displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5
Suicidality and Antidepressant Drugs
displayName: BOXED WARNING SECTION
FDA Article Code: 34066-1
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 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 any 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 is not approved for use in pediatric patients. (See
WARNINGS: Clinical Worsening and Suicide Risk
PRECAUTIONS: Information for Patients
PRECAUTIONS: Pediatric Use
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3
Venlafaxine hydrochloride (HCl), USP is a structurally novel antidepressant for oral administration. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87.
The structural formula is shown below.
Venlafaxine HCl, USP 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.
Compressed tablets contain venlafaxine HCl, USP equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine. Inactive ingredients consist of anhydrous lactose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose,and sodium starch glycolate.
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1
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, histaminergic, or α-1 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.
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 dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV.
The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected.
Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens.
Age and Gender
A 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 due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION).
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).
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).
The efficacy of venlafaxine HCl as a treatment for major depressive disorder was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with venlafaxine HCl in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed venlafaxine HCl doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of adult inpatients meeting DSM-III-R criteria for major depression with melancholia whose venlafaxine HCl doses were titrated in a range of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, venlafaxine HCl was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day.
While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2/3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
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 HCl extended-release (75, 150, or 225 mg, qAM) were randomized to continuation of their same venlafaxine HCl extended-release 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 Tablets 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 depression, 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 HCl (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same venlafaxine HCl 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 HCl treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.
INDICATIONS AND USAGE
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9
Venlafaxine tablets, USP are indicated for the treatment of major depressive disorder.
The efficacy of Venlafaxine Hydrochloride Tablets in the treatment of major depressive disorder was established in 6-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
The efficacy of venlafaxine HCl extended-release capsules in maintaining an antidepressant response for up to 26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Venlafaxine tablets, USP immediate-release in maintaining an antidepressant response in patients with recurrent depression 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 tablets, USP immediate-release/venlafaxine HCl extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3
Hypersensitivity to venlafaxine HCl, USP or to any excipients in the formulation.
The use of MAOIs intended to treat psychiatric disorders with venlafaxine HCl, USP or within 7 days of stopping treatment with venlafaxine HCl, USP is contraindicated because of an increased risk of serotonin syndrome. The use of venlafaxine HCl, USP within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and
DOSAGE AND ADMINISTRATION
Starting venlafaxine HCl, USP in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndromeMAOI (see WARNINGS and DOSAGE AND ADMINISTRATION
displayName: WARNINGS SECTION
FDA Article Code: 34071-1
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.
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 and DOSAGE AND ADMINISTRATION
, Discontinuation of Treatment with venlafaxine HCl, for a description of the risks of discontinuation of venlafaxine HCl).
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 HCl should be written for the smallest quantity of tablets 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 HCl are not approved for use in treating bipolar depression.
||Drug-Placebo Difference in Number of Case of Suicidality per 1000 Patients
||Increases Compared to Placebo
||14 additional cases
|18 to 24
||5 additional cases
||Decreases Compared to Placebo
|25 to 64
||1 fewer case
||6 fewer cases
The development of a potentially life-threatening serotonin syndrome have been reported with SNRIs and SSRIs, including venlafaxine HCl, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort) with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea, vomiting diarrhea) Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of venlafaxine HCl with MAOIs intended to treat psychiatric disorders is contraindicated. Venlafaxine HCl should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking venlafaxine HCl. Venlafaxine HCl should be discontinued before initiating treatment with the MAOI (see
CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of venlafaxine HCl with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk of serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with venlafaxine HCl and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Venlafaxine treatment is associated with sustained increases in blood pressure in some patients. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine:
An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude 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 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.
Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored (see PRECAUTIONS, Information for Patients).
|Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies)
||Incidence of Sustained
Elevation in SDBP
|< 100 mg/day
|101 to 200 mg/day
|201 to 300 mg/day
|> 300 mg/day
displayName: PRECAUTIONS SECTION
FDA Article Code: 42232-9
Discontinuation of Treatment with Venlafaxine HCl
Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in Generalized Anxiety Disorder and 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 HCl, 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 HCl. 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).
