VENLAFAXINE 37.5 MG TABLETS

Active substance: VENLAFAXINE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Venlafaxine 37.5 mg Tablets.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 37.5 mg of Venlafaxine as Venlafaxine Hydrochloride Ph.Eur. as
the active substance.
Excipients of known effect: Also contains 52.08 mg of Lactose Monohydrate.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Peach coloured, circular, flat faced, bevelled edged, uncoated tablets having ‘37.5’
embossed on one side and ‘BL’ on the other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Venlafaxine tablets are indicated for the



4.2

treatment of major depressive disorder
prevention of the recurrence of major depressive episodes.

Posology and method of administration
Major depressive episodes:
The recommended starting dose is 75mg per day given in two divided doses (37.5 mg
twice daily).

Patients not responding to the initial 75mg/day dose may benefit from dose increases
upto a maximum dose of 375mg/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.
There may be an increased risk of side effects at higher doses and dose increments
should be made only after a clinical evaluation and after at least 3-4 weeks of therapy
(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. Longer-term treatment may also be appropriate for prevention of recurrence
of major depressive episodes (MDE). Usually, the dosage for prevention of relapse or
for prevention of recurrence of a new episode is similar to that used during the index
episode. Patients should be re-assessed regularly on a case-by-case basis.
Anti-depressive medicinal products should continue for at least 6 months following
remission.

Use in patients with renal impairment
For patients with mild renal impairment with glomerular filtration rate (GFR between
30-70ml/minute) no change in dosage is necessary but caution is advised.
For patients that require haemodialysis and in patients with severe renal impairment
(GFR <30ml/minute) the dose should be reduced by 50%.
Because of inter-individual variability in clearance in these patients, individualization
of dosage may be desirable.

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
Elderly Patients
No specific dosage adjustment in the usual dosage is recommended for elderly
patients, based on the 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/adolescents under 18 years of age

Venlafaxine is not recommended for use in children and adolescents under 18 years of
age. 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.
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.

Route of administration: oral
It is recommended to take venlafaxine tablets with food, at approximately the same
time each day. Tablets must be swallowed whole with fluid, not divided, crushed,
chewed, or dissolved.
Patients treated with venlafaxine tablets may be switched to venlafaxine prolongedrelease capsules at the nearest equivalent daily dosage. For example, venlafaxine
tablets 37.5mg (immediate-release) twice daily may be switched to venlafaxine
prolonged-release capsules 75mg once daily. Individual dosage adjustments may be
necessary.

4.3

Contraindications



Known hypersensitivity to venlafaxine or any of the excipients.

• Concomitant use of venlafaxine with irreversible monoamine oxidase inhibitors
(MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms
such as agitation, tremor and hyperthermia. Venlafaxine must not be initiated for at
least 14 days after discontinuation of treatment with an irreversible MAOI.
• Venlafaxine tablets must be discontinued for at least 7 days before starting treatment
with an irreversible MAOI (see sections 4.4 and 4.5).

4.4

Special warnings and precautions for use

Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self-harm and
suicide (suicide-related 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 placebo-controlled 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
Venlafaxine should not be used in the treatment of children and adolescents under 18
years of age. Suicide-related behaviours (suicide attempt and suicidal thoughts) and
hostility (predominantly aggression, oppositional behavior and anger) were more
frequently observed in clinical trials among children and adolescents treated with
anti-depressants 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.

Withdrawal symptoms seen on discontinuation of venlafaxine 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 in approximately 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
abnormal dreams), agitation or anxiety, nausea and/or vomiting, tremor and,
headache, most commonly reported withdrawal 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)

Mania or hypomania
Mania or hypomania may occur in a small proportion of patients with mood disorders
who have received antidepressants, including venlafaxine. As with all
antidepressants, Venlafaxine tablets should be used with caution 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.

Psychomotor restlessness (Akathisia)
The use of venlafaxine has been associated with the development of psychomotor
restlessness, 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.

Patients with 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 post marketing experience, fatal cardiac arrhythmias have been reported with 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.

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.

Blood pressure
Dose related increases in blood pressure has been reported commonlywith
venlafaxine. In some cases, severely elevated blood pressure requiring immediate
treatment has been reported in post marketing experience. Periodic measurement of
blood pressure is therefore recommended for patients receiving venlafaxine after
initiation of treatment. Pre-existing hypertension should be controlled before
treatment with venlafaxine. Caution should be exercised in patients whose underlying
conditions might be compromised by increases in blood pressure, e.g., those with
impaired cardiac function.
Seizures (convulsions)
Convulsions may occur with venlafaxine therapy. As with all antidepressants,
venlafaxine tablets should be introduced with caution in patients with a history of
seizure and concerned patients should be closely monitored. Treatment should be
discontinued in any patient developing a seizure.

Hyponatraemia (Syndrome of Inappropriate Antidiuretic Hormone (SIADH))
Cases of hyponatraemia and or the 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.

