomly to placebo or to the same dose of Venlafaxine () hydrochloride extended-release capsules (75, 150, or 225 mg/day, qAM) during 26 weeks of maintenance treatment as they had received during the acute stabilization phase, longer-term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of Venlafaxine () hydrochloride immediate-release tablets 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 randomly assigned to placebo or Venlafaxine () hydrochloride immediate-release tablets for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule)[]. Based on these limited data, it is not known whether or not the dose of Venlafaxine () Extended Release Tablets needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
Venlafaxine () Dosage Forms And Strengths
Venlafaxine () Extended Release Tablets are available as:
Venlafaxine () Contraindications
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated [].
Venlafaxine () Warnings And Precautions
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 18-24) 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
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 [].
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.
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 () Extended Release Tablets are not approved for use in treating bipolar depression.
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 () Extended Release Tablets (Venlafaxine () hydrochloride) 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.
The development of a potentially life-threatening serotonin syndrome may occur with Venlafaxine () Extended Release Tablets treatment, particularly with concomitant use of serotonergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including MAOIs). 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) [].
The concomitant use of Venlafaxine () Extended Release Tablets with MAOIs intended to treat depression is contraindicated [].
If concomitant treatment of Venlafaxine () Extended Release Tablets with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [].
The concomitant use of Venlafaxine () Extended Release Tablets with serotonin precursors (such as tryptophan supplements) is not recommended [].
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 ).
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 ).
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.
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. Pre-existing 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.
Discontinuation symptoms have been systematically evaluated in patients taking Venlafaxine () , to include prospective analyses of clinical trials and retrospective surveys of trials in major depressive disorder and social anxiety 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, 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 SNRI's (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRI's (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse reactions 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 reactions are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Venlafaxine () Extended Release Tablets. 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 [].
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 other clinical studies, as shown in Table 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.
In other clinical trials, insomnia and nervousness led to drug discontinuation in 2% and 1%, respectively, of the patients treated with Venlafaxine () hydrochloride extended-release capsules up to 12 weeks.
Hyponatremia may occur as a result of treatment with SSRI's and SNRI's, including Venlafaxine () Extended Release Tablets. 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 []. Discontinuation of Venlafaxine () Extended Release Tablets 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.
SSRIs and SNRIs, including Venlafaxine () Extended Release Tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants 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 () Extended Release Tablets and NSAIDs, aspirin, or other drugs that affect coagulation.
Premarketing experience with Venlafaxine () in patients with concomitant systemic illness is limited. Caution is advised in administering Venlafaxine () Extended Release Tablets to patients with diseases or conditions that could affect hemodynamic responses.
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 as well as for 195 patients who received Venlafaxine () hydrochloride extended-release capsules and 228 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline in corrected QT interval (QTc) for patients treated with Venlafaxine () hydrochloride extended-release capsules 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 for patients treated with Venlafaxine () hydrochloride extended-release capsules in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 2.8 msec for Venlafaxine () hydrochloride extended-release capsules and decrease of 2.0 msec for placebo).
In these same trials, the mean change from baseline in heart rate for patients treated with Venlafaxine () hydrochloride extended-release capsules 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 patients treated with Venlafaxine () hydrochloride extended-release capsules in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for Venlafaxine () hydrochloride extended-release capsules and no change for placebo).
In a flexible-dose study, with doses of Venlafaxine () hydrochloride immediate-release tablets in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, patients treated with Venlafaxine () hydrochloride immediate-release tablets 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 immediate-release tablets 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.
Venlafaxine () Drug Interactions
See and
There have been reports of elevated clozapine levels that were temporally associated with adverse reactions, including seizures, following the addition of Venlafaxine () .
There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when Venlafaxine () was given to patients receiving warfarin therapy.
Venlafaxine () Use In Specific Populations
Safety and effectiveness in the pediatric population have not been established []. Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in another disorder in 793 pediatric patients have been conducted with Venlafaxine () hydrochloride extended-release capsules, and the data were not sufficient to support a claim for use in pediatric patients.
Anyone considering the use of Venlafaxine () Extended Release Tablets in a child or adolescent must balance the potential risks with the clinical need.
Although no studies have been designed to primarily assess impact of Venlafaxine () hydrochloride extended-release capsules on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that Venlafaxine () Extended Release Tablets may adversely affect weight and height []. Should the decision be made to treat a pediatric patient with Venlafaxine () Extended Release Tablets, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term. The safety of Venlafaxine () Extended Release Tablets treatment for pediatric patients has not been systematically assessed for chronic treatment longer than six months in duration.
In the studies conducted in pediatric patients (ages 6-17), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in pediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to pediatric patients [].
Approximately 4% (14/357) and 2% (6/277) of patients treated with Venlafaxine () hydrochloride extended-release capsules in placebo-controlled premarketing major depressive disorder and Social Anxiety Disorder trials, respectively, were 65 years of age or over. Of 2,897 patients treated with Venlafaxine () hydrochloride immediate-release tablets in premarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including Venlafaxine () hydrochloride extended-release capsules have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [].
The pharmacokinetics of Venlafaxine () and ODV are not substantially altered in the elderly []. No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction [].
Venlafaxine () Drug Abuse And Dependence
In vitro studies revealed that Venlafaxine () has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.
Venlafaxine () was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, Venlafaxine () showed no significant stimulant or depressant abuse liability.
