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FORAVEN XL 150MG MODIFIED RELEASE CAPSULES

Active substance: VENLAFAXINE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
FORAVEN XL 150mg modified release capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
FORAVEN XL 150mg modified release capsules contain 169.8mg of venlafaxine
hydrochloride, equivalent to 150mg of venlafaxine free base, in an extended release
formulation.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Modified release capsule, hard. The capsules are dark orange opaque having a thick
and a thin radial circular band on the body in white ink and a thick and a thin radial
circular band on the cap in white ink.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Major depressive disorder
FORAVEN XL 150mg modified release capsules are indicated for the treatment of
major depressive disorder including depression accompanied by anxiety. All patients
should be evaluated for the risk of suicidality and monitored for clinical worsening
(see section 4.2 and 4.4).
Following an initial response venlafaxine capsules are indicated for the prevention of
relapses of the initial episode of depression or for the prevention of the recurrence of
new episodes.

4.2

Posology and method of administration
Depression
The recommended dose is 75mg per day given once daily. Most patients
respond to this dose.
If, after an adequate trial and evaluation, further clinical improvement is
required, the dose may be increased to 150mg per day given once daily. 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.
In more severely depressed or hospitalised patients, and under close
supervision of a physician, the daily dose may then be increased to the
maximum recommended dose of FORAVEN XL capsules, 375mg given once
daily. In those more severely depressed or hospitalised patients who require
daily venlafaxine doses of 300mg or more, treatment with venlafaxine tablets
should be initiated under specialist supervision including shared care
arrangements.
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).
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 in order to evaluate the benefit of long-term therapy.
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.
Patients with 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 capsules 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.
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.
Maintenance/continuation/extended treatment
The physician should periodically re-evaluate the usefulness of long-term
treatment with venlafaxine modified release capsules for the individual patient.
It is generally agreed that acute episodes of major depression require several
months or longer of sustained therapy. Venlafaxine has been shown to be
efficacious during long-term (up to 12 months) treatment.
In clinical trials venlafaxine was demonstrated to be effective for preventing
relapse, or recurrence of new episodes, in patients responding to venlafaxine
treatment during the index episode.
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.
Venlafaxine prolonged-release capsules contain mini-tablets, which release the
active substance slowly into the digestive tract. The insoluble coating of these
mini-tablets is eliminated and may be seen in faeces.
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 life-threatening
condition, may occur with venlafaxine treatment, particularly with concomitant use of
other agents, such as MAO-inhibitors, that may affect the serotonergic
neurotransmitter systems (see sections 4.3 and 4.5).
Serotonin syndrome symptoms may include mental status changes (e.g. agitation,
hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure,
hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).
Concomitant use of neuroleptics
As with SSRIs, venlafaxine should be used with caution in patients already receiving
neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome cases
have been reported with this combination.
Narrow-angle glaucoma
Mydriasis may occur in association with venlafaxine. It is recommended that patients
with raised intraocular pressure or patients at risk for acute narrow angle glaucoma
(angle closure glaucoma) be closely monitored.
Blood pressure
Dose-related increases in blood pressure have been commonly reported with
venlafaxine. In some cases, severely elevated blood pressure requiring immediate
treatment has been reported in postmarketing experience. All patients should be
carefully screened for high blood pressure and 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.
Postural hypotension
Postural hypotension has been observed occasionally during venlafaxine treatment.
Patients, especially the elderly, should be alerted to the possibility of dizziness or
unsteadiness.
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 post-marketing 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 volume-depleted 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
should be considered during long-term treatment.
Co-administration with weight loss agents
The safety and efficacy of venlafaxine therapy in combination with weight loss
agents, including phentermine, have not been established. Co-administration of
venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated
for weight loss alone or in combination with other products.
Mania/hypomania
Mania/hypomania may occur in a small proportion of patients with mood disorders
who have received antidepressants, including venlafaxine. As with other
antidepressants, venlafaxine should be used cautiously in patients with a history or
family history of bipolar disorder.
Aggression
Aggression may occur in a small number of patients who have received
antidepressants, including venlafaxine. This has been reported under initiation, dose
changes and discontinuation of treatment.
As with other antidepressants, venlafaxine should be used cautiously in patients with
a history of aggression.
Possibility of drug abuse
Due to the possibility of drug abuse with CNS-active drugs, physicians should
evaluate patients for a history of drug abuse, and follow such patients closely. Clinical
studies have shown no evidence of drug-seeking behaviour, development of tolerance,
or dose escalation over time among patients taking venlafaxine.
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 patients 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.
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 nonselective MAOI (see sections 4.3 and 4.4).
Reversible, selective MAOI-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 Wart (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
CVP2D6 PM and EM subjects respectively) following administration of
ketoconazole. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir,
clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole,
nelfinavir, ritanovir, saquinavir, telithromycin) and venlafaxine may increase levels of
venlafaxine and O-desmethylvenlafaxine. Therefore, caution is advised if a patient’s
therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.
Cimetidine
Cimetidine inhibited the first-pass metabolism of venlafaxine but had no significant
effect on the formation or elimination of O-desmethylvenlafaxine, which is present in
much greater quantities in the systemic circulation. No dosage adjustment therefore
seems necessary when venlafaxine is co-administered with cimetidine. For elderly
patients, or patients with hepatic dysfunction the interaction could potentially be more
pronounced, and for such patients clinical monitoring is indicated when venlafaxine is
administered with cimetidine.
Effect of venlafaxine on other medicinal products
Lithium
Serotonin syndrome may occur with the concomitant use of venlafaxine and lithium
(see Serotonin syndrome).
Diazepam
Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of

