VENAXX XL 150 MG PROLONGED-RELEASE CAPSULES

Active substance: VENLAFAXINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Venaxx XL 150 mg prolonged-release capsules, hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One prolonged-release capsule, hard contains venlafaxine hydrochloride
equivalent to 150 mg of venlafaxine.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged-release capsule, hard.
Venaxx XL 150 mg: scarlet opaque hard gelatine capsules (size 00) containing
three round, biconvex film-coated tablets, with imprint VEN on cap and 150
on body.

4

CLINICAL PARTICULARS

4.1

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

4.2

Posology and method of administration
Major depressive episodes
The recommended starting dose for prolonged-release venlafaxine is 75 mg
given once daily. Patients not responding to the initial 75 mg/day dose may
benefit from dose increases up to a maximum dose of 375 mg/day. Dosage
increases can be made at intervals of 2 weeks or more. If clinically warranted
due to symptom severity, dose increases can be made at more frequent
intervals, but not less than 4 days.

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

The efficacy and safety of venlafaxine for other indications in children and
adolescents under the age of 18 have not been established.
Use in patients with hepatic impairment
In patients with mild and moderate hepatic impairment, in general a 50% dose
reduction should be considered. However, due to inter-individual variability in
clearance, individualisation of dosage may be desirable.
There are limited data in patients with severe hepatic impairment. Caution is
advised, and a dose reduction by more than 50% should be considered. The
potential benefit should be weighed against the risk in the treatment of patients
with severe hepatic impairment.
Use in patients with renal impairment
Although no change in dosage is necessary for patients with glomerular
filtration rate (GFR) between 30-70 ml/minute, caution is advised. For patients
that require haemodialysis and in patients with severe renal impairment (GFR
< 30 ml/min), the dose should be reduced by 50%. Because of inter-individual
variability in clearance in these patients, individualisation of dosage may be
desirable.
Withdrawal symptoms seen on discontinuation of venlafaxine
Abrupt discontinuation should be avoided. When stopping treatment with
venlafaxine, the dose should be gradually reduced over a period of at least one
to two weeks in order to reduce the risk of withdrawal reactions (see sections
4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or
upon discontinuation of treatment, then resuming the previously prescribed
dose may be considered. Subsequently, the physician may continue decreasing
the dose, but at a more gradual rate.
For oral use.
It is recommended that venlafaxine prolonged-release capsules be taken with
food, at approximately the same time each day. Capsules must be swallowed
whole with fluid and not divided, crushed, chewed, or dissolved.
Patients treated with venlafaxine immediate-release tablets may be switched to
venlafaxine 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.

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 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 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 lifethreatening condition, may occur with venlafaxine treatment, particularly with
concomitant use of other agents, such as MAO-inhibitors, that may affect the
serotonergic neurotransmitter systems (see sections 4.3 and 4.5).
Serotonin syndrome symptoms may include mental status changes (e.g.,
agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile
blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia,
incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting,
diarrhoea).
Narrow-angle glaucoma
Mydriasis may occur in association with venlafaxine. It is recommended that
patients with raised intraocular pressure or patients at risk for acute 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 preexisting
hypertension should be controlled before initiation of treatment. Blood
pressure should be reviewed periodically, after initiation of treatment and after
dose increases. Caution should be exercised in patients whose underlying
conditions might be compromised by increases in blood pressure, e.g., those
with impaired cardiac function.
Heart rate
Increases in heart rate can occur, particularly with higher doses. Caution
should be exercised in patients whose underlying conditions might be
compromised by increases in heart rate.
Cardiac disease and risk of arrhythmia
Venlafaxine has not been evaluated in patients with a recent history of
myocardial infarction or unstable heart disease. Therefore, it should be used
with caution in these patients.

