Treatment of major depressive episodes. 
For prevention of recurrence of major depressive episodes.  
 Treatment of social anxiety disorder

Major depressive episodes
The recommended starting dose for prolonged-release venlafaxine is 75 mg given once daily. Patients 
not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 375 mg/day. Dosage increases can be made at intervals of 2 weeks or more. If clinically warranted due 
to symptom severity, dose increases can be made at more frequent intervals, but not less than 4 days. 
Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical 
evaluation (see section 4.4). The lowest effective dose should be maintained. 
Patients should be treated for a sufficient period of time, usually several months or longer. Treatment 
should be reassessed regularly on a case-by-case basis. Longer-term treatment may also be appropriate 
for prevention of recurrence of major depressive episodes (MDE). In most of the cases, the 
recommended dose in prevention of recurrence of MDE is the same as the one used during the current 
episode. 
Antidepressive medicinal products should continue for at least six months following remission

Social anxiety disorder
The recommended dose for prolonged-release venlafaxine is 75 mg given once daily. There is no 
evidence that higher doses confer any additional benefit. 
However, in individual patients not responding to the initial 75 mg/day, increases up to a maximum 
dose of 225 mg/day may be considered. Dosage increases can be made at intervals of 2 weeks or more.
Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical
evaluation (see section 4.4). The lowest effective dose should be maintained.
Patients should be treated for a sufficient period of time, usually several months or longer. Treatment 
should be reassessed regularly, on a case-by-case basis.
Use in elderly patients 
No specific dose adjustments of venlafaxine are considered necessary based on patient age alone. 
However, caution should be exercised in treating the elderly (e.g., due to the possibility of renal 
impairment, the potential for changes in neurotransmitter sensitivity and affinity occurring with aging). 
The lowest effective dose should always be used, and patients should be carefully monitored when an 
increase in the dose is required. 
Use in children and adolescents under the age of 18 years
Venlafaxine is not recommended for use in children and adolescents. 
Controlled clinical studies in children and adolescents with major depressive disorder failed to 
demonstrate efficacy and do not support the use of venlafaxine in these patients (see sections 4.4 and 
4.8). 
The efficacy and safety of venlafaxine for other indications in children and adolescents under the age of 
18 have not been established.

Use in patients with hepatic impairment 
In patients with mild and moderate hepatic impairment, in general a 50% dose reduction should be 
considered. However, due to inter-individual variability in clearance, individualisation of dosage may 
be desirable. 
There are limited data in patients with severe hepatic impairment. Caution is advised, and a dose 
reduction by more than 50% should be considered. The potential benefit should be weighed against the 
risk in the treatment of patients with severe hepatic impairment. 
Use in patients with renal impairment 
Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 
30-70 ml/minute, caution is advised. For patients that require haemodialysis and in patients with severe 
renal impairment (GFR < 30 ml/min), the dose should be reduced by 50%. Because of inter-individual 
variability in clearance in these patients, individualisation of dosage may be desirable. 
Withdrawal symptoms seen on discontinuation of venlafaxine 
Abrupt discontinuation should be avoided. When stopping treatment with venlafaxine, the dose should
be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal 
reactions (see sections 4.4 and 4.8). 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. 
For oral use. 
It is recommended that venlafaxine prolonged-release capsules be taken with food, at approximately the 
same time each day. Capsules must be swallowed whole with fluid and not divided, crushed, chewed, or 
dissolved. 
Patients treated with venlafaxine immediate-release tablets may be switched to venlafaxine prolongedrelease capsules at the nearest equivalent daily dosage. For example, venlafaxine immediate-release 
tablets 37.5 mg twice daily may be switched to venlafaxine prolonged-release capsules 75 mg once 
daily. Individual dosage adjustments may be necessary. 

