Treatment of major depressive episodes.
For prevention of recurrence of major depressive episodes.
Treatment of generalised anxiety disorder.
Treatment of social anxiety disorder.
Treatment of panic disorder, with or without agoraphobia.

Posology
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.

Generalised anxiety disorder
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 225 mg/day. 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.
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.
Panic disorder
It is recommended that a dose of 37.5 mg/day of prolonged-release venlafaxine be used for 7 days.
Dosage should then be increased to 75 mg/day. Patients not responding to the 75 mg/day dose may
benefit from dose increases up to a maximum dose of 225 mg/day. 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.
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.
Paediatric population
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 section 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.

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.
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 interindividual
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). However, the time period required for tapering and
the amount of dose reduction may depend on the dose, duration of therapy and the individual patient.
In some patients, discontinuation may need to occur very gradually over periods of months or longer.
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.
Method of administration
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
prolonged-release 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.
Venlafaxine prolonged-release capsules contain spheroids, which release the active substance slowly
into the digestive tract. The insoluble portion of these spheroids is eliminated and may be seen in
faeces.

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 significant 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.
Paediatric population
Venlafaxine 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 that may affect
the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, amphetamines, lithium,
sibutramine, St.John's Wort [Hypericum perforatum], fentanyl and its analogues, tramadol,
dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicinal agents that
impair metabolism of serotonin (such as MAOIs e.g. methylene blue), with serotonin precursors (such
as tryptophan supplements) or with antipsychotics or other dopamine antagonists (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). Serotonin syndrome in its most severe form, can resemble NMS, which includes
hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and
mental status changes.
If concomitant treatment with venlafaxine and other agents that may affect the serotonergic and/or
dopaminergic neurotransmitter systems 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.

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 post
marketing 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, cases of QTc prolongation, Torsade de Pointes (TdP), ventricular
tachycardia, and fatal cardiac arrhythmias have been reported with the use of venlafaxine, especially
in overdose or in patients with other risk factors for QTc prolongation/TdP. The balance of risks and
benefits should be considered before prescribing venlafaxine to patients at high risk of serious cardiac
arrhythmia or QTc prolongation.

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
volume-depleted may be at greater risk for this event.
Abnormal bleeding
Medicinal products that inhibit serotonin uptake may lead to reduced platelet function. Bleeding
events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and
petechiae to gastrointestinal and life-threatening haemorrhages. The risk of 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. SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections
4.6, 4.8).
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 small 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
Discontinuation effects are well known to occur with antidepressants, and sometimes these effects
can be protracted and severe. Suicide/suicidal thoughts and aggression have been observed in patients
during changes in venlafaxine dosing regimen, including during discontinuation. Therefore, patients
should be closely monitored when the dose is reduced or during discontinuation (see above in section
4.4 - Suicide/suicidal thoughts or clinical worsening, and Aggression). 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, headache, visual impairment and hypertension 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 dose. Generally, these symptoms are self-limiting 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). In some patients, discontinuation could
take months or longer.
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.
Diabetes
In patients with diabetes, treatment with an SSRI or venlafaxine may alter glycaemic control. Insulin
and/or oral antidiabetic dosage may need to be adjusted.

Sexual dysfunction
Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs)
may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting
sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI.
Drug-Laboratory Test Interactions
False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have
been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests.
False positive test results may be expected for several days following discontinuation of venlafaxine
therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish
venlafaxine from PCP and amphetamine.
Sucrose
Binoven XL contains sugar spheres, containing sucrose. Patients with rare hereditary problems of
fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not
take this medicine.
Binoven XL contains Sodium
This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially
'sodium-free'.