In postmarketing experience, fatal cardiac arrhythmias have been reported
with the use of venlafaxine, especially in overdose. The balance of risks and
benefits should be considered before prescribing venlafaxine to patients at
high risk of serious cardiac arrhythmia.
Convulsions
Convulsions may occur with venlafaxine therapy. As with all antidepressants,
venlafaxine should be introduced with caution in patients with a history of
convulsions, and concerned patients should be closely monitored. Treatment
should be discontinued in any patient who develops seizures.
Hyponatraemia
Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic
Hormone (SIADH) secretion may occur with venlafaxine. This has most
frequently been reported in volume-depleted or dehydrated patients. Elderly
patients, patients taking diuretics, and patients who are otherwise volumedepleted may be at greater risk for this event.
Abnormal bleeding
Medicinal products that inhibit serotonin uptake may lead to reduced platelet
function. The risk of skin and mucous membrane bleeding, including
gastrointestinal haemorrhage, may be increased in patients taking venlafaxine.
As with other serotonin-reuptake inhibitors, venlafaxine should be used
cautiously in patients predisposed to bleeding, including patients on
anticoagulants and platelet inhibitors.
Serum cholesterol
Clinically relevant increases in serum cholesterol were recorded in 5.3% of
venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at
least 3 months in placebo-controlled clinical trials. Measurement of serum
cholesterol levels should be considered during long-term treatment.
Co-administration with weight loss agents
The safety and efficacy of venlafaxine therapy in combination with weight
loss agents, including phentermine, have not been established. 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). In clinical trials,
adverse events seen on treatment discontinuation (tapering and post-tapering)
occurred in approximately 31% of patients treated with venlafaxine and 17%
of patients taking placebo.
The risk of withdrawal symptoms may be dependent on several factors,
including the duration and dose of therapy and the rate of dose reduction.
Dizziness, sensory disturbances (including paraesthesia), sleep disturbances
(including insomnia and intense dreams), agitation or anxiety, nausea and/or
vomiting, tremor and headache are the most commonly reported reactions.
Generally, these symptoms are mild to moderate; however, in some patients
they may be severe in intensity. They usually occur within the first few days of
discontinuing treatment, but there have been very rare reports of such
symptoms in patients who have inadvertently missed a 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).
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.

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 nonselective MAOI.
Venlafaxine must be discontinued for at least 7 days before starting treatment
with an irreversible non-selective MAOI (see sections 4.3 and 4.4).
Reversible, selective MAO-A inhibitor (moclobemide)
Due to the risk of serotonin syndrome, the combination of venlafaxine with a
reversible and selective MAOI, such as moclobemide, is not recommended.
Following treatment with a reversible 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 may occur with
venlafaxine treatment, particularly with concomitant use of other agents that
may affect the serotonergic neurotransmitter system (including triptans,
SSRIs, SNRIs, lithium, sibutramine, tramadol, or St. John's Wort [Hypericum
perforatum]), with medicinal agents which impair metabolism of serotonin
(including MAOIs), or with serotonin precursors (such as tryptophan
supplements).
If concomitant treatment of venlafaxine with an SSRI, an SNRI or a serotonin
receptor agonist (triptan) is clinically warranted, careful observation of the
patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of venlafaxine with serotonin precursors (such as
tryptophan supplements) is not recommended (see section 4.4).
CNS-active substances
The risk of using venlafaxine in combination with other CNS-active
substances has not been systematically evaluated. Consequently, caution is
advised when venlafaxine is taken in combination with other CNS-active
substances.