Suicide/suicidal thoughts or clinical worsening 
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suiciderelated events). This risk persists until significant remission occurs. As improvement may not occur 
during the first few weeks or more of treatment, patients should be closely monitored until such 
improvement occurs. It is general clinical experience that the risk of suicide may increase in the early 
stages of recovery. 
Other psychiatric conditions for which venlafaxine is prescribed can also be associated with an 
increased risk of suicide-related events. In addition, these conditions may be co-morbid with major 
depressive disorder. The same precautions observed when treating patients with major depressive 
disorder should therefore be observed when treating patients with other psychiatric disorders. 
Patients with a history of suicide-related events, or those exhibiting a si gnificant degree of suicidal 
ideation prior to commencement of treatment, are known to be at greater risk of suicidal thoughts or 
suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebocontrolled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 
years old. 
Close supervision of patients, and in particular those at high risk, should accompany drug therapy, 
especially in early treatment and following dose changes. Patients (and caregivers of patients) should be 
alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual 
changes in behaviour, and to seek medical advice immediately if these symptoms present
Use in children and adolescents under 18 years of age 
[Product name] should not be used in the treatment of children and adolescents under 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. In addition, long-term safety data in children and adolescents 
concerning growth, maturation and cognitive and behavioural development are lacking. 
Serotonin syndrome 
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may 
occur with venlafaxine treatment, particularly with concomitant use of other agents, such as MAO inhibitors, that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5). 
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, 
coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular 
aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, 
vomiting, diarrhoea). 
Narrow-angle glaucoma 
Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised 
intraocular pressure or patients at risk for acute narrow-angle glaucoma (angle-closure glaucoma) be 
closely monitored. 
Blood pressure 
Dose-related increases in blood pressure have been commonly reported with venlafaxine. In some 
cases, severely elevated blood pressure requiring immediate treatment has been reported in 
postmarketing experience. All patients should be carefully screened for high blood pressure and preexisting hypertension should be controlled before initiation of treatment. Blood pressure should be 
reviewed periodically, after initiation of treatment and after dose increases. Caution should be exercised 
in patients whose underlying conditions might be compromised by increases in blood pressure, e.g., 
those with impaired cardiac function. 
Heart rate
Increases in heart rate can occur, particularly with higher doses. Caution should be exercised in patients 
whose underlying conditions might be compromised by increases in heart rate. 
Cardiac disease and risk of arrhythmia 
Venlafaxine has not been evaluated in patients with a recent history of myocardial infarction or unstable 
heart disease. Therefore, it should be used with caution in these patients. 
In postmarketing experience, fatal cardiac arrhythmias have been reported with the use of venlafaxine, 
especially in overdose. The balance of risks and benefits should be considered before prescribing 
venlafaxine to patients at high risk of serious cardiac arrhythmia. 
Convulsions 
Convulsions may occur with venlafaxine therapy. As with all antidepressants, venlafaxine should be 
introduced with caution in patients with a history of convulsions, and concerned patients should be 
closely monitored. Treatment should be discontinued in any patient who develops seizures. 
Hyponatraemia

Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) 
secretion may occur with venlafaxine. This has most frequently been reported in volume-depleted or 
dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volumedepleted may be at greater risk for this event. 
Abnormal bleeding 
Medicinal products that inhibit serotonin uptake may lead to reduced platelet function. The risk of skin 
and mucous membrane bleeding, including gastrointestinal haemorrhage, may be increased in patients 
taking venlafaxine. As with other serotonin-reuptake inhibitors, venlafaxine should be used cautiously 
in patients predisposed to bleeding, including patients on anticoagulants and platelet inhibitors. 
Serum cholesterol 
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 clinical trials. 
Measurement of serum cholesterol levels should be considered during long-term treatment. 
Co-administration 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. 
Mania/hypomania 
Mania/hypomania may occur in a small proportion of patients with mood disorders who have received 
antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used 
cautiously in patients with a history or family history of bipolar disorder. 
Aggression 
Aggression may occur in a sm all number of patients who have received antidepressants, including 
venlafaxine. This has been reported under initiation, dose changes and discontinuation of treatment. 
As with other antidepressants, venlafaxine should be used cautiously in patients with a history of 
aggression. 
Discontinuation of treatment 
Withdrawal symptoms, when treatment is discontinued, are common, particularly if discontinuation is 
abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation (tapering and 
post-tapering) occurred in approximately 31% of patients treated with venlafaxine and 17% of patients 
taking placebo.