Anxiety and Insomnia
Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short-term, double-blind, placebo-controlled depression studies:
Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depression studies.
DRUG ABUSE AND DEPENDENCE
displayName: DRUG ABUSE AND DEPENDENCE SECTION
FDA Article Code: 42227-9
Controlled Substance Class
Venlafaxine Hydrochloride Tablets are not a controlled substance.
Physical and Psychological 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 DOSAGE AND ADMINISTRATION).
While venlafaxine HCl has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine HCl (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5
There were 14 reports of acute overdose with venlafaxine HCl, either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of venlafaxine HCl 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 mcg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 mcg/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 events 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 HCl should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Management of Overdosage
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 Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATION
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7
The recommended starting dose for venlafaxine tablets, USP is 75 mg/day, administered in two or three divided doses, taken with food. Depending on tolerability and the need for further clinical effect, the dose may be increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day for moderately depressed patients, but more severely depressed inpatients responded to a mean dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant Illness).
Treatment of Pregnant Women During the Third Trimester
Neonates exposed to venlafaxine tablets, USP, other SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with venlafaxine tablets, USP during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Dosage for Patients with Hepatic Impairment
Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients.
Dosage for Patients with Renal Impairment
Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR=10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients.
Dosage for Elderly Patients
No dose adjustment is recommended for elderly patients on the basis of age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.
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 HCI extended-release capsules were assigned randomly to placebo or to the same dose of venlafaxine HCI 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 tablets, USP immediate-release in maintaining an antidepressant response in patients with recurrent depression who had responded and continued to be improved during an initial 26 weeks of treatment and were then randomly assigned to placebo or venlafaxine tablets,USP immediate-release for periods of up to 52 weeks on the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known whether or not the dose of venlafaxine tablets,USP immediate-release/ venlafaxine HCI extended-release capsules 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.
Discontinuing Venlafaxine Tablets, USP
Symptoms associated with discontinuation of venlafaxine tablets, USP, other SNRIs, and SSRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. 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.
Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders:
At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with venlafaxine tablets, USP. In addition, at least 7 days should be allowed after stopping Venlafaxine Hydrochloride Tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).
Use of Venlafaxine Tablets, USP With Other MAOIs, Such as Linezolid or Methylene Blue: Do not start venlafaxine tablets, USP in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving therapy with venlafaxine tablets, USP may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, venlafaxine tablets, USP should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with venlafaxine tablets, USP may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with venlafaxine tablets, USP is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5
Venlafaxine tablets, USP, 25 mg, are supplied as light orange, round deep convex tablets debossed “IP” bisect “301” on one side. It is available as follows:
Bottles of 90: NDC 42291-892-90
Venlafaxine tablets, USP, 37.5 mg, are supplied as light orange, round deep convex tablets debossed “IP” bisect “302” on one side. It is available as follows:
Bottles of 90: NDC 42291-893-90
Venlafaxine tablets, USP, 50 mg, are supplied as light orange, circular tablets debossed “IP” bisect “303” on one side. It is available as: Bottles of 90:
Venlafaxine tablets, USP, 75 mg, are supplied as light orange, oval tablets debossed “IP” bisect “304” on one side. It is available as:
Bottles of 90: NDC 42291-895-90
Repackaged by Aphena Pharma Solutions – TN.
for available configurations.
Bottles of 500: NDC 42291-895-50
Venlafaxine tablets, USP, 100 mg, are supplied as light orange, oval tablets debossed “IP” bisect “305” on one side. It is available as:
Bottles of 90: NDC 42291-896-90
Bottles of 500: NDC 42291-896-50
Store at 20 to 25°C (68 to 77 °F) [see USP Controlled Room Temperature] in a dry place.
Dispense in a well-closed container as defined in the USP.
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5
Pulaski, TN 38478
Mfg. Rev. 11/13
AV Rev. 01/14 (P)
Venlafaxine Tablets, USP
Read the Medication Guide that comes with venlafaxine HCl before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.
