VENLOR XR Capsule Ref.[50467] Active ingredients: Venlafaxine

General

Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Patients with MDD, both adult and paediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour (suicidality) or unusual changes in behaviour, 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 behaviour (suicidality) in children, adolescents, and young adults (ages 18-24) with 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. Difference in the number of cases of suicidality per 1,000 patients treated versus placebo:

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 paediatric patients being treated with antidepressants for MDD 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 behaviour, 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 capsules should be written for the smallest quantity of capsules 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 is not approved for use in treating bipolar depression.

Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including VENLOR XR 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 others, such as linezolid or intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma) autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, flushing, and dizziness), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination); seizures and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of VENLOR XR TABLETS with MAOIs (intended to treat psychiatric disorders) is contraindicated. VENLOR XR 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 VENLOR XR TABLETS. It should be discontinued before initiating treatment with the MAOI [see Contraindications (4.2), Dosage and Administration (2.6), and Drug Interactions (7.3)]. If concomitant use of VENLOR XR TABLETS with other serotonergic drugs (e.g., triptans, tricyclic antidepressants, mirtazapine, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, or St. John's wort) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions (7.3)]. Patients should be made aware of the potential risk of serotonin syndrome. Treatment with VENLOR XR TABLETS and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated.

Sustained Hypertension

Venlafaxine ER treatment is associated with sustained hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive on-therapy visits [see Table 2].

An analysis for patients in venlafaxine (immediate release) studies meeting criteria for sustained hypertension revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine (immediate release) [see Table 3].

An insufficient number of patients received mean doses of venlafaxine ER over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at these higher doses.

Table 2. Incidence (%) of sustained elevations in SDBP in venlafaxine premarketing studies by indication:

MDD = major depressive disorder GAD = generalized anxiety disorder

Table 3. Incidence (%) of sustained elevations in SDBP in venlafaxine immediate release studies:

In premarketing MDD studies, 0.7% (5/705) of the venlafaxine ER-treated patients discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). In premarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and 1.3% (7/535) of the venlafaxine ER-treated patients, respectively, discontinued treatment because of elevated blood pressure. Among these patients, most of the blood pressure increases were in a modest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). In premarketing Social Anxiety Disorder studies up to 6 months, 0.6% (5/771) of the venlafaxine ER-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were modest (1-24 mm Hg, SDBP). In premarketing panic disorder studies up to 12 weeks, 0.5% (5/1001) of the venlafaxine ER-treated patients discontinued treatment because of elevated blood pressure. In these patients, the blood pressure increases were in a modest range (7 to 19 mm Hg, SDBP).

Sustained increases of SDBP could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is recommended that patients receiving venlafaxine 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.

Elevations in Systolic and Diastolic Blood Pressure

In placebo-controlled premarketing studies, there were changes in mean blood pressure [see Table 4 for mean changes in supine systolic and supine diastolic blood pressure]. Across most indications, a dose-related increase in supine systolic and diastolic blood pressure was evident in venlafaxine ERtreated patients.

Table 4. Final on-therapy mean changes from baseline in supine systolic and diastolic blood pressure (mm Hg) results by indication, study duration, and dose in placebo-controlled trials:

¹ Supine Systolic Blood Pressure
² Supine Diastolic Blood Pressure

Across all clinical trials in MDD, GAD, Social Anxiety Disorder and panic disorder, 1.4% of patients in the venlafaxine-treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure with blood pressure ≥105 mm Hg compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in the venlafaxine-treated groups experienced a ≥20 mm Hg increase in supine systolic blood pressure with blood pressure ≥180 mm Hg compared to 0.3% of patients in the placebo groups.

Patients with Cardiac Disease

Venlafaxine should be used with caution in patients with established cardiac disease, which may increase the risk of ventricular arrhythmias (e.g. recent myocardial infarction).

Significant Electrocardiogram Findings:

Significant electrocardiogram findings were observed in 0.8% of venlafaxine-treated patients compared with 0.7% of placebo-treated patients. Significant changes in PR, QRS or QTc intervals were rarely observed in patients treated with venlafaxine during clinical trials.

Increase in Heart Rate:

As increases in the heart rate were observed, especially at higher doses, caution should be exercised in patients whose underlying medical conditions might be compromised by such increases (e.g. patients with hyperthyroidism, heart failure or recent myocardial infarction).