The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose 
of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), 
sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or 
vomiting, tremor and headache are the most commonly reported reactions. Generally, these symptoms 
are mild to moderate; however, in some patients they may be severe in intensity. They usually occur 
within the first few days of discontinuing treatment, but there have been very rare reports of such 
symptoms in patients who have inadvertently missed a d ose. Generally, these symptoms are selflimiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 
months or more). It is therefore advised that venlafaxine should be gradually tapered when 
discontinuing treatment over a period of several weeks or months, according to the patient’s needs (see 
section 4.2). 
Akathisia/psychomotor restlessness 
The use of venlafaxine has been associated with the development of akathisia, characterised 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. 
Dry mouth 
Dry mouth is reported in 10% of patients treated with venlafaxine. This may increase the risk of caries, 
and patients should be advised upon the importance of dental hygiene.

Monoamine Oxidase Inhibitors (MAOI) 
Irreversible non-selective MAOIs 
Venlafaxine must not be used in combination with irreversible non-selective MAOIs. Venlafaxine must 
not be initiated for at least 14 days after discontinuation of treatment with an irreversible nonselective 
MAOI. Venlafaxine must be discontinued for at least 7 days before starting treatment with an 
irreversible non-selective MAOI (see sections 4.3 and 4.4). 
Reversible, selective MAO-A inhibitor (moclobemide) 
Due to the risk of serotonin syndrome, the combination of venlafaxine with a reversible and selective 
MAOI, such as moclobemide, is not recommended. Following treatment with a reversible MAOinhibitor, a shorter withdrawal period than 14 da ys may be used before initiation of venlafaxine 
treatment. It is recommended that venlafaxine should be discontinued for at least 7 days before starting 
treatment with a reversible MAOI (see section 4.4). 
Reversible, non-selective MAOI (linezolid) 
The antibiotic linezolid is a w eak reversible and non-selective MAOI and should not be given to patients treated with venlafaxine (see section 4.4).

Severe adverse reactions have been reported in patients who have recently been discontinued from an 
MAOI and started on venlafaxine, or have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. 
Serotonin syndrome 
As with other serotonergic agents, serotonin syndrome may occur with venlafaxine treatment, 
particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter 
system (including triptans, SSRIs, SNRIs, lithium, sibutramine, tramadol, or St. John's Wort 
[Hypericum perforatum]), with medicinal agents which impair metabolism of serotonin (including 
MAOIs), or with serotonin precursors (such as tryptophan supplements). 
If concomitant treatment of venlafaxine with an SSRI, an SNRI or a serotonin receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see section 4.4). 
CNS-active substances 
The risk of using venlafaxine in combination with other CNS-active substances has not been 
systematically evaluated. Consequently, caution is advised when venlafaxine is taken in combination 
with other CNS-active substances. 
Ethanol 
Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by 
ethanol. However, as with all CNS-active substances, patients should be advised to avoid alcohol 
consumption. 
Effect of other medicinal products on venlafaxine 
Ketoconazole (CYP3A4 inhibitor) 
A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and poor metabolisers (PM) resulted in higher AUC of venlafaxine (70% and 21% in CYP2D6 PM and EM subjects, respectively) and O-desmethylvenlafaxine (33% and 23% in CYP2D6 PM and EM subjects, respectively) following administration of ketoconazole. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) and venlafaxine may increase levels of venlafaxine and Odesmethylvenlafaxine. Therefore, caution is advised if a patient’s therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly. 
Effect of venlafaxine on other medicinal products 
Lithium 
Serotonin syndrome may occur with the concomitant use of venlafaxine and lithium (see Serotonin syndrome). 

