Venlafaxine Hydrochloride (Page 2 of 13)

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 with normal subjects [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)], it is recommended that the total daily dose be reduced by 25% to 50%.

In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50% . Because there was much individual variability in clearance between patients with renal impairment, individualization of dosage may be desirable in some patients.

Elderly Patients

No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug for the treatment of major depressive disorder or Social Anxiety Disorder, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose.

2.4 Discontinuing Venlafaxine Extended Release Tablets

Symptoms associated with discontinuation of venlafaxine hydrochloride extended-release capsules, other SNRI’s, and SSRI’s have been reported [see Warnings and Precautions (5.6) ]. 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. In clinical trials with venlafaxine hydrochloride extended-release capsules, tapering was achieved by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary.

2.5 Switching Patients from Venlafaxine Hydrochloride Immediate-Release Tablets

Depressed patients who are currently being treated at a therapeutic dose with venlafaxine hydrochloride immediate-release tablets may be switched to Venlafaxine Extended Release Tablets at the nearest equivalent dose (mg/day), e.g., 37.5 mg venlafaxine two-times-a-day to 75 mg Venlafaxine Extended Release Tablets once daily. However, individual dosage adjustments may be necessary.

2.6 Switching Patients To or From a Monoamine Oxidase Inhibitor

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Venlafaxine Extended Release Tablets. In addition, at least 7 days should be allowed after stopping Venlafaxine Extended Release Tablets before starting an MAOI [see Contraindications (4) and Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHS

Venlafaxine Extended Release Tablets are available as:

–

37.5 mg tablets (round, biconvex, white coated tablets with OS301 printed on one side)

–

75 mg tablets (round, biconvex, white coated tablets with OS302 printed on one side)

–

150 mg tablets (round, biconvex, white coated tablets with OS303 printed on one side)

–

225 mg tablets (round, biconvex, white coated tablets with OS304 printed on one side)

4 CONTRAINDICATIONS

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated [see Warnings and Precautions (5.2) ].

5 WARNINGS AND PRECAUTIONS

5.1 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 18-24) 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
18-24	5 additional cases
	Decreases Compared to Placebo
25-64	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 Dosage and Administration (2.5 ) and Warnings and Precautions (5.7)].

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

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Venlafaxine Extended Release Tablets are not approved for use in treating bipolar depression.