diazepam and its active metabolite, desmethyldiazepam. Diazepam does not appear to
affect the pharmacokinetics of either venlafaxine or O-desmethylvenlafaxine. It is
unknown whether a pharmacokinetic and/or pharmacodynamic interaction with other
benzodiazepines exists.
Imipramine
Venlafaxine did not affect the pharmacokinetics of imipramine and 2-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 O-desmethylvenlafaxine. The
clinical significance of this interaction is unknown. Caution should be exercised with
co-administration of venlafaxine and imipramine.
Haloperidol
A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral
clearance, a 70% increase in AUC, an 88% increase in Cmax, but no change in half-life
for haloperidol. This should be taken into account in patients treated with haloperidol
and venlafaxine concomitantly. The clinical significance of this interaction is
unknown.
Risperidone
Venlafaxine increased the risperidone AUC by 50%, but did not significantly alter the
pharmacokinetic profile of the total active moiety (risperidone plus 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, -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 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.
Warfarin
Potentiation of anticoagulant effects including increases in PT or INR have been
reported in patients taking warfarin 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 FORAVEN XL capsules 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 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 breastfeeding. 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
See also Special Warnings and Special Precautions for Use.

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

Uncommon

Rare

Ecchymosis,
Gastrointestinal
haemorrhage

Metabolic/
Nutritional

Serum cholesterol
increased, Weight
loss

Weight gain

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

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

Altered taste
sensation,
Tinnitus

Cardiovascular

Abnormality of
accommodation,
Mydriasis, Visual
disturbance
Hypertension,
Vasodilation
(mostly hot
flashes/flushes),
Palpitations

Respiratory

Yawning

Nervous

Dry mouth
(10%),
Headache
(30.3%)*

Special senses

Digestive

Nausea
(20.0%)

Skin

Sweating
(including
night
sweats)
[12.2%]

Musculoskeletal
Urinogenital

Appetite
decreased
(anorexia),
Constipation,
Vomiting

Akathisia/
Psychomotor
restlessness,
Convulsion,
Manic
reaction

Postural
hypotension,
Syncope,
Tachycardia

Bruxism,
Diarrhoea

Abnormal
orgasm
(females),
Urinary
retention

Mucous membrane
bleeding, Prolonged
bleeding time,
Thrombocytopaenia,
Blood dyscrasias,
(including
agranulocytosis,
aplastic anaemia,
neutropaenia and
pancytopaenia)
Abnormal liver
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
dyskinesia), Tardive
dyskinesia, Suicidal
ideation and
behaviours**,
Vertigo,
Aggression***
Angle-closure
glaucoma