Ethanol
Venlafaxine has been shown not to increase the impairment of mental and
motor skills caused by ethanol. However, as with all CNS-active substances,
patients should be advised to avoid alcohol consumption.
Effect of other medicinal products on venlafaxine
Ketoconazole (CYP3A4 inhibitor)
A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and
poor metabolisers (PM) resulted in higher AUC of venlafaxine (70% and 21%
in CYP2D6 PM and EM subjects, respectively) and O-desmethylvenlafaxine
(33% and 23% in CYP2D6 PM and EM subjects, respectively) following
administration of ketoconazole. Concomitant use of CYP3A4 inhibitors (e.g.,
atazanavir,
clarithromycin,
indinavir,
itraconazole,
voriconazole,
posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin)
and venlafaxine may increase levels of venlafaxine and Odesmethylvenlafaxine. Therefore, caution is advised if a patient’s therapy
includes a CYP3A4 inhibitor and venlafaxine concomitantly.
Effect of venlafaxine on other medicinal products
Lithium
Serotonin syndrome may occur with the concomitant use of venlafaxine and
lithium (see Serotonin syndrome).
Diazepam
Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of
diazepam and its active metabolite, desmethyldiazepam. Diazepam does not
appear to affect the pharmacokinetics of either venlafaxine or 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.

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 Venaxx 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. 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 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.

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

Metabolic/

Uncommon
Ecchymosis,
Gastrointestinal
haemorrhage

Serum

Weight gain

Rare

Not Known
Mucous membrane
bleeding, Prolonged
bleeding time,
Thrombocytopaenia,
Blood dyscrasias,
(including
agranulocytosis,
aplastic anaemia,
neutropaenia and
pancytopaenia)
Abnormal liver

Nutritional

Nervous

cholesterol
increased,
Weight loss

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

Special Senses

Cardiovascular

Respiratory

Abnormal
dreams,
Decreased
libido,
Dizziness,
Increased
muscle tonus
(hypertonia),
Insomnia,
Nervousness,
Paresthesia,
Sedation,
Tremor,
Confusion,
Depersonalisati
on
Abnormality of
accommodation,
Mydriasis,
Visual
disturbance,
Hypertension,
Vasodilatation
(mostly hot
flashes/flushes),
Palpitations

Nausea
(20.0%)

Skin

Appetite
decreased
(anorexia),
Constipation,
Vomiting

Sweating
(including
night sweats)
[12.2%]

Angle-closure
glaucoma

Postural
hypotension,
Syncope,
Tachycardia

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

Bruxism,
Diarrhoea

Rash, Alopecia

Abnormal
ejaculation/orga
sm (males),
Anorgasmia,
Erectile
dysfunction
(impotence),
Urination
impaired

Akathisia/
Psychomot
or
restlessness,
Convulsion,
Manic
reaction

Altered taste
sensation,
Tinnitus

Yawning

Digestive

Musculoskeletal
Urogenital

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

function tests,
Hyponatraemia,
Hepatitis, Syndrome
of Inappropriate
Antidiuretic
Hormone Secretion
(SIADH), Prolactin
increased
Neuroleptic
Malignant Syndrome
(NMS), Serotonergic
syndrome, Delirium,
Extrapyramidal
reactions (including
dystonia and
dyskinaesia), Tardive
dyskinaesia, Suicidal
ideation and
behaviours**

Abnormal orgasm
(females),
Urinary retention

Erythema
multiforme, Toxic
epidermal necrolysis,
Stevens-Johnson
syndrome, Pruritus,
Urticaria
Rhabdomyolysis

Body as a Whole

(mostly
hesitancy),
Menstrual
disorders
associated with
increased
bleeding or
increased
irregular
bleeding (e.g.,
menorrhagia,
metrorrhagia),
Pollakiuria
Asthenia
(fatigue), Chills

Photosensitivity
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).
Discontinuation of venlafaxine (particularly when abrupt) commonly leads to
withdrawal symptoms. Dizziness, sensory disturbances (including
paraethesia), sleep disturbances (including insomnia and intense dreams),
agitation or anxiety, nausea and/or vomiting, tremor, headache and flu
syndrome are the most commonly reported reactions. Generally, these events
are mild to moderate and are 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, hemoperfusion 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: Other antidepressants - ATC code: NO6A X16.
The mechanism of venlafaxine's antidepressant action in humans is believed to
be associated with its potentiation of neurotransmitter activity in the central
nervous system. Preclinical studies have shown that venlafaxine and its major
metabolite, O-desmethylvenlafaxine (ODV), are inhibitors of serotonin and
noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake.
Venlafaxine and its active metabolite reduce β-adrenergic responsiveness after
both acute (single dose) and chronic administration. Venlafaxine and ODV are
very similar with respect to their overall action on neurotransmitter reuptake
and receptor binding.