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 nonselective 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 days 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 weak 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, a potentially life-threatening condition, may
occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect
the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, amphetamines, lithium,
sibutramine, St. John's Wort [Hypericum perforatum], fentanyl and its analogues, tramadol,
dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicinal agents that
impair metabolism of serotonin (such as MAOIs e.g. methylene blue), with serotonin precursors (such
as tryptophan supplements) or with antipsychotics or other dopamine antagonists (see section 4.3 and
4.4).
If concomitant treatment with venlafaxine and 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.
Drugs that Prolong the QT Interval
The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant
use of other medicinal products which prolong the QTc interval. Co-administration of such medicinal
products should be avoided (see section 4.4).
Relevant classes include:
• class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)
• some antipsychotics (e.g. thioridazine)
• some macrolides (e.g. erythromycin)
• some antihistamines
• some quinolone antibiotics (e.g. moxifloxacin)

The above list is not exhaustive and other individual medicinal products known to significantly
increase QT interval should be avoided.
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 O
desmethylvenlafaxine. Therefore, caution is advised if a patient's therapy includes a CYP3A4
inhibitor and venlafaxine concomitantly.
Effect of venlafaxine on other medicinal products
Drugs Metabolized by Cytochrome P450 Isoenzymes
In vivo studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did
not inhibit CYP3A4 (alprazolam and carbamazepine), CYP1A2 (caffeine), and CYP2C9
(tolbutamide) or CYP2C19 (diazepam) in vivo.
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 Odesmethylvenlafaxine. It is unknown whether a pharmacokinetic and/or
pharmacodynamics 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
O-desmethylvenlafaxine. 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
Cmax for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and Odesmethylvenlafaxine.
The clinical significance of this interaction is unknown.
Oral contraceptives
In post-marketing experience unintended pregnancies have been reported in subjects taking oral
contraceptives while on venlafaxine. There is no clear evidence these pregnancies were a result of
drug interaction with venlafaxine. No interaction study with hormonal contraceptives has been
performed.

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 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).
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.
Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following
SSRI/SNRI exposure within the month prior to birth (see sections 4.4, 4.8).

Breast-feeding
Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are excreted in breast milk. There
have been postmarketing reports of breast-fed infants who experienced crying, irritability, and
abnormal sleep patterns. Symptoms consistent with venlafaxine drug discontinuation have also been
reported after stopping breast-feeding. A risk to the suckling child cannot be excluded. Therefore, a
decision to continue/discontinue breast-feeding or to continue/discontinue therapy with venlafaxine
should be made, taking into account the benefit of breast-feeding to the child and the benefit of
venlafaxine therapy to the woman.
Fertility
Reduced fertility was observed in a study in which both male and female rats were exposed to Odesmethylvenlafaxine.
The human relevance of this finding is unknown (see section 5.3).

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).

*ADR identified post-marketing
a*Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy
or early after treatment discontinuation (see section 4.4).
b** see section 4.4.
c***In pooled clinical trials, the incidence of headache with venlafaxine and placebo were similar.
d This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4, 4.6).
Discontinuation of treatment
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, vertigo, headache and flu
syndrome are the most commonly reported reactions. Generally, these events are mild to moderate
and are self-limiting; 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. However, in some patients severe aggression, and suicidal ideation
occurred when the dose was reduced or during discontinuation (see sections 4.2 and 4.4).
Paediatric population
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.

Reporting of suspected adverse reactions
• Saudi Arabia
- The National Pharmacovigilance Center (NPC)
• SFDA Call Center: 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: https://ade.sfda.gov.sa/
 

In post marketing 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 deaths.
Published retrospective studies report that venlafaxine over dosage 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 venlafaxinetreated
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
over dosage, 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.

Pharmacotherapeutic group: Other antidepressants, ATC code: N06AX16
Mechanism of action
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 affinity 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.

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 at 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.
Biotransformation
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 minor, 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.
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).
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 half-life 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.

Sugar spheres (containing sucrose)
Hypromellose
Talc
Ethyl cellulose
Shell contents
Cap
Gelatin
Iron oxide red (E172)
Titanium dioxide (E171)
Sodium lauryl sulfate
Body
Gelatin
Iron oxide red (E172)
Titanium dioxide (E171)
Sodium lauryl sulfate
Printing ink:
Shellac
Black iron oxide (E172)

Not applicable.

Store below 30°C

Binoven XL capsules are supplied in blister pack of 30 Capsules (10’s blister x 3).

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.