Discontinuation effects have been reported in patients receiving Venlafaxine () [see and
Venlafaxine () Overdosage
Among the patients included in the premarketing evaluation of Venlafaxine () hydrochloride extended-release capsules, there were 2 reports of acute overdosage with Venlafaxine () hydrochloride extended-release capsules in major depressive disorder trials, either alone or in combination with other drugs. One patient took a combination of 6 g of Venlafaxine () hydrochloride extended-release capsules and 2.5 mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any untoward effects. The other patient took 2.85 g of Venlafaxine () hydrochloride extended-release capsules. This patient reported paresthesia of all four limbs but recovered without sequelae.
There were no reports of acute overdose with Venlafaxine () hydrochloride extended-release capsules in Social Anxiety Disorder trials.
Among the patients included in the premarketing evaluation with Venlafaxine () hydrochloride immediate-release tablets, there were 14 reports of acute overdose with Venlafaxine () , either alone or in combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which the total dose of Venlafaxine () taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of Venlafaxine () for the latter 2 patients were 6.24 and 2.35 µg/mL, respectively, and the peak plasma levels of O-desmethylVenlafaxine () were 3.37 and 1.30 µg/mL, respectively. Plasma Venlafaxine () levels were not obtained for the patient who ingested 6.75 g of Venlafaxine () . All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of Venlafaxine () was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients.
In postmarketing experience, overdose with Venlafaxine () has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported reactions in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported.
Published retrospective studies report that Venlafaxine () overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that Venlafaxine () -treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of Venlafaxine () in overdosage as opposed to some characteristic(s) of Venlafaxine () -treated patients is not clear. Prescriptions for Venlafaxine () Extended Release Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.
Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for Venlafaxine () are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the ().
Venlafaxine () Description
Venlafaxine () Extended Release Tablets (Venlafaxine () hydrochloride) are extended-release tablets for oral administration that contain Venlafaxine () hydrochloride, a structurally novel antidepressant. Venlafaxine () hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of CHNO HCl. Its molecular weight is 313.87. The structural formula is shown below.
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 () Extended Release Tablets are formulated as extended-release tablet for once-a-day oral administration. Venlafaxine () Extended Release Tablets use osmotic pressure to deliver Venlafaxine () hydrochloride at a controlled rate over approximately 24 hours. The system, which resembles a conventional tablet in appearance, comprises an osmotically active core surrounded by a semipermeable membrane. The unitary tablet core is composed of the drug and excipients (including the osmotically active components). There is a precision-laser drilled orifice in the semipermeable membrane on the side of the tablet. In an aqueous environment, such as the gastrointestinal tract, water permeates through the membrane into the tablet core, causing the drug to dissolve and the osmotic components to expand. This expansion pushes the drug out through the orifice. The semipermeable membrane controls the rate at which water permeates into the tablet core, which in turn controls the rate of drug delivery. The controlled rate of drug delivery into the gastrointestinal lumen is thus independent of pH or gastrointestinal motility. The function of Venlafaxine () Extended Release Tablets depends on the existence of an osmotic gradient between the contents of the core and the fluid in the gastrointestinal tract. Since the osmotic gradient remains constant, drug delivery remains essentially constant.
The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.
Tablets contain Venlafaxine () hydrochloride equivalent to 37.5 mg, 75 mg, 150 mg, or 225 mg Venlafaxine () . Inactive ingredients consist of mannitol, povidone, microcrystalline cellulose, polyethylene glycol, colloidal silicon dioxide, magnesium stearate, cellulose acetate, hypromellose lactose, titanium dioxide, triacetin, black iron oxide, and propylene glycol.
Venlafaxine () Clinical Studies
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 capsules 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 capsules 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 immediate-release tablets in a range of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of Venlafaxine () hydrochloride immediate-release 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 capsules 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 capsules 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 immediate-release tablets (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same dose of Venlafaxine () hydrochloride immediate-release tablets 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 treatment with Venlafaxine () hydrochloride immediate-release tablets experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.
The efficacy of Venlafaxine () hydrochloride extended-release capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in two double-blind, parallel group, 12-week, multicenter, placebo-controlled, flexible-dose studies in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. Patients received doses in a range of 75 to 225 mg/day. Efficacy was assessed with the Liebowitz Social Anxiety Scale (LSAS). In these two trials, Venlafaxine () hydrochloride extended-release capsules were significantly more effective than placebo on change from baseline to endpoint on the LSAS total score.
Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.
Venlafaxine () How Supplied/storage And Handling
Venlafaxine () Extended Release Tablets 37.5 mg are round, biconvex, white coated tablets with OS301 printed on one side. They are supplied as follows: Bottles of 100 Tablets NDC 42843-301-10 Box of single units of 100 NDC 42843-301-11
Venlafaxine () Extended Release Tablets 75 mg are round, biconvex, white coated tablets with OS302 printed on one side. They are supplied as follows: Bottles of 100 Tablets NDC 42843-302-10 Box of single units of 100 NDC 42843-302-11
Venlafaxine () Extended Release Tablets 150 mg are round, biconvex, white coated tablets with OS303 printed on one side. They are supplied as follows: Bottles of 100 Tablets NDC 42843-303-10 Box of single units of 100 NDC 42843-303-11
Venlafaxine () Extended Release Tablets 225 mg are round, biconvex, white coated tablets with OS304 printed on one side. They are supplied as follows: Bottles of 100 Tablets NDC 42843-304-10 Box of single units of 100 NDC 42843-304-11
Venlafaxine ()
Venlafaxine () Patient Counseling Information
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Venlafaxine () Extended Release Tablets and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and Other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for Venlafaxine () Extended Release Tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Venlafaxine () Extended Release Tablets.
