WARNINGS
Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.
There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.
The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across indications.
These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 .
Table 1: Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials.
There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION , Discontinuing Venlafaxine Tablets , for a description of the risks of discontinuation of venlafaxine tablets).
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 healthcare providers.
Such monitoring should include daily observation by families and caregivers.
Prescriptions for venlafaxine tablets 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 tablets are not approved for use in treating bipolar depression.
Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including venlafaxine hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St.
John’s Wort) and 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 hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated.
Venlafaxine hydrochloride 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 hydrochloride.
Venlafaxine hydrochloride should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION ).
If concomitant use of venlafaxine hydrochloride 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 hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including venlafaxine tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Sustained Hypertension 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: Probability of Sustained Elevation in SDBP (Pool of Premarketing Venlafaxine Studies) Treatment Group Incidence of Sustained Elevation in SDBP Venlafaxine 300 mg/day 13% Placebo 2% 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 postmarketing experience.
Preexisting 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.
DRUG INTERACTIONS
Drug Interactions As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
Alcohol A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects.
Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.
Cimetidine Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects.
The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (C max ) of the drug were increased by about 60%.
However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine.
The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults.
However, for patients with preexisting hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced.
Therefore, caution is advised with such patients.
Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects.
Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.
Haloperidol Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC.
In addition, the haloperidol C max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t 1/2 ) was unchanged.
The mechanism explaining this finding is unknown.
Lithium The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects.
O-desmethylvenlafaxine (ODV) also was unaffected.
Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs , below).
Drugs Highly Bound to Plasma Protein Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine hydrochloride to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis.
Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.
Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin.
Patients receiving warfarin therapy should be carefully monitored when venlafaxine hydrochloride is initiated or discontinued.
Drugs That Inhibit Cytochrome P450 Isoenzymes CYP2D6 Inhibitors In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants.
Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine.
However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected.
Additionally, in a clinical study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups.
Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.
Ketoconazole A pharmacokinetic study with ketoconazole 100 mg b.i.d.
with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desvenlafaxine (ODV) in most subjects following administration of ketoconazole.
Venlafaxine C max increased by 26% in EM subjects and 48% in PM subjects.
C max values for ODV increased by 14% and 29% in EM and PM subjects, respectively.
Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs – 2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs – 38% to 105%) subjects, respectively.
Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMs and 53% in PMs, (range in PMs 4% to 134%).
Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV.
Therefore, caution is advised if a patient’s therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.
CYP3A4 Inhibitors In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4.
Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small.
The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied.
Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems.
Drugs Metabolized by Cytochrome P450 Isoenzymes CYP2D6 In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6.
These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.
Imipramine Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine.
However, desipramine AUC, C max , and C min increased by about 35% in the presence of venlafaxine.
The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h).
Imipramine did not affect the pharmacokinetics of venlafaxine and ODV.
The clinical significance of elevated 2-OH-desipramine levels is unknown.
Metoprolol Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30 to 40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol.
Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine.
Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study.
The clinical relevance of this finding for hypertensive patients is unknown.
Caution should be exercised with coadministration of venlafaxine and metoprolol.
Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients.
It is recommended that patients receiving venlafaxine hydrochloride have regular monitoring of blood pressure (see WARNINGS ).
Risperidone Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC.
However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).
CYP3A4 Venlafaxine did not inhibit CYP3A4 in vitro .
This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.
Indinavir In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C max .
Indinavir did not affect the pharmacokinetics of venlafaxine and ODV.
The clinical significance of this finding is unknown.
CYP1A2 Venlafaxine did not inhibit CYP1A2 in vitro .
This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.
CYP2C9 Venlafaxine did not inhibit CYP2C9 in vitro .
In vivo , venlafaxine 75 mg by mouth every 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation of 4-hydroxy-tolbutamide.
CYP2C19 Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above).
Monoamine Oxidase Inhibitors See CONTRAINDICATIONS .
CNS-Active Drugs The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above).
Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required (see CONTRAINDICATIONS and WARNINGS ).
Serotonergic Drugs Based on the mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St.