Diazepam 
Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam. Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or O-desmethylvenlafaxine. It is unknown whether a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines exists. 

Imipramine

 Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. There was a dose-dependent increase of 2-OH-desipramine AUC by 2.5 to 4.5-fold when venlafaxine 75 mg to 150 mg daily was administered. Imipramine did not affect the pharmacokinetics of venlafaxine and Odesmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised with co-administration of venlafaxine and imipramine. 
 
Haloperidol 
A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, a 70% increase in AUC, an 88% increase in Cmax, but no change in half-life for haloperidol. This should be taken into account in patients treated with haloperidol and venlafaxine concomitantly. The clinical significance of this interaction is unknown. 
Risperidone 

Venlafaxine increased the risperidone AUC by 50%, but did not significantly alter the pharmacokinetic 
profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown. 

Metoprolol 
Concomitant administration of venlafaxine and metoprolol to healthy volunteers in a pharmacokinetic 
interaction study for both medicinal products resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active 
metabolite, α-hydroxymetoprolol. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, 
O-desmethylvenlafaxine. Caution should be exercised with co-administration of venlafaxine and metoprolol. 

Indinavir 
A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a 36% decrease in Cmaxfor indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown.

Pregnancy 
There are no adequate data from the use of venlafaxine in pregnant women. 
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Venlafaxine must only be administered to pregnant women if the expected benefits outweigh any possible risk. 
As with other serotonin reuptake inhibitors (SSRIs/SNRIs), discontinuation symptoms may occur in the newborns if venlafaxine is used until or shortly before birth. Some newborns exposed to venlafaxine late in the third trimester have developed complications requiring tube-feeding, respiratory support or prolonged hospitalisation. Such complications can arise immediately upon delivery. 
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 newborn (PPHN). Although no s tudies have investigated an association of PPHN to SNRI treatment, this potential risk cannot be ruled out with [Product name] t aking into account the related 
mechanism of action (inhibition of the re-uptake of serotonin). 
The following symptoms may be observed in neonates if the mother has used an SSRI/SNRI late in pregnancy: irritability, tremor, hypotonia, persistent crying, and difficulty in sucking or in sleeping. 
These symptoms may be due to either serotonergic effects or exposure symptoms. In the majority of cases, these complications are observed immediately or within 24 hours after partus. 
Lactation 
Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are excreted in breast milk. A risk to the suckling child cannot be excluded. Therefore, a decision to continue/discontinue breast-feeding or to continue/discontinue therapy with [Product name] should be made, taking into account the benefit of breast-feeding to the child and the benefit of [Product name] therapy to the woman.

Any psychoactive medicinal product may impair judgment, thinking, and motor skills. Therefore, any patient receiving venlafaxine should be cautioned about their ability to drive or operate hazardous machinery. 

The most commonly (>1/10) reported adverse reactions in clinical studies were nausea, dry mouth, headache and sweating (including night sweats).  
 
Adverse reactions are listed below by system organ class and frequency.  
 
Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data).  

*In pooled clinical trials, the incidence of headache was 30.3% with venlafaxine versus 31.3% with placebo.

**Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment discontinuation (see section 4.4). Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraethesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, headache and flu syndrome are 
the most commonly reported reactions. Generally, these events are mild to moderate and are selflimiting; however, in some patients, they may be severe and/or prolonged. It is therefore advised that 
when venlafaxine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4). 
Paediatric patients 

In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical trials) in children 
and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, 
weight loss, increased blood pressure, and increased serum cholesterol were observed (see section 4.4). 
In paediatric clinical trials the adverse reaction suicidal ideation was observed. There were also increased reports of hostility and, especially in major depressive disorder, self-harm. Particularly, the following adverse reactions were observed in paediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

In postmarketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other medicinal products. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other reported events include electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, vertigo, and death. 
Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher burden of suicide risk factors than SSRI patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristics of venlafaxine-treated patients, is not clear. Prescriptions for venlafaxine should be written for the smallest quantity of the medicinal product consistent with good patient management in order to reduce the risk of overdose. 