Mydriasis (Narrow angle glaucoma)
Mydriasis has been reported in association with venlafaxine; therefore patients with
raised intra-ocular pressure or patients at a risk of narrow angle glaucoma (angleclosure glaucoma) should be monitored closely.

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 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.

Serotonin syndrome
As with other serotonergic agents, serotonin syndrome or Neuroleptic Malignant
Syndrome (NMS), potentially life threatening conditions may occur with venlafaxine
treatment, particularly with concomitant use of other agents(including SSRIs, SNRIs
and triptans), with agents that impair metabolism of serotonin such as MAOIs, or
with antipsychotics or other dopamine agonists (see sections 4.3 and 4.5)
Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood
pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia,
incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting and
diarrhoea).
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.
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 anti-diabetic dosage may need to be adjusted

Lactose intolerance
These tablets contain lactose and therefore should not be administered to patients with
rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
glucose-galactose malabsorption.

4.5

Interaction with other medicinal products and other forms of interaction
MAOIs:
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 non-selective 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 MAO-inhibitor, 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).
Adverse reactions, some serious, have been reported when venlafaxine therapy is
initiated soon after discontinuation of an MAOI, and when an MAOI is initiated soon
after discontinuation of venlafaxine. These reactions have included tremor,
myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with
features resembling neuroleptic malignant syndrome, seizures and death

Serotonergic drugs
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, 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).

Ethanol
Venlafaxine has been shown not to increase the impairment of mental or motor skills
caused by ethanol. However, as with all CNS-active drugs, patients should be advised
to avoid alcohol consumption.

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.
Effect of venlafaxine on other medicinal products:
Lithium
Serotonin syndrome may occur with the concominant use of venlafaxine and lithium
(see Serotonin syndrome)

Imipramine
Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OHimipramine. There was a dose-dependent increase of 2-OH-desipramine AUC by 2.5
to 4.5-fold when venlafaxine 75mg to 150mg 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
In a pharmacokinetic study co-administration of venlafaxine with a single 2mg oral
dose of haloperidol resulted in a 42% decrease in total oral clearance, a 70% increase
in AUC and an 88% increase in Cmax 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 9hydroxyrisperidone). The clinical significance of the 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, -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, odesmethylvenlafaxine. Caution should be exercised with co-administration of
venlafaxine and metoprolol.

α

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 ODV. The clinical significance of this interaction is not known.

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 0-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 0-desmethylvenlafaxine. Therefore, caution is
advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine
concomitantly.

4.6

Fertility, pregnancy and lactation
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 (SSRI’s), if venlafaxine is used until or
shortly before birth, discontinuation symptoms may occur in the newborns. 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 Tablets
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.

Lactation
There is evidence to suggest that venlafaxine and its metabolite, ODV(Odesmethylvenlafaxine), are excreted in breast milk. There have been post-marketing
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.

4.7

Effects on ability to drive and use machines
Any psychoactive drug may impair judgement, thinking or motor skills. Therefore,
patients receiving venlafaxine should be cautioned about their ability to drive or
operate hazardous machinery.

4.8

Undesirable effects
The most commonly (>1/10) observed adverse events associated with the use of
venlafaxine in clinical trials were: nausea, dry mouth, headache, sweating, (including
night sweats)
Adverse events observed with venlafaxine, are classified by system organ class and
frequency listed below as:

very common (>1/10); common (<1/10 and >1/100); uncommon (<1/100 and
>1/1000) rare (<1/1000); not known (cannot be estimated from available data).

Blood and lymphatic system disorders
Uncommon: ecchymosis, gastrointestinal haemorrhage
Not known: blood dyscrasias (including agranulocytosis, aplastic anaemia,
neutropenia and pancytopenia), thrombocytopenia, mucous membrane bleeding,
prolonged bleeding time

Cardiovascular and vascular disorders
Common: hypertension, palpitation, vasodilatation (mostly hot flashes/flushes)
Uncommon: postural hypotension, syncope, tachycardia
Not known: hypotension, Torsade de Pointes, QT prolongation, ventricular
tachycardia, ventricular fibrillation.

Gastrointestinal disorders –
Very common: nausea (20.0%)
Common: anorexia (appetite decreased), constipation, vomiting
Uncommon: bruxism; diarrhoea
Not known: pancreatitis.

General disorders
Common: asthenia (fatigue), chills
Uncommon: angioedema, photosensitivity reaction
Not known: anaphylaxis.

Metabolic and nutritional disorders
Common: serum cholesterol increased,, weight loss
Uncommon: weight gain
Not known: abnormal liver function tests, hyponatraemia, hepatitis, Syndrome of
Inappropriate Antidiuretic Hormone Secretion (SIADH), increased prolactin

Musculo-skeletal disorders
Not known: rhabdomyolysis.