John’s Wort and methylene blue (see CONTRAINDICATIONS and WARNINGS , Serotonin Syndrome ).
If concomitant treatment of venlafaxine with these drugs is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see CONTRAINDICATIONS and WARNINGS , Serotonin Syndrome ).
The concomitant use of venlafaxine with tryptophan supplements is not recommended (see CONTRAINDICATIONS and WARNINGS , Serotonin Syndrome ).
Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan.
If concomitant treatment of venlafaxine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS , Serotonin Syndrome ).
OVERDOSAGE
Human Experience There were 14 reports of acute overdose with venlafaxine hydrochloride, 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 hydrochloride 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 QT c 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 preexisting 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 hydrochloride 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 ).
DESCRIPTION
Venlafaxine hydrochloride, 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-[(dimethylamino)methyl]- p -methoxybenzyl]cyclohexanol hydrochloride.
The structural formula is shown below.
C 17 H 27 NO 2 •HCl M.W.
313.87 Venlafaxine hydrochloride, 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 hydrochloride, USP equivalent to 37.5 mg or 75 mg venlafaxine.
Inactive ingredients consist of colloidal silicon dioxide, ferric oxide yellow, ferric oxide red, lactose monohydrate, magnesium stearate, and sodium starch glycolate.
Structural formula for venalfaxine hydrochloride, USP
CLINICAL STUDIES
CLINICAL TRIALS The efficacy of venlafaxine hydrochloride 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 hydrochloride in a range of 75 to 225 mg/day (t.i.d.
schedule), the third involving fixed venlafaxine hydrochloride 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 hydrochloride doses were titrated in a range of 150 to 375 mg/day (t.i.d.
schedule).
In these 5 studies, venlafaxine hydrochloride 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 hydrochloride extended-release capsules (75, 150, or 225 mg, qAM) were randomized to continuation of their same venlafaxine hydrochloride extended-release capsule dose or to placebo, for up to 26 weeks of observation for relapse.
Response during the open phase was defined as a CGI Severity of Illness item score of ≤ 3 and a HAM-D-21 total score of ≤ 10 at the day 56 evaluation.
Relapse during the double-blind phase was defined as follows: (1) a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness item score of ≥ 4 (moderately ill), (2) 2 consecutive CGI Severity of Illness item scores of ≥ 4, or (3) a final CGI Severity of Illness item score of ≥ 4 for any patient who withdrew from the study for any reason.
Patients receiving continued venlafaxine hydrochloride extended-release capsule treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared with those receiving placebo.
In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major 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 hydrochloride (100 to 200 mg/day, on a b.i.d.
schedule) were randomized to continuation of their same venlafaxine hydrochloride dose or to placebo.
The follow-up period to observe patients for relapse, defined as a CGI Severity of Illness item score ≥ 4, was for up to 52 weeks.
Patients receiving continued venlafaxine hydrochloride treatment experienced significantly lower relapse rates over the subsequent 52 weeks compared with those receiving placebo.
HOW SUPPLIED
Venlafaxine tablets USP are available as follows: 37.5 mg – mottled peach, round, flat beveled tablet, on one side scored and debossed “9” on one side of the score and “3” on the other side of the score.
Debossed with “7380” on the opposite side of the tablet.
It is available in blister packs of 30 (NDC 58118-0059-08).
75 mg – mottled peach, round, flat beveled tablet, on one side scored and debossed “9” on one side of the score and “3” on the other side of the score.
Debossed with “7382” on the opposite side of the tablet.
It is available in blister packs of 30 (NDC 58118-0032-08).
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] in a dry place.
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
Manufactured In Israel By: TEVA PHARMACEUTICAL IND.
LTD.
Jerusalem, 9777402, Israel Manufactured For: TEVA PHARMACEUTICALS USA, INC.
North Wales, PA 19454 Repackaged by: CLINICAL SOLUTIONS WHOLESALE Franklin, TN 37067 Rev.
1 9/15
GERIATRIC USE
Geriatric Use Of the 2,897 patients in Phase 2 and Phase 3 depression studies with venlafaxine hydrochloride, 12% (357) were 65 years of age or over.