Recommended treatment 
General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs must be monitored. When there is a risk of aspiration, induction of emesis is not recommended. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Administration of activated charcoal may also limit absorption of the active substance. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for 
venlafaxine are known.

5.1 Pharmacodynamic properties 
Pharmacotherapeutic group: Other antidepressants - ATC code: NO6A X16. 
The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its 
potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown 
that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are inhibitors of serotonin 
and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its 
active metabolite reduce β-adrenergic responsiveness after both acute (single dose) and chronic 
administration. Venlafaxine and ODV are very similar with respect to their overall action on 
neurotransmitter reuptake and receptor binding. 
Venlafaxine has virtually no a ffinity for rat brain muscarinic, cholinergic, H1-histaminergic or α1-
adrenergic receptors in vitro. Pharmacological activity at these receptors may be related to various side 
effects seen with other antidepressant medicinal products, such as anticholinergic, sedative and 
cardiovascular side effects. 
 
Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity. 
In vitro studies revealed that venlafaxine has virtually no affinity for opiate or benzodiazepine sensitive 
receptors. 
Major depressive episodes 
The efficacy of venlafaxine immediate-release as a treatment for major depressive episodes was 
demonstrated in five randomised, double-blind, placebo-controlled, short-term trials ranging from 4 to 6 
weeks duration, for doses up t o 375 m g/day. The efficacy of venlafaxine prolonged-release as a 
treatment for major depressive episodes was established in two placebo-controlled, short-term studies 
for 8 and 12 weeks duration, which included a dose range of 75 to 225 mg/day. 
In one longer-term study, adult outpatients who had responded during an 8-week open trial on 
venlafaxine prolonged-release (75, 150, o r 225 m g) were randomised to continuation of their same 
venlafaxine prolonged-release dose or to placebo, for up to 26 weeks of observation for relapse. 
In a second longer-term study, the efficacy of venlafaxine in prevention of recurrent depressive 
episodes for a 12-month period was established in a placebo-controlled double-blind clinical trial in 
adult outpatients with recurrent major depressive episodes who had responded to venlafaxine treatment 
(100 to 200 mg/day, on a b.i.d. schedule) on the last episode of depression. 
Social anxiety disorder 
The efficacy of venlafaxine prolonged-release capsules as a treatment for social anxiety disorder was 
established in four double-blind, parallel-group, 12-week, multi-center, placebo-controlled, flexible dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose 
study in adult outpatients. Patients received doses in a range of 75 to 225 mg/day. There was no 
evidence for any greater effectiveness of the 150 to 225 mg/day group compared to the 75 m g/day 
group in the 6-month study.

Venlafaxine is extensively metabolised, primarily to the active metabolite, O-desmethylvenlafaxine 
(ODV). Mean ± SD plasma half-lives of venlafaxine and ODV are 5±2 hours and 11±2 hours, 
respectively. Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral 
multiple-dose therapy. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75 mg to 
450 mg/day. 
Absorption 
At least 92% of venlafaxine is absorbed following single oral doses of immediate-release venlafaxine. 
Absolute bioavailability is 40% to 45% due to presystemic metabolism. After immediate-release 
venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 
hours, respectively. Following the administration of venlafaxine prolonged-release capsules, peak 
plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. 
When equal daily doses of venlafaxine are administered as either an immediate-release tablet or 
prolonged-release capsule, the prolonged-release capsule provides a slower rate of absorption, but the 
same extent of absorption compared with the immediate-release tablet. Food does not affect the 
bioavailability of venlafaxine and ODV. 
Distribution 
Venlafaxine and ODV are minimally bound a t therapeutic concentrations to human plasma proteins 
(27% and 30%, respectively). The volume of distribution for venlafaxine at steady-state is 4.4±1.6 L/kg 
following intravenous administration. 
Metabolism 
Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that 
venlafaxine is biotransformed to its major active metabolite, ODV, by CYP2D6. In vitro and in vivo 
studies indicate that venlafaxine is metabolised to a m inor, less active metabolite, Ndesmethylvenlafaxine, by CYP3A4. In vitro and in vivo studies indicate that venlafaxine is a weak 
inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9, or CYP3A4. 
Elimination 
Venlafaxine and its metabolites are excreted primarily through the kidneys. Approximately 87% of a 
venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), 
unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Mean ± 
SD plasma steady-state clearances of venlafaxine and ODV are 1.3±0.6 L/h/kg and 0.4±0.2 L/h/kg, 
respectively. 