Neurological disorders
Very common: dry mouth (10.0%), headache (30.3%)*
Common: abnormal dreams, decreased libido, dizziness, insomnia, nervousness,
sedation, confusion, increased muscle tonus ( hypertonia), paraesthesia, tremor,
depersonalistaion
Uncommon: apathy, hallucinations, myoclonus, agitation, impaired coordination and
balance
Rare: akathisia/psychomotor restlessness, convulsion, manic reaction
Not known: neuroleptic malignant syndrome-(NMS), serotonergic syndrome,
delirium, extrapyramidal disorders including dyskinesia and dystonia, tardive
dyskinesia, suicidal ideation and behaviours**, vertigo, aggression***

Renal and urinary disorders
Common: pollakiuria (abnormal urinary frequency), urination impaired (mostly
hesitancy)
Uncommon: urinary retention.

Reproductive and breast disorders
Common: anorgasmia, erectile dysfunction (impotence), abnormal ejaculation/orgasm
(males), menstrual disorders associated with increased bleeding or increased irregular
bleeding (e.g. menorrhagia, metrorrhagia)
Uncommon: abnormal orgasm (females)

Respiratory system disorders
Common: yawning
Not known: pulmonary eosinophilia.

Skin and subcutaneous tissue disorders
Very common: sweating (including night sweats [12.2%])
Uncommon: rash, alopecia
Not known: erythema multiforme, Stevens Johnson syndrome, Toxic epidermal
necrolysis, pruritus, urticaria

Special senses
Common: abnormal vision/ accommodation, mydriasis,
Uncommon: altered taste sensation, tinnitus

Not known: angle closure glaucoma.

*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).
*** See section 4.4.

Withdrawal symptoms seen on discontinuation of venlafaxine treatment
Discontinuation of venlafaxine (particularly when abrupt) commonly leads to
withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia and
electric shock sensations), sleep disturbances (including insomnia and abnormal
dreams), agitation or anxiety, nausea and/or vomiting, tremor, vertigo, headache and
flu syndrome are the most commonly reported withdrawal 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
(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.

4.9

Overdose

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 Electrocardiogram changes (e.g. prolongation of QT
interval, bundle branch block, QRS prolongation), ventricular tachycardia,
bradycardia and hypotension, vertigo and death.
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 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
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.

Management of over dosage
Ensure an adequate airway, oxygenation and ventilation. Monitoring of cardiac
rhythm and vital signs is recommended, as are general supportive and symptomatic
measures.. Where there is a risk of aspiration, induction of emesis is not
recommended. No specific antidotes for venlafaxine are known. 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, haemoperfusion and exchange transfusion are
unlikely to be of benefit.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
ATC Code: NO6AX16
Pharmacotherapeutic group: Antidepressants

Venlafaxine tablets are a structurally novel antidepressant which is chemically
unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is a race
mate with two active enantiomers.

The mechanism of Venlafaxine tablets 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, Odesmethylvenlafaxine, are potent neuronal serotonin and noradrenaline re-uptake
inhibitors (SNRI). In addition, venlafaxine and O-desmethylvenlafaxine reduce adrenergic responsiveness in animals after both acute (single dose) and chronic
administration. Venlafaxine and its major metabolite ODV appear to be equipotent
with respect to their overall action on neurotransmitter re-uptake and receptor
binding.

β

Venlafaxine has virtually no affinity for rat brain muscarinic, cholinergic, H1histaminergic or 1- adrenergic receptors in vitro. Pharmacologic activity at these
receptors may be related to various side effects seen with other antidepressant drugs,
such as anticholinergic, sedative and cardiovascular effects.

α

Venlafaxine does not possess monoamine oxidase (MAO) inhibitor 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 to 375mg/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 225mg/day.
In one longer-term study, adult outpatients who had responded during an 8-week open
trial on venlafaxine prolonged-release (75, 150, or 225mg) 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 200mg/day, on a b.i.d.
schedule) on the last episode of depression

5.2

Pharmacokinetic properties
Venlafaxine is extensively metabolised, primarily to the active metabolite, Odesmethylvenlafaxine (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 75mg to
450mg/day.
Absorption
At least 92% of venlafaxine is absorbed following single oral doses of immediaterelease 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 immediaterelease 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.
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
minor, less active metabolite, N-desmethylvenlafaxine, 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±0.6L/h/kg and 0.4±0.2L/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 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).

5.3

Preclinical safety data
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
30mg/kg/day, 4 times the human daily dose of 375mg 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 the major metabolite of venlafaxine (ODV). This exposure was
approximately 1 to 2 times that of a human dose of 375mg/day of venlafaxine. The
human relevance of this finding is unknown

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Microcrystalline cellulose
Lactose monohydrate
Sodium starch glycollate
Pregelatinised starch
Magnesium stearate
Yellow iron oxide (E172)
Red iron oxide (E172).

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Do not store above 25°C.
Store in the original package

6.5

Nature and contents of container
PVC /Aluminium foil blisters of 28 or 56 tablets.

6.6

Special precautions for disposal
None.

7

MARKETING AUTHORISATION HOLDER
Bristol Laboratories Limited
Unit 3, Canalside, Northbridge Road
Berkhamsted, Herts, HP4 1EG
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 17907/ 0250

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
24/02/2011

10

DATE OF REVISION OF THE TEXT
21/05/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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