No overall differences in effectiveness or safety were observed between these 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, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS , Hyponatremia ).
The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see CLINICAL PHARMACOLOGY ).
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 (see DOSAGE AND ADMINISTRATION ).
INDICATIONS AND USAGE
Venlafaxine tablets USP are indicated for the treatment of major depressive disorder.
The efficacy of venlafaxine tablets USP 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 hydrochloride 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 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/venlafaxine hydrochloride extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
PEDIATRIC USE
Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS , Clinical Worsening and Suicide Risk ).
Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD 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 tablets in a child or adolescent must balance the potential risks with the clinical need.
Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-release capsule’s impact on the growth, development, and maturation of children and adolescents, the studies that have been done suggest that venlafaxine hydrochloride extended-release capsules may adversely affect weight and height (see PRECAUTIONS , General , Changes in Height and Changes in Weight ).
Should the decision be made to treat a pediatric patient with venlafaxine hydrochloride, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long term.
The safety of venlafaxine hydrochloride extended-release capsule 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 to 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 (see WARNINGS , Sustained Hypertension and PRECAUTIONS , General , Serum Cholesterol Elevation ).
PREGNANCY
Pregnancy Teratogenic Effects Pregnancy Category C Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m 2 basis.
However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning.
The cause of these deaths is not known.
These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m 2 ) the maximum human daily dose.
The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m 2 basis.
There are no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nonteratogenic Effects Neonates exposed to venlafaxine hydrochloride, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.
Such complications can arise immediately upon delivery.
Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.
These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.
It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS , Drug Interactions , CNS-Active Drugs ).
When treating a pregnant woman with venlafaxine hydrochloride during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION ).
NUSRING MOTHERS
Nursing Mothers Venlafaxine and ODV have been reported to be excreted in human milk.
Because of the potential for serious adverse reactions in nursing infants from venlafaxine hydrochloride, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
BOXED WARNING
Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders.
Anyone considering the use of venlafaxine tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need.
Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.
Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.
Families and caregivers should be advised of the need for close observation and communication with the prescriber.
Venlafaxine tablets are not approved for use in pediatric patients (see WARNINGS, Clinical Worsening and Suicide Risk; PRECAUTIONS, Information for Patients; and PRECAUTIONS, Pediatric Use).
INFORMATION FOR PATIENTS
Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with venlafaxine 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 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 tablets.
Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.
Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.
Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Interference With Cognitive and Motor Performance Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals.
The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance.
However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that venlafaxine hydrochloride therapy does not adversely affect their ability to engage in such activities.
Angle-Closure Glaucoma Patients should be advised that taking venlafaxine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.
Preexisting glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy.
Open-angle glaucoma is not a risk factor for angle closure glaucoma.
Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Nursing Patients should be advised to notify their physician if they are breastfeeding an infant.
Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, including herbal preparations and nutritional supplements, since there is a potential for interactions.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of venlafaxine hydrochloride and triptans, tramadol, tryptophan supplements or other serotonergic agents (see CONTRAINDICATIONS and WARNINGS , Serotonin Syndrome and PRECAUTIONS , Drug Interactions , CNS-Active Drugs, Serotonergic Drugs ).
Patients should be cautioned about the concomitant use of venlafaxine hydrochloride and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding (see PRECAUTIONS , Abnormal Bleeding ).
Alcohol Although venlafaxine hydrochloride has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine hydrochloride.
Allergic Reactions Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.
DOSAGE AND ADMINISTRATION
Initial Treatment The recommended starting dose for venlafaxine hydrochloride tablets 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 ).
Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to venlafaxine tablets, 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 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.
Maintenance Treatment 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 tablets 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 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/venlafaxine hydrochloride 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 Symptoms associated with discontinuation of venlafaxine tablets, 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.
Conversely, at least 7 days should be allowed after stopping venlafaxine tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS ).
Use of Venlafaxine Tablets With Other MAOls, Such as Linezolid or Methylene Blue Do not start venlafaxine tablets 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 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 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 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 is unclear.
The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS ).