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VENSIR XL 75MG PROLONGED RELEASE HARD CAPSULES

Active substance(s): VENLAFAXINE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Vensir XL 75mg prolonged release hard capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains venlafaxine hydrochloride equivalent to 75mg of venlafaxine
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged release hard capsules. The capsules are peach opaque / peach opaque size
‘1’ hard gelatin capsules having thick and thin radial circular band on the body in red
ink and thick and thin radial circular band on the cap in red ink. The capsule is filled
with 6 white to off-white round biconvex film coated mini tablets of 12.5mg.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
The treatment of major depressive disorder
The prevention of relapses of the initial episode of depression or for the prevention of
the recurrence of new episodes.
All patients should be evaluated for the risk of suicidality and monitored for clinical
worsening (see section 4.2 and 4.4).”

4.2

Posology and method of administration
For oral administration to adults only. The capsules should be swallowed
unchewed and with liquid (e.g. a glass of water) and taken with food.

Major depressive disorder: Adults and the elderly: 75mg/day to 150mg/day. A
dose of 75mg/day is recommended as the initial dose. Although there may be
an increased potential for undesirable effects at higher doses, a dose increase
may be considered after three weeks if there is no response.
In more severely depressed or hospitalised patients, and under close
supervision of a physician, the daily dose may then be increased by up to
75mg every two or three days until the desired response is achieved. In those
more severely depressed or hospitalised patients who require daily doses of
300 mg or more, treatment should be initiated under specialist supervision
including shared care arrangements. The maximum recommended dose is
375mg/day.
The dose should then be gradually reduced, to the minimum effective dose
consistent with patient response and tolerance. A limited amount of
venlafaxine should be provided to reduce the risk from overdose (see section
4.4).
Prevention of relapse or for prevention of recurrence of a new episode: The
dosage is similar to that used during the index episode. Patients should be reassessed regularly in order to evaluate the benefit of long-term therapy.

Patients at increased risk for suicide (see also sections 4.4 and 4.9)
Patients with increased risk factors for suicide should be carefully evaluated
for the presence or worsening of suicide-related behaviour (see sections 4.4
and 4.9) and a limited number of tablets should be provided to reduce the risk
from overdose. A maximum of two weeks supply should be considered in
these patients at initiation of treatment, during any dosage adjustment and until
improvement occurs.

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 Vensir
XL in these patients (see sections 4.4 and 4.8).
The efficacy and safety of Vensir XL for other indications in children and
adolescents under the age of 18 have not yet 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. This dose may be
given once daily due to the longer half-lives of venlafaxine and Odesmethylvenlafaxine (ODV) in these patients.
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 Vensir XL 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
Vensir XL at the nearest equivalent daily dosage. For example, venlafaxine
immediate-release tablets 37.5 mg twice daily may be switched to Vensir XL
75 mg once daily. Individual dosage adjustments may be necessary.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Concomitant treatment 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 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 Vensir XL 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

Use in children and adolescents under 18 years of age
Vensir XL 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, the development of a potentially lifethreatening serotonin-syndrome or Neuroleptic Malignant Syndrome (NMS)like reactions, may occur with venlafaxine treatment, particularly with
concomitant use of other serotonergic agents (including SSRIs, SNRIs and
triptans), with agents that impair metabolism of serotonin such as MAOinhibitors, 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 narrowangle 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 pre-existing
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. Coadministration 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
Withdrawal symptoms when treatment is discontinued are common,
particularly if discontinuation is abrupt (see section 4.8 Undesirable effects).
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 placebo patients.
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 and electric shock
sensations), sleep disturbances (including insomnia and abnormal dreams),
agitation or anxiety, nausea and/or vomiting, tremor, sweating, headache,
diarrhoea, palpitations and emotional instability are the 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 "Withdrawal
Symptoms Seen on Discontinuation of Venlafaxine", Section 4.2 Posology
and Method of Administration).

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 anti-diabetic dosage may need to be
adjusted.

4.5

Interaction with other medicinal products and other forms of interaction

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 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).
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 lifethreatening 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 that impair metabolism of serotonin (such as MAOIs), or
with serotonin precursors (such as tryptophan supplements).
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.
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 Odesmethylvenlafaxine. 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-OHimipramine. 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 9hydroxyrisperidone). 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, Odesmethylvenlafaxine. 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 O-desmethylvenlafaxine. The clinical
significance of this interaction is unknown.
Clozapine
Increased levels of clozapine, that were temporally associated with adverse
events, including seizures, have been reported following the addition of
venlafaxine.
ECT
There is little clinical experience of the concurrent use of venlafaxine with
ECT. As prolonged seizure activity has been reported with concomitant SSRI
antidepressants, caution is advised.
4.6

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 (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 Vensir XL, 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
Venlafaxine and its active metabolite, O-desmethylvenlafaxine, 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 Vensir XL should be made, taking into
account the benefit of breast-feeding to the child and the benefit of Vensir XL
therapy to the woman.

4.7

Effects on ability to drive and use machines
Although venlafaxine has been shown not to affect psychomotor, cognitive, or
complex behaviour performance in healthy volunteers, any psychoactive drug may
impair judgement, thinking or motor skills. Therefore patients should be cautioned
about their ability to drive or operate hazardous machinery.

4.8

Undesirable effects

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).