Postural Hypotension

Postural hypotension has been observed occasionally during venlafaxine treatment. Patients, especially the elderly, should be alerted to the possibility of dizziness or unsteadiness.

Mydriasis

Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored.

Aggression

Treatment with venlafaxine (especially starting and discontinuing treatment) has been associated with reports of aggression.

Psychomotor Restlessness

The use of venlafaxine has been associated with the development of psychomotor restlessness, which clinically may be very similar to akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often, accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental and it may be necessary to review the use of venlafaxine.

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

Discontinuation Syndrome

Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include prospective analyses of clinical trials in GAD and retrospective surveys of trials in MDD, and SAD. Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be associated with the appearance of new symptoms, the frequency of which increased with increased dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, impaired coordination and balance, diarrhoea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.

There have been spontaneous reports of undesirable effects occurring upon discontinuation of venlafaxine, other SNRIs and SSRIs particularly when abrupt. The undesirable effects reported included the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paraesthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with venlafaxine extended-release. 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.

Insomnia and Nervousness

Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with venlafaxine extended-release capsules than with placebo in pooled analyses of short-term MDD, GAD, social anxiety disorder and panic disorder studies as shown in Table 5.

Table 5. Incidence of insomnia and nervousness in placebo-controlled major depressive disorder, GAD, social anxiety disorder, and panic disorder trials:

^* XR: extended-release

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with venlafaxine in MDD studies.

In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively, of the patients treated with venlafaxine extended release capsules up to 8 weeks and 2% and 0.7%, respectively, of the patients treated with venlafaxine ER up to 6 months.

In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in 2% and 1%, respectively, of the patients treated with venlafaxine ER capsules up to 12 weeks and 2% and 3% respectively, of the patients treated with venlafaxine ER up to 6 months.

In panic disorder trials, insomnia and nervousness led to drug discontinuation in 1% and 0.1%, respectively, of the patients treated with venlafaxine ER up to 12 weeks.

Changes in Weight

Adult Patients:

A loss of 5% or more of body weight occurred in 7% of venlafaxine XR -treated and 2% of placebotreated patients in the short-term placebo-controlled MDD trials. The discontinuation rate for weight loss associated with venlafaxine XR was 0.1% in MDD studies. In placebo-controlled GAD studies, a loss of 7% or more of body weight occurred in 3% of venlafaxine XR patients and 1% of placebo patients who received treatment for up to 6 months. The discontinuation rate for weight loss was 0.3% for patients receiving venlafaxine in GAD studies for up to eight weeks. In placebo-controlled Social Anxiety Disorder trials, 4% of the venlafaxine XR-treated and 1% of the placebo-treated patients sustained a loss of 7% or more of body weight during up to 6 months of treatment. None of the patients receiving venlafaxine XR in Social Anxiety Disorder studies discontinued for weight loss. In placebo-controlled panic disorder trials, 3% of the venlafaxine XR-treated and 2% of the placebotreated patients sustained a loss of 7% or more of body weight during up to 12 weeks of treatment. None of the patients receiving venlafaxine XR in panic disorder studies discontinued for weight loss.

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine XR and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.

Pediatric Patients:

Weight loss has been observed in pediatric patients (ages 6-17) receiving venlafaxine XR. In a pooled analysis of four eight-week, double-blind, placebo-controlled, flexible dose outpatient trials for MDD and GAD, venlafaxine XR-treated patients lost an average of 0.45 kg (n = 333), while placebo-treated patients gained an average of 0.77 kg (n = 333). More patients treated with venlafaxine XR than with placebo experienced a weight loss of at least 3.5% in both the MDD and the GAD studies (18% of venlafaxine XR -treated patients vs. 3.6% of placebo-treated patients; p<0.001). In a 16-week, double-blind, placebo-controlled, flexible dose outpatient trial for Social Anxiety Disorder, venlafaxine XR-treated patients lost an average of 0.75 kg (n = 137), while placebo-treated patients gained an average of 0.76 kg (n = 148). More patients treated with venlafaxine XR than with placebo experienced a weight loss of at least 3.5% in the Social Anxiety Disorder study (47% of venlafaxinetreated patients vs. 14% of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent anorexia.

The risks associated with longer-term venlafaxine XR use were assessed in an open-label MDD study of children and adolescents who received venlafaxine XR for up to six months. The children and adolescents in the study had increases in weight that were less than expected based on data from age- and sex-matched peers. The difference between observed weight gain and expected weight gain was larger for children (<12 years old) than for adolescents (≥12 years old).

