AVISINE

Venlafaxine is an antidepressant and a serotonin and norepinephrine reuptake inhibitor (SNRI).

Its active metabolite, desvenlafaxine, works by blocking the reuptake of serotonin and norepinephrine, which are key neurotransmitters in mood regulation.

Venlafaxine is officially approved to treat major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder, and panic disorder in adults.

The immediate formulation of the drug, marketed as Effexor, was first approved by the FDA in and the extended-release formulation, Effexor XR, was later introduced in 1997.

Venlafaxine has been used as a first-line treatment for MDD, GAD, social anxiety disorder, and panic disorder in Canada for many years.

It was also considered a second-line treatment for obsessive-compulsive disorder (OCD). 2, 5 Venlafaxine was also investigated in off-label uses for the prophylaxis of migraine headaches, 1, 3 for reduction of vasomotor symptoms associated with menopause, 6 and for the management of neuropathic pain (although there is only minimal evidence of efficacy for this condition).

Venlafaxine is indicated for the management of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder.

Venlafaxine is an antidepressant agent that works to ameliorate the symptoms of various psychiatric disorders by increasing the level of neurotransmitters in the synapse.

Venlafaxine does not mediate muscarinic, histaminergic, or adrenergic effects.

Venlafaxine is well absorbed after oral administration with an absolute bioavailability of approximately 45%.

In mass balance studies, at least 92% of a single oral dose of venlafaxine was absorbed.

After twice-daily oral administration of immediate-release formulation of 150 mg venlafaxine, C max was 150 ng/mL and T max was 5.5 hours.

C max and T max of

ODV were 260 ng/mL and nine hours, respectively.

The extended-release formulation of venlafaxine has a slower rate of absorption, but the same extent of absorption as the immediate-release formulation.

After once-daily administration of extended-release formulation of 75 mg venlafaxine, C max was 225 ng/mL and T max was two hours.

ODV were 290 ng/mL and three hours, respectively.

Food does not affect the bioavailability of venlafaxine or its active metabolite, O-desmethylvenlafaxine (ODV).

The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV.

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver.

It primarily undergoes

CYP2D6-mediated demethylation to form its active metabolite O-desmethylvenlafaxine (ODV).

Venlafaxine can also undergo N-demethylation mediated by CYP2C9, and CYP2C19, and CYP3A4 to form N-desmethylvenlafaxine (NDV) but this is a minor metabolic pathway.

ODV and NDV further metabolized by

CYP2C19, CYP2D6 and/or CYP3A4 to form N,O-didesmethylvenlafaxine (NODV) 9 and NODV can be further metabolized to form N, N, O-tridesmethylvenlafaxine, followed by a possible glucuronidation.

Hover over products below to view reaction partners Venlafaxine Desvenlafaxine O-Desmethylvenlafaxine glucuronide N,O-Didesmethylvenlafaxine N,N,O-tridesmethylvenlafaxine N,O-didesmethylvenlafaxine glucuronide N-Desmethylvenlafaxine N,O-Didesmethylvenlafaxine.

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%).

The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV.

Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV.

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LD was 350 mg/kg in female rats and 700 mg/kg in male rats.

There are reports of acute overdosage with venlafaxine either alone or in combination with other drugs including alcohol.

Doses up to several-fold higher than the usual therapeutic dose have been ingested in these cases of acute overdosage.

Somnolence is the most commonly reported symptom, along with other symptoms such as paresthesia of the extremities, moderate dizziness, altered consciousness, nausea, vomiting, numb hands and feet, hot-cold spells (which occur a few days after the overdose event), hypotension, convulsions, sinus and ventricular tachycardia, rhabdomyolysis, vertigo, liver necrosis, electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), serotonin syndrome, and death.

There is no known antidote for venlafaxine overdose.

Cases of overdose have been managed with or without symptomatic treatment, hospitalization, and activated charcoal.

Retrospective studies suggest that the risk of fatal outcomes from venlafaxine overdosage is higher than that of SSRI antidepressants, but lower than that of tricyclic antidepressants.

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 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 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 to 24 5 additional cases Decreases Compared to Placebo 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.

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 tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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.

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including venlafaxine tablets, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, 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 tablets with MAOIs intended to treat psychiatric disorders is contraindicated.

Venlafaxine tablets 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 tablets.

Venlafaxine tablets should be discontinued before initiating treatment with the MAOI See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION.

If concomitant use of venlafaxine tablets 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 tablets and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

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.

Venlafaxine treatment is associated with sustained increases in blood pressure in some patients.

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 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group.

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 < 100 mg/day 3% 101 to 200 mg/day 5% 201 to 300 mg/day 7% > 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 post marketing 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.

Sexual Dysfunction Use of

SNRIs, including venlafaxine tablets, may cause symptoms of sexual dysfunction See ADVERSE REACTIONS.

In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction.

In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of venlafaxine tablets and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.

When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder.

Discuss potential management strategies to support patients in making informed decisions about treatment.

Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.

The use of

MAOIs intended to treat psychiatric disorders with venlafaxine tablets or within 7 days of stopping treatment with venlafaxine tablets is contraindicated because of an increased risk of serotonin syndrome.

The use of venlafaxine tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated See WARNINGS and DOSAGE AND ADMINISTRATION.

Starting venlafaxine tablets 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 syndrome See WARNINGS and DOSAGE AND ADMINISTRATION.

The recommended starting dose for venlafaxine 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.

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.

When treating pregnant women with venlafaxine tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

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, 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.

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, 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.

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 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) .

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.

Symptoms associated with discontinuation of venlafaxine tablets, other SNRIs, and SSRIs, have been reported.

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.

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.

Tablets, USP equivalent to 37.5 mg of venlafaxine are peach-colored, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "65" and other side is plain and are supplied as follows: NDC 68071-3431-0 in bottles of 100 tablets Storage Store at 20° to 25°C (68° to 77°F) in a dry place.

Dispense in a well-closed container as defined in the USP.

KEEP THIS AND ALL MEDICINES OUT OF THE REACH OF CHILDREN.

Guide available at or call 1-877-993-8779.

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 tablets therapy does not adversely affect their ability to engage in such activities.

Patients should be advised that taking venlafaxine tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.

Pre-existing 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.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to notify their physician if they are breastfeeding an infant.

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 tablets 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 tablets 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.

Although venlafaxine tablets have 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 tablets.

Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.

Venlafaxine and

ODV have been reported to be excreted in humanmilk.

Because of the potential for serious adverse reactions in nursing infants from venlafaxine tablets, 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.

Safety and effectiveness in the pediatric population have not been established.

Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in 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.

Should the decision be made to treat a pediatric patient with venlafaxine tablets, 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 capsules 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 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.

Of the 2,897 patients in Phase and Phase 3 depression studies with venlafaxine tablets, 12% 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, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.

The pharmacokinetics of venlafaxine and

ODV are not substantially altered in the elderly.

No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction See DOSAGE AND ADMINISTRATION.