Special populations 
Age and gender 
Subject age and gender do not significantly affect the pharmacokinetics of venlafaxine and ODV. 
CYP2D6 extensive/poor metabolisers 
Plasma concentrations of venlafaxine are higher in CYP2D6 poor metabolisers than extensive 
metabolisers. Because the total exposure (AUC) of venlafaxine and ODV is similar in poor and 
extensive metabolisers, there is no need for different venlafaxine dosing regimens for these two 
groups. 
Patients with hepatic impairment 
In Child-Pugh A (mildly hepatically impaired) and Child-Pugh B (moderately hepatically impaired) 
subjects, venlafaxine and ODV half-lives were prolonged compared to normal subjects. The oral 
clearance of both venlafaxine and ODV was reduced. A large degree of intersubject variability was 
noted. There are limited data in patients with severe hepatic impairment (see section 4.2). 
Patients with renal impairment 
In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance 
reduced by about 57% compared to normal subjects, while ODV elimination halflife was prolonged by 
about 142% and clearance reduced by about 56%. Dosage adjustment is necessary in patients with 
severe renal impairment and in patients that require haemodialysis (see section 4.2)

Studies with venlafaxine in rats and mice revealed no evidence of carcinogenesis. Venlafaxine was not 
mutagenic in a wide range of in vitro and in vivo tests.
Animal studies regarding reproductive toxicity have found in rats a decrease in pup weight, an increase 
in stillborn pups, and an increase in pup deaths during the first 5 days of lactation. The cause of these 
deaths is unknown. These effects occurred at 30 mg/kg/day, 4 times the human daily dose of 375 mg of 
venlafaxine (on an mg/kg basis). The no-effect dose for these findings was 1.3 times the human dose. 
The potential risk for humans is unknown. 
Reduced fertility was observed in a study in which both male and female rats were exposed to ODV. 
This exposure was approximately 1 to 2 times that of a human venlafaxine dose of 375 mg/day. The 
human relevance of this finding is unknown. 

75 mg prolonged-release capsules, hard:
Capsule content: 
Hypromellose 
Ammonio methacrylate copolymer (type B)
Sodium larilsulfate

Magnesium stearate
Coating: 
Basic butylated methacrylate copolymer 12.5% 
Capsule shell: 
Gelatin
Titanium dioxide (E 171) 
Red iron oxide (E172) 
Printing ink:
Shellac
Black iron oxide (E172) 
Propylene glycol (E1520)

150 mg prolonged-release capsules, hard:
Capsule content: 
Hypromellose 
Ammonio methacrylate copolymer (type B)
Sodium larilsulfate 
Magnesium stearate
Coating: 
Basic butylated methacrylate copolymer 12.5% 
Capsule shell: 
Gelatin
Titanium dioxide (E 171) 
Erythrosine (E127)
Indigotin I (E 132) 
Printing ink:
Shellac
Black iron oxide (E172) 
Propylene glycol (E1520)

Not applicable.

Store below 30ºC

PVC/PE/PVDC/Al blister
37.5 mg: 10, 14, 28, 30 and 98 prolonged-release capsules, hard 
75 mg: 10, 14, 28, 30, 60 and 98 prolonged-release capsules, hard 
150 mg: 10, 14, 28, 30, 60 and 98 prolonged-release capsules, hard 
Not all pack sizes may be marketed.

No special requirements.