What is the most important information I should know about venlafaxine HCl?
Venlafaxine HCl and other antidepressant medicines may cause serious side effects, including:
1. Suicidal thoughts or actions:
• Venlafaxine HCl and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.
• Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
• Watch for these changes and call your healthcare provider right away if you notice:
• New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
• Pay particular attention to such changes when venlafaxine HCl is started or when the dose is changed.
Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.
Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:
• attempts to commit suicide
Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Venlafaxine HCl may be associated with these serious side effects:
• acting on dangerous impulses
• acting aggressive or violent
• thoughts about suicide or dying
• new or worse depression
• new or worse anxiety or panic attacks
• feeling agitated, restless, angry or irritable
• trouble sleeping
• an increase in activity or talking more than what is normal for you
• other unusual changes in behavior or mood
2. Serotonin Syndrome
This condition can be life-threatening and may include:
• agitation, hallucinations, coma or other changes in mental status
3. Changes in blood pressure.
• coordination problems or muscle twitching (overactive reflexes)
• racing heartbeat, high or low blood pressure
• sweating or fever
• nausea, vomiting, or diarrhea
• muscle rigidity
Venlafaxine HCl may:
• increase your blood pressure. Control high blood pressure before starting treatment and monitor blood pressure regularly
4. Enlarged pupils (mydriasis).
5. Anxiety and insomnia.
6. Changes in appetite or weight.
• children and adolescents should have height and weight monitored during treatment
7. Manic/hypomanic episodes:
• greatly increased energy
• severe trouble sleeping
• racing thoughts
• reckless behavior
• unusually grand ideas
• excessive happiness or irritability
• talking more or faster than usual
8. Low salt (sodium) levels in the blood.
Elderly people may be at greater risk for this. Symptoms may include:
10.Abnormal bleeding: Venlafaxine HCl and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin®, Jantoven®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.
• weakness or feeling unsteady
• confusion, problems concentrating or thinking or memory problems
12.Lung disease and pneumonia: Venlafaxine HCl may cause rare lung problems. Symptoms include:
13.Severe allergic reactions:
• worsening shortness of breath
• chest discomfort
• trouble breathing
• swelling of the face, tongue, eyes or mouth
• rash, itchy welts (hives) or blisters, alone or with fever or joint pain
Do not stop venlafaxine HCl without first talking to your healthcare provider. Stopping venlafaxine HCl too quickly or changing from another antidepressant too quickly may cause serious symptoms including:
What is venlafaxine HCl?
• anxiety, irritability
• feeling tired, restless or problems sleeping
• headache, sweating, dizziness
• electric shock-like sensations, shaking, confusion, nightmares
• vomiting, nausea, diarrhea
Venlafaxine HCl is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.
Talk to your healthcare provider if you do not think that your condition is getting better with venlafaxine HCl treatment.
Who should not take venlafaxine HCl?
What should I tell my healthcare provider before taking venlafaxine HCl? Ask if you are not sure.
Do not take venlafaxine HCl if you:
• are allergic to venlafaxine HCl or any of the ingredients in venlafaxine HCl tablets. See the end of this Medication Guide for a complete list of ingredients in venlafaxine HCl tablets.
• have uncontrolled narrow-angle glaucoma
• take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
• Do not take an MAOI within 7 days of stopping venlafaxine HCl unless directed to do so by your physician.
• Do not start venlafaxine HCl if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.
People who take venlafaxine HCl close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:
• high fever
• uncontrolled muscle spasms
• stiff muscles
• rapid changes in heart rate or blood pressure
• loss of consciousness (pass out)
Before starting venlafaxine HCl, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Venlafaxine HCl and some medicines may interact with each other, may not work as well, or may cause serious side effects.