Body System

Very
Common
Common

Haematological
/ Lymphatic

Rare

Ecchymosis,
Gastrointestinal
haemorrhage

Metabolic/
Nutritional

Nervous

Uncommon

Mucous
membrane
bleeding,
Prolonged
bleeding time,
Thrombocytop
aenia, Blood
dyscrasias,
(including
agranulocytosi
s, aplastic
anaemia,
neutropaenia
and
pancytopaenia
)

Serum cholesterol Weight gain
increased, Weight
loss

Dry
mouth
(10.0%),
Headache
(30.3%)*

Abnormal dreams,
Decreased libido,
Dizziness,
Increased muscle
tonus (hypertonia),
Insomnia,
Nervousness,
Paresthesia,
Sedation, Tremor,
Confusion,
Depersonalisation

Apathy,
Hallucinations,
Myoclonus,
Agitation,
Impaired
coordination
and balance

Not Known

Abnormal
liver function
tests,
Hyponatraemi
a, Hepatitis,
Syndrome of
Inappropriate
Antidiuretic
Hormone
Secretion
(SIADH),
Prolactin
increased
Akathisia/
Psychomotor
restlessness,
Convulsion,
Manic
reaction

Neuroleptic
Malignant
Syndrome
(NMS),
Serotonergic
syndrome,
Delirium,
Extrapyramida
l reactions
(including
dystonia and

dyskinesia),
Tardive
dyskinesia,
Suicidal
ideation and
behaviours**,
Vertigo,
Aggression***
Special Senses

Abnormality of
accommodation,
Mydriasis, Visual
disturbance,

Altered taste
sensation,
Tinnitus

Angle-closure
glaucoma

Cardiovascular

Hypertension,
Vasodilatation
(mostly hot
flashes/flushes),
Palpitations

Postural
hypotension,
Syncope,
Tachycardia

Hypotension,
QT
prolongation,
Ventricular
fibrillation,
Ventricular
tachycardia
(including
torsade de
pointes)

Respiratory

Yawning

Digestive

Nausea
(20.0%)

Skin

Sweating
(including
night
sweats)
[12.2%]

Appetite
decreased
(anorexia),
Constipation,
Vomiting

Pulmonary
eosinophilia
Bruxism,
Diarrhoea

Pancreatitis

Rash, Alopecia

Erythaema
multiforme,
Toxic
epidermal
necrolysis,
StevensJohnson
syndrome,
Pruritus,
Urticaria

Musculoskeletal
Urogenital

Rhabdomyolys
is
Abnormal
ejaculation/orgasm
(males),
Anorgasmia,
Erectile

Abnormal
orgasm
(females),
Urinary
retention

Urinary
incontinence

dysfunction
(impotence),
Urination
impaired (mostly
hesitancy),
Menstrual
disorders
associated with
increased bleeding
or increased
irregular bleeding
(e.g., menorrhagia,
metrorrhagia),
Pollakiuria
Body as a
Whole

Asthenia (fatigue), Angioedema,
Chills
Photosensitivit
y reaction

Anaphylaxis

*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
Discontinuation of venlafaxine (particularly when abrupt) commonly leads to
withdrawal symptoms. Dizziness, sensory disturbances (including
paraesthesia), 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 (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 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, haemoperfusion and exchange transfusion are unlikely to be
of benefit. No specific antidotes for venlafaxine are known.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic Group: Venlafaxine.

ATC code: N06AX16
Vensir XL is a structurally novel antidepressant which is chemically unrelated to
tricyclic, tetracyclic, or other available antidepressant agents. It is a racemate with
two active enantiomers.
The mechanism of Vensir XL’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, Odesmethylvenlafaxine, are potent neuronal serotonin and noradrenaline re-uptake
inhibitors (SNRI) and weak inhibitors of dopamine reuptake. In addition, venlafaxine
and O-desmethylvenlafaxine reduce β-adrenergic responsiveness in animals after both
acute (single dose) and chronic administration. Venlafaxine and its major metabolite
appear to be equipotent with respect to their overall action on neurotransmitter reuptake.
Venlafaxine has virtually no affinity for rat brain muscarinic, histaminergic or
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.

5.2

Pharmacokinetic properties
Absorption:
Venlafaxine is well absorbed and undergoes extensive first-pass metabolism. Mean
peak plasma concentrations of venlafaxine range from approximately 33 to 172ng/ml
after 25 to 150mg single doses, and are reached in approximately 2.4 hours.
Distribution:
Venlafaxine and O-desmethylvenlafaxine are 27% and 30% bound to plasma proteins
respectively.
Metabolism:
Venlafaxine is extensively metabolised in the liver. O-desmethylvenlafaxine is the
major active metabolite of venlafaxine. The mean disposition half-life of venlafaxine
and O-desmethylvenlafaxine is approximately 5 and 11 hours, respectively. Mean
peak O-desmethylvenlafaxine plasma concentrations range from approximately 61 to
325ng/ml and are reached in approximately 4.3 hours. Plasma concentrations of
venlafaxine and O-desmethylvenlafaxine generally correlated well with dose levels.
Elimination:
O-desmethylvenlafaxine, other minor venlafaxine metabolites, and non-metabolised
venlafaxine are excreted primarily through the kidneys.

5.3

Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies on
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential,
toxicity reproduction.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients


Microcrystalline cellulose



Copovidone



Ethyl cellulose



Magnesium stearate



Povidone



Colloidal anhydrous silica



Talc
Capsule shell components



Gelatin



Titanium dioxide (E171)



Black iron oxide (E172)



Red iron oxide (E172)
Printing ink

6.2



Shellac



Propylene glycol



Red iron oxide (E172)

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 container to protect from moisture

6.5

Nature and contents of container
PVC/ACLAR* film and Aluminium lidding foil.
PVC/PVdC film and Aluminium foil.
Blister packs of 10, 14, 15 20, 28, 30, 56, 60 and 100 capsules.
Not all pack sizes may be marketed

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Morningside Healthcare Ltd
115 Narborough Road
Leicester
LE3 0PA
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20117/0067

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/02/2012

10

DATE OF REVISION OF THE TEXT

16/10/2012

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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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