Changes in Height

Pediatric Patients:

During the eight-week, placebo-controlled GAD studies, venlafaxine XR-treated patients (ages 6-17) grew an average of 0.3 cm (n=122), while placebo-treated patients grew an average of 1.0 cm (n=132); p=0.041. This difference in height increase was most notable in patients younger than twelve. During the eight-week placebo-controlled MDD studies, venlafaxine XR-treated patients grew an average of 0.8 cm (n=146), while placebo-treated patients grew an average of 0.7 cm (n=147). During the 16-week, placebo-controlled Social Anxiety Disorder study, both the venlafaxine-treated (n=109) and the placebo-treated (n=112) patients each grew an average of 1.0 cm. In the sixmonth, open-label MDD study, children and adolescents had height increases that were less than expected based on data from age- and sex-matched peers. The difference between observed growth rates and expected growth rates was larger for children (<12 years old) than for adolescents (≥12 years old).

Changes in Appetite

Adult Patients:

Treatment-emergent anorexia was more commonly reported for venlafaxine XR-treated (8%) than placebo-treated patients (4%) in the pool of short-term, double-blind, placebo-controlled MDD studies. The discontinuation rate for anorexia associated with venlafaxine-XR was 1.0% in MDD studies. Treatment-emergent anorexia was more commonly reported for venlafaxine XR-treated (8%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled GAD studies. The discontinuation rate for anorexia was 0.9% for patients receiving venlafaxine XR for up to 8 weeks in GAD studies. Treatment-emergent anorexia was more commonly reported for venlafaxine-treated (17%) than placebo-treated patients (2%) in the pool of short-term, double-blind placebo-controlled Social Anxiety Disorder studies. The discontinuation rate for anorexia was 0.6% for patients receiving venlafaxine for up to 12 weeks in Social Anxiety Disorder studies; no patients discontinued for anorexia between week 12 and month 6. Treatment-emergent anorexia was more commonly reported for venlafaxine XR-treated (8%) than placebo-treated patients (3%) in the pool of short-term, double-blind, placebo-controlled panic disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving venlafaxine XR for up to 12 weeks in panic disorder studies.

Pediatric Patients:

Decreased appetite has been observed in pediatric patients receiving venlafaxine XR. In the placebocontrolled trials for GAD and MDD, 10% of patients aged 6-17 treated with venlafaxine XR for up to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased appetite). None of the patients receiving venlafaxine XR discontinued for anorexia or weight loss. In the placebo-controlled trial for Social Anxiety Disorder, 22% and 3% of patients aged 8-17 treated for up to 16 weeks with venlafaxine XR and placebo, respectively, reported treatmentemergent anorexia (decreased appetite). The discontinuation rates for anorexia were 0.7% and 0.0% for patients receiving venlafaxine XR and placebo, respectively; the discontinuation rates for weight loss were 0.7% for patients receiving either venlafaxine or placebo.

Activation of Mania/Hypomania

During premarketing MDD studies, mania or hypomania occurred in 0.3% of venlafaxine XR-treated patients and no placebo patients. In premarketing GAD studies, no venlafaxine-treated patients and 0.2% of placebo-treated patients experienced mania or hypomania. In premarketing Social Anxiety Disorder studies, 0.2% venlafaxine XR-treated patients and no placebo-treated patients experienced mania or hypomania. In premarketing panic disorder studies, 0.1% of venlafaxine XR-treated patients and no placebo-treated patients experienced mania or hypomania. In all premarketing MDD trials with venlafaxine (immediate release), mania or hypomania occurred in 0.5% of venlafaxinetreated patients compared with no placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs to treat MDD. As with all drugs effective in the treatment of MDD, venlafaxine should be used cautiously in patients with a history of mania.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including venlafaxine XR. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of venlafaxine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Seizures

During premarketing experience, no seizures occurred among 705 venlafaxine XR-treated patients in the MDD studies, among 1381 venlafaxine XR-treated patients in GAD studies, or among 819 venlafaxine-treated patients in Social Anxiety Disorder studies. In panic disorder studies, 1 seizure occurred among 1,001 venlafaxine XR-treated patients. In all premarketing MDD trials with venlafaxine (immediate release), seizures were reported at various doses in 0.3% (8/3082) of venlafaxine-treated patients. Venlafaxine XR, like many antidepressants, should be used cautiously in patients with a history of seizures and should be discontinued in any patient who develops seizures.

Abnormal Bleeding

SSRIs and SNRIs, including venlafaxine XR, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening haemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of venlafaxine XR and NSAIDs, aspirin, or other drugs that affect coagulation.

Serum Cholesterol Elevation

Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled trials. Measurement of serum cholesterol levels should be considered during long-term treatment.

Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been rarely reported. The possibility of these undesirable effects should be considered in venlafaxinetreated patients who present with progressive dyspnea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered.

Use in Patients with Concomitant Illness

Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering venlafaxine to patients with diseases or conditions that could affect hemodynamic responses or metabolism.

Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during venlafaxine&#39;s premarketing testing. The electrocardiograms were analyzed for 275 patients who received venlafaxine XR and 220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in MDD, for 610 patients who received venlafaxine and 298 patients who received placebo in 8-week doubleblind, placebo-controlled trials in GAD, for 593 patients who received venlafaxine and 534 patients who received placebo in 12-week double-blind, placebo-controlled trials in Social Anxiety Disorder, and for 661 patients who received venlafaxine and 395 patients who received placebo in three 10- to 12-week double-blind, placebo-controlled trials in panic disorder. The mean change from baseline in corrected QT interval (QTc) for venlafaxine XR-treated patients in MDD studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine and decrease of 1.9 msec for placebo). The mean change from baseline in QTc interval for venlafaxine XR-treated patients in the GAD studies did not differ significantly from that with placebo. The mean change from baseline in QTc interval for venlafaxine XR-treated patients in the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase of 3.4 msec for venlafaxine and decrease of 1.6 msec for placebo). The mean change from baseline in QTc interval for venlafaxine XR-treated patients in the panic disorder studies was increased relative to that for placebo-treated patients (increase of 1.5 msec for venlafaxine and decrease of 0.7 msec for placebo).

In these same trials, the mean change from baseline in heart rate for venlafaxine XR-treated patients in the MDD studies was significantly higher than that for placebo (a mean increase of 4 beats per minute for venlafaxine and 1 beat per minute for placebo). The mean change from baseline in heart rate for venlafaxine XR-treated patients in the GAD studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for venlafaxine XR and no change for placebo). The mean change from baseline in heart rate for venlafaxine XR-treated patients in the Social Anxiety Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute for venlafaxine XR and no change for placebo). The mean change from baseline in heart rate for venlafaxine XR-treated patients in the panic disorder studies was significantly higher than that for placebo (a mean increase of 3 beats per minute for venlafaxine XR and a mean decrease of less than 1 beat per minute for placebo).

In a flexible-dose study, with venlafaxine (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, venlafaxine-treated patients had a mean increase in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group.

As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g., patients with hyperthyroidism, heart failure, or recent myocardial infarction).

Abuse and Dependence

Venlafaxine XR capsules is not a controlled substance. In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP) or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. Due to the possibility of drug abuse with CNS-active drugs, physicians should evaluate patients for a history of drug abuse, and follow such patients closely. Clinical studies have shown no evidence of drug-seeking behaviour, development of tolerance or dose escalation over time among patients taking venlafaxine.

The most common side effects that are seen on venlafaxine administration are abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, anorexia, constipation and flatulence), CNS complaints (dizziness, somnolence, insomnia, nervousness and tremor, and abnormal dreams) along with sweating, abnormalities of sexual function (impotence in men, anorgasmia in women, and libido decreased), problems of special senses (abnormal vision), cardiovascular effects (hypertension and vasodilatation), yawning, paraesthesia, asthenia, weight loss, abnormal dreams, agitation, hypertonia, impotence, headache, twitching, accidental injury and orgasmic dysfunction.

Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Venlafaxine XR

Undesirable effects Associated with Discontinuation of Treatment

Approximately 11% of the 357 patients who received venlafaxine extended-release capsules in placebo-controlled clinical trials for major depressive disorder discontinued treatment due to an adverse experience, compared with 6% of the 285 placebo-treated patients in those studies. Approximately 18% of the 1381 patients who received venlafaxine extended-release capsules in placebo-controlled clinical trials for GAD discontinued treatment due to an adverse experience, compared with 12% of the 555 placebo-treated patients in those studies. Approximately 15% of the 819 patients who received venlafaxine extended-release capsules in placebo-controlled clinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience, compared with 5% of the 695 placebo-treated patients in those studies. Approximately 7% of the 1,001 patients who received venlafaxine extended-release capsules in placebo-controlled clinical trials for panic disorder discontinued treatment due to an adverse experience, compared with 6% of the 662 placebo-treated patients in those studies. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the venlafaxine extended-release treated patients at a rate at least twice that of placebo for any indication) are shown in Table 6.

Table 6. Common undesirable effects leading to discontinuation of treatment in placebo-controlled trials¹:

^* XR: extended-release
¹ Two of the major depressive disorder studies were flexible dose and one was fixed dose. Four of the GAD studies were fixed dose and one was flexible dose. Four of the Social Anxiety Disorder studies were flexible dose and one was fixed/flexible dose. Two of the panic disorder studies were flexible dose and two were fixed dose.
² In U.S. placebo-controlled trials for major depressive disorder, the following were also common events leading to discontinuation and were considered to be drug-related for venlafaxine extended-release-treated patients (% Venlafaxine extended-release [n = 192], % Placebo [n = 202]): hypertension (1%, <1%); diarrhea (1%, 0%); paresthesia (1%, 0%); tremor (1%, 0%); abnormal vision, mostly blurred vision (1%, 0%); and abnormal, mostly delayed, ejaculation (1%, 0%).
³ In two short-term U.S. placebo-controlled trials for GAD, the following were also common events leading to discontinuation and were considered to be drug-related for venlafaxine extended-release -treated patients (%venlafaxine extended-release [n = 476]), % Placebo [n = 201]: headache (4%, <1%); vasodilatation (1%, 0%); anorexia (2%, <1%); dizziness (4%, 1%); thinking abnormal (1%, 0%); and abnormal vision (1%, 0%).
⁴ In long-term placebo-controlled trials for GAD, the following was also a common event leading to discontinuation and was considered to be drug-related for venlafaxine extended-release – treated patients (%venlafaxine extended-release [n = 535], % Placebo [n = 257]): decreased libido (1%, 0%).
⁵ In a 6-month placebo-controlled trial for Social Anxiety Disorder, the following was also a common event leading to discontinuation and was considered to be drug-related for venlafaxine extended-release -treated patients (%venlafaxine extended-release [n = 257], % Placebo [n = 129]: depression (5%, 0%), libido decrease (1%, 0%), and nervousness (3%, 0%).
⁶ Incidence is based on the number of men (venlafaxine extended-release = 454, placebo = 357).

Commonly observed undesirable effects from Tables 7, 8, 9, and 10:

Table 7. Treatment-emergent undesirable effects incidence in short-term placebo-controlled venlafaxine XR* clinical trials in patients with major depressive disorder^1,2:

^* XR: extended-release
¹ Incidence, rounded to the nearest , for events reported by at least 2 of patients treated with venlafaxine extended-release, except the following events which had an incidence equal to or less than placebo: abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis, and sinusitis.
² <1% indicates an incidence greater than zero but less than 1%.
³ Mostly "hot flashes."
⁴ Mostly “vivid dreams,” “nightmares,” and "increased dreaming."
⁵ Mostly “blurred vision” and "difficulty focusing eyes."
⁶ Mostly "delayed ejaculation."
⁷ Incidence is based on the number of male patients.
⁸ Mostly “delayed orgasm” or "anorgasmia."
⁹ Incidence is based on the number of female patients.

Table 8. Treatment-emergent undesirable effects incidence in short-term placebo-controlled venlafaxine XR* clinical trials in GAD patients^1,2:

^* XR: extended-release
¹ Undesirable effects for which the venlafaxine extended-release reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, pain, palpitation, pharyngitis, rhinitis, tinnitus, and urinary frequency.
² <1% means greater than zero but less than 1%.
³ Mostly "hot flashes."
⁴ Mostly “vivid dreams,” “nightmares,” and "increased dreaming."
⁵ Mostly “blurred vision” and "difficulty focusing eyes."
⁶ Includes “delayed ejaculation” and "anorgasmia."
⁷ Percentage based on the number of males (venlafaxine extended-release = 525, placebo = 220).
⁸ Includes “delayed orgasm,” “abnormal orgasm,” and "anorgasmia."
⁹ Percentage based on the number of females (venlafaxine extended-release = 856, placebo = 335).

Table 9. Treatment-emergent undesirable effects incidence in short-term placebo-controlled venlafaxine XR* clinical trials in social anxiety disorder patients^1,2:

^* XR: extended-release
¹ Undesirable effects for which the venlafaxine extended-release reporting rate was less than or equal to the placebo rate are not included. These events are: arthralgia, back pain, dysmenorrhea, flu syndrome, infection, pain, pharyngitis, rhinitis, and upper respiratory infection.
² <1% means greater than zero but less than 1%.
³ Mostly "hot flashes."
⁴ Mostly “decreased appetite” and "loss of appetite."
⁵ Mostly “vivid dreams,” “nightmares,” and "increased dreaming."
⁶ Mostly "blurred vision."
⁷ Includes “delayed ejaculation” and "anorgasmia."
⁸ Percentage based on the number of males (venlafaxine extended-release = 454, placebo = 357).
⁹ Includes “abnormal orgasm” and "anorgasmia."
¹⁰ Percentage based on the number of females (venlafaxine extended-release = 365, placebo = 338).

Table 10. Treatment-emergent undesirable effects incidence in short-term placebo-controlled venlafaxine XR* clinical trials in panic disorder patients^1,2:

^* XR: extended-release
¹ Undesirable effects for which the venlafaxine extended-release reporting rate was less than or equal to the placebo rate are not included. These events are: abdominal pain, abnormal vision, accidental injury, anxiety, back pain, diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, nervousness, pain, paresthesia, pharyngitis, rash, rhinitis, and vomiting.
² <1% means greater than zero but less than 1%.
³ Mostly "hot flushes."
⁴ Mostly “decreased appetite” and "loss of appetite."
⁵ Includes “delayed or retarded ejaculation” and "anorgasmia."
⁶ Percentage based on the number of males (venlafaxine extended-release = 335, placebo = 238).
⁷ Includes “anorgasmia” and "delayed orgasm."
⁸ Percentage based on the number of females (venlafaxine extended-release = 666, placebo = 424)

Vital Sign Changes

Venlafaxine extended-release capsules treatment for up to12 weeks in premarketing placebocontrolled major depressive disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for placebo. Venlafaxine extended-release treatment for up to 8 weeks in premarketing placebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rate of approximately 2 beats per minute, compared with less than 1 beat per minute for placebo. Venlafaxine extended-release treatment for up to 12 weeks in premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 3 beats per minute, compared with an increase of 1 beat per minute for placebo. Venlafaxine extended-release treatment for up to 12 weeks in premarketing placebo-controlled panic disorder trials was associated with a mean final on-therapy increase in pulse rate of approximately 1 beat per minute, compared with a decrease of less than 1 beat per minute for placebo.

In a flexible-dose study, with venlafaxine (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo.

Laboratory Changes

Serum Cholesterol

Venlafaxine extended-release extended-release capsules treatment for up to 12 weeks in premarketing placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final decrease of 7.4 mg/dL for placebo. Venlafaxine extended-release treatment for up to 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dL and 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7 mg/dL, respectively. Venlafaxine extended-release treatment for up to 12 weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL, respectively, for placebo. Venlafaxine extended-release treatment for up to 12 weeks in premarketing placebocontrolled panic disorder trials was associated with mean final on-therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean final decrease of 3.7 mg/dL for placebo.

Patients treated with venlafaxine (immediate release) for at least 3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients.

Serum Triglycerides

Venlafaxine extended-release treatment for up to 12 weeks in pooled premarketing Social Anxiety Disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 8.2 mg/dL, compared with a mean final increase of 0.4 mg/dL for placebo. Venlafaxine extended-release treatment for up to 6 months in a premarketing Social Anxiety Disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 11.8 mg/dL, compared with a mean final on-therapy increase of 1.8 mg/dL for placebo.

Venlafaxine extended-release treatment for up to 12 weeks in pooled premarketing Panic Disorder trials was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 5.9 mg/dL, compared with a mean final increase of 0.9 mg/dL for placebo. Venlafaxine extended-release treatment for up to 6 months in a premarketing Panic Disorder trial was associated with a mean final on-therapy increase in fasting serum triglyceride concentration of approximately 9.3 mg/dL, compared with a mean final on-therapy decrease of 0.3 mg/dL for placebo.

ECG Changes

In a flexible-dose study, with venlafaxine (immediate release) doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo.