Venlafaxine has virtually no affinity for rat brain muscarinic, cholinergic, H1histaminergic or α1-adrenergic receptors in vitro. Pharmacological activity at
these receptors may be related to various side effects seen with other
antidepressant medicinal products, such as anticholinergic, sedative and
cardiovascular side effects.
Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.
In vitro studies revealed that venlafaxine has virtually no affinity for opiate or
benzodiazepine sensitive receptors.
Major depressive episodes
The efficacy of venlafaxine immediate-release as a treatment for major
depressive episodes was demonstrated in five randomised, double-blind,
placebo-controlled, short-term trials ranging from 4 to 6 weeks duration, for
doses up to 375 mg/day. The efficacy of venlafaxine prolonged-release as a
treatment for major depressive episodes was established in two placebocontrolled, short-term studies for 8 and 12 weeks duration, which included a
dose range of 75 to 225 mg/day.
In one longer-term study, adult outpatients who had responded during an 8week open trial on venlafaxine prolonged-release (75, 150, or 225 mg) were
randomised to continuation of their same venlafaxine prolonged-release dose
or to placebo, for up to 26 weeks of observation for relapse.
In a second longer-term study, the efficacy of venlafaxine in prevention of
recurrent depressive episodes for a 12-month period was established in a
placebo-controlled double-blind clinical trial in adult outpatients with
recurrent major depressive episodes who had responded to venlafaxine
treatment (100 to 200 mg/day, on a b.i.d. schedule) on the last episode of
depression.
Social anxiety disorder
The efficacy of venlafaxine prolonged-release capsules as a treatment for
social anxiety disorder was established in four double-blind, parallel-group,
12-week, multi-center, placebo-controlled, flexible-dose studies and one
double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose
study in adult outpatients. Patients received doses in a range of 75 to 225
mg/day. There was no evidence for any greater effectiveness of the 150 to 225
mg/day group compared to the 75 mg/day group in the 6-month study.

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 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 prolongedrelease 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.
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, Ndesmethylvenlafaxine, by CYP3A4. In vitro and in vivo studies indicate that
venlafaxine is a weak inhibitor of CYP2D6. Venlafaxine did not inhibit
CYP1A2, CYP2C9, or CYP3A4.
Elimination
Venlafaxine and its metabolites are excreted primarily through the kidneys.
Approximately 87% of a venlafaxine dose is recovered in the urine within 48
hours as either unchanged venlafaxine (5%), unconjugated ODV (29%),
conjugated ODV (26%), or other minor inactive metabolites (27%). Mean ±
SD plasma steady-state clearances of venlafaxine and ODV are 1.3±0.6 L/h/kg
and 0.4±0.2 L/h/kg, respectively.
Special populations

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

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 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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
150 mg prolonged-release capsules, hard:
Capsule content:
Hypromellose
Ammonio methacrylate copolymer (type B)
Sodium larilsulfate
Magnesium stearate

Coating:
Basic butylated methacrylate copolymer 12.5%
Capsule shell:
Gelatin
Titanium dioxide (E 171)
Erythrosine (E127)
Indigotin I (E 132)
Printing ink:
Shellac
Black iron oxide (E172)
Propylene glycol (E1520)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Store below 30ºC

6.5

Nature and contents of container
PVC/PE/PVDC/Al blister
150 mg: 10, 28, 30, 56, 98 and 100 capsules
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Mercury Pharmaceuticals Ltd
No. 1 Croydon,
12-16 Addiscombe Road,
Croydon CR0 0XT, UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 12762/0455

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
11/06/2008

10

DATE OF REVISION OF THE TEXT
11/09/2013

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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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