• Are taking certain drugs such as:
• Medicines used to treat migraine headaches such as:
• Medicines used to treat mood, anxiety, psychotic or thought disorders, such as:
◦ tricyclic antidepressants
◦ antipsychotic drugs
• Medicines used to treat pain such as:
• Medicines used to thin your blood such as:
• Medicines used to treat heartburn such as:
• Over-the-counter medicines or supplements such as:
◦ Aspirin or other NSAIDs
◦ St. John’s Wort
• have heart problems
• have diabetes
• have liver problems
• have kidney problems
• have thyroid problems
• have glaucoma
• have or had seizures or convulsions
• have bipolar disorder or mania
• have low sodium levels in your blood
• have high blood pressure
• have high cholesterol
• have or had bleeding problems
• are pregnant or plan to become pregnant. It is not known if venlafaxine HCl will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy
• are breast-feeding or plan to breast-feed. Some venlafaxine HCl may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking venlafaxine HCl.
Your healthcare provider or pharmacist can tell you if it is safe to take venlafaxine HCl with your other medicines. Do not start or stop any medicine while taking venlafaxine HCl without talking to your healthcare provider first.
How should I take venlafaxine HCl?
|If you take venlafaxine tablets, you should not take any other medicines that contain (venlafaxine) including: venlafaxine HCl.
• Take venlafaxine HCl exactly as prescribed. Your healthcare provider may need to change the dose of venlafaxine HCl until it is the right dose for you.
Venlafaxine HCl may cause serious side effects, including:
• Venlafaxine HCl is to be taken with food.
• If you miss a dose of venlafaxine HCl, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of venlafaxine HCl at the same time.
• If you take too much venlafaxine HCl, call your healthcare provider or poison control center right away, or get emergency treatment.
• When switching from another antidepressant to venlafaxine HCl your doctor may want to lower the dose of the initial antidepressant first to avoid side effects
What should I avoid while taking venlafaxine HCl?
Venlafaxine HCl can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how venlafaxine HCl affects you. Do not drink alcohol while using venlafaxine HCl.
• See “What is the most important information I should know about venlafaxine HCl?”
• Increased cholesterol- have your cholesterol checked regularly
• Newborns whose mothers take venlafaxine HCl in the third trimester may have problems right after birth including:
• problems feeding and breathing
• shaking, jitteriness or constant crying
• Narrow-angle glaucoma/enlarged pupils. Check eye pressure regularly if you:
• have a history of increased eye pressure
• are at risk for certain types of glaucoma
Common possible side effects in people who take venlafaxine HCl include:
• unusual dreams
• sexual problems
• loss of appetite, constipation, diarrhea, nausea or vomiting, or dry mouth
• feeling tired, fatigued or overly sleepy
• change in sleep habits, problems sleeping
• tremor or shaking
• dizziness, blurred vision
• feeling anxious, nervous or jittery
• increase in heart rate
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of venlafaxine HCl. For more information, ask your healthcare provider or pharmacist.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.
How should I store venlafaxine HCl tablets?
• Store venlafaxine HCl tablets at room temperature between 68°F and 77°F (20°C to 25°C).
• Keep venlafaxine HCl tablets in a dry place.
Keep venlafaxine HCl and all medicines out of the reach of children.
General information about venlafaxine HCl
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use venlafaxine HCl for a condition for which it was not prescribed. Do not give venlafaxine HCl to other people, even if they have the same condition. It may harm them.
This medication Guide summarizes the most important information about venlafaxine HCl. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about venlafaxine HCl that is written for healthcare professionals.
For more information about venlafaxine HCl call 1-877-835-5472.
What are the ingredients in venlafaxine HCl tablets?
Active ingredient: (venlafaxine HCl)
• Tablets: anhydrous lactose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose and sodium starch glycolate.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5
Pulaski, TN 38478
Mfg. Rev. 11/13
AV 01/14 (P)
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5
Please reference the
section listed above for a description of individual tablets or capsules. This drug product has been received by Aphena Pharma – TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:
Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.
Cookeville, TN 38506
PRINCIPAL DISPLAY PANEL – 37.5mg
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
NDC 43353-802 – Venlafaxine HCI 37.5mg – Rx Only
PRINCIPAL DISPLAY PANEL – 75mg
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
NDC 43353-798 – Venlafaxine HCI 75mg – Rx Only