Postmarketing Reports

Undesirable Effects

Voluntary reports of other undesirable effects temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements, LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly).

Drug Interactions

There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024.

Alcohol

A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or Odesmethylvenlafaxine (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.

Although venlafaxine 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.

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 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 pre-existing 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 co-administered 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. ODV also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below).

Drugs Highly Bound to Plasma Proteins

Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine 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 Haemostasis (e.g. NSAIDs, Aspirin and Warfarin)

Serotonin release by platelets plays an important role in haemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin re-uptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when venlafaxine extended-release 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 the CYP2D6-mediated metabolism of venlafaxine, reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers. Therefore, no dosage adjustment is required when venlafaxine is co-administered 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-desmethylvenlafaxine (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 (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

Concomitant use of CYP3A4 inhibitors and venlafaxine may increase the levels of venlafaxine and ODV. Therefore, caution is advised if a patient’s therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.

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 with 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-O-desipramine AUC’s 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 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, Odesmethylvenlafaxine.

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 co-administration 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 have regular monitoring of blood pressure.

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].

Warfarin

Potentiation of anticoagulant effects, including increases in the prothrombin time (PT) or the international normalized ratio (INR) have been reported in patients taking warfarin following the addition of venlafaxine.

MAO Inhibitors

Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on venlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with an MAOI, there have also been reports of serious, sometimes fatal, reactions. For a SSRI, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on a MAOI. The effects of combined use of venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore, because venlafaxine is an inhibitor of both norepinephrine and serotonin reuptake, it is recommended that venlafaxine not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should be allowed after stopping venlafaxine before starting an MAOI.

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.

Serotonergic Drugs

Based on the mechanism of action of venlafaxine and the potential for serotonin syndrome, caution is advised when venlafaxine is co-administered 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 MAO inhibitor), lithium, tramadol, or St. John’s wort. 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. The concomitant use of venlafaxine with tryptophan supplements is not recommended.

For SSRIs, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome.

Triptans

There have been rare post marketing reports of serotonin syndrome with the use of a 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.

Use of Venlafaxine in Combination with Weight Loss Agents

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.

There are no adequate data from the use of venlafaxine in pregnant women. Animal studies are insufficient with respect to the effects on pregnancy. The potential risk for humans is unknown. Venlafaxine should not be used during pregnancy unless clearly necessary. If venlafaxine is used until or shortly before birth, discontinuation effects in the new-born should be considered. Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the new-born (PPHN). Although no studies have investigated an association of PPHN to SNRI treatment, this potential risk cannot be ruled out with venlafaxine, taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

Neonates exposed to venlafaxine, other SNRIs or SSRIs, 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, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyper-reflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of the SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin. When treating a pregnant woman with venlafaxine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

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, 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.

The effect of venlafaxine on labour and delivery in humans is unknown.

Children and Adolescents below 18 Years of Age

Venlafaxine XR should not be used in the treatment of children and adolescents below the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants, compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. Safety and effectiveness in the paediatric population have not been established. Anyone considering the use of venlafaxine in a child or adolescent must balance the potential risks with the clinical need.

Although no studies have been designed to primarily assess the impact of venlafaxine extendedrelease on the growth, development and maturation of children and adolescents, the studies that have been done suggest that venlafaxine extended-release may adversely affect weight and height. Should the decision be made to treat a paediatric patient with venlafaxine extended-release, regular monitoring of weight and height is recommended during treatment, particularly if it is to be continued long-term. The safety of venlafaxine treatment for paediatric patients has not been systematically assessed for continuous treatment longer than 6 months in duration.

In the studies conducted in paediatric patients (aged 6 to 17 years), the occurrence of blood pressure and cholesterol increases considered to be clinically relevant in paediatric patients was similar to that observed in adult patients. Consequently, the precautions for adults apply to paediatric patients.

No overall differences in effectiveness or safety were observed between geriatric patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, the greater sensitivity of some elderly individuals cannot be ruled out. SSRIs and SNRIs, including venlafaxine XR have been associated with cases of clinically significant hyponatraemia in elderly patients who may be at greater risk for this undesirable effect.

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.

Renal Impairment and Liver Cirrhosis

In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolites were decreased, thus prolonging the elimination half-lives of these substances. Dose of venlafaxine XR should be reduced in patients with moderate and severe renal impairment or hepatic cirrhosis.