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

Rash, Alopecia

Abnormal
ejaculation/orgasm
(males),
Anorgasmia,
Erectile
dysfunction

Not known

Erythema
multiforme, Toxic
epidermal
necrolysis, StevensJohnson syndrome,
Pruritus, Urticaria
Rhabdomyolysis
Urinary
incontinence

Body as a whole

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

Angioedema,
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)
***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, 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.
Special notes
In all pre-marketing depression trials with venlafaxine tablets, seizures were reported
in 0.3% of all venlafaxine-treated patients (see section 4.4).
Nausea is most common at the start of treatment with the incidence decreasing over the
first few weeks.

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 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
Pharmacotherapeutic group: Other antidepressants - ATC code: NO6A X16.

5.1

Pharmacodynamic properties
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 potent inhibitors of serotonin
and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake.
Studies in animals show that tricyclic antidepressants may reduce β-adrenergic
responsiveness following chronic administration. In contrast, venlafaxine and
its active metabolite reduced 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.
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 drugs, 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,
benzodiazepine, phencyclidine (PCP), or N-methyl-d-aspartic acid (NMDA)
receptors. It has no significant central nervous system (CNS) stimulant
activity in rodents. In primate drug discrimination studies, venlafaxine
showed no significant or depressant abuse liability.

5.2

Pharmacokinetic properties
At least 92% of a single oral dose of venlafaxine is absorbed. After administration of
an extended release formulation dose, the peak plasma concentrations of venlafaxine
and ODV are attained within 6.0±1.5 and 8.8 ±2.2 hours, respectively. The rate of
absorption of venlafaxine from the extended release formulation capsule is slower
than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine
following administration of such extended release formulation capsule (15± 6 hours)
is actually the absorption half-life instead of the true disposition half-life (5±2 hours)
observed following administration of an immediate release tablet.
When equal daily doses of venlafaxine were administered as either the immediate
release tablet, or the modified/extended release capsule, the exposure (AUC, area
under the concentration curve) to both venlafaxine and ODV was similar for the two
treatments, and the fluctuation in plasma concentrations was slightly lower following
treatment with the modified/extended release capsule. Therefore, the
modified/extended release capsule provides a slower rate of absorption, but the same
extent of absorption (i.e. AUC), as the immediate release tablet.
Venlafaxine undergoes extensive first-pass metabolism in the liver, primarily by
CYP2D6, to the major metabolite ODV. Venlafaxine is also metabolised to Ndesmethylvenlafaxine, catalysed by CYP3A3/4, and to other minor metabolites.
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, unconjugated ODV, conjugated ODV, or other minor
metabolites.
The half-lives of venlafaxine and its active metabolite O-desmethylvenlafaxine
(ODV) are increased in patients with renal and hepatic impairment.
Administration of the modified/extended release capsules with food has no effect on the
absorption of venlafaxine, or on the subsequent formation of ODV.
Subject age and sex do not significantly affect the pharmacokinetics of venlafaxine.
No accumulation of venlafaxine or ODV has been observed during chronic
administration in healthy subjects.
Venlafaxine 150mg modified release capsules contain mini-tablets; the coating of
those mini-tablets is extended-release coating.

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.
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 2 to 3 times that of a human dose of 225mg/day.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Microcrystalline cellulose E460
Povidone E1201
Talc E553b
Colloidal anhydrous silica
Magnesium stearate E470b
Ethylcellulose E462
Copovidone
Capsule shell components
Gelatine
Titanium dioxide E171
Blue # 1 E133
Red # 40 E129
Yellow # 6 E110
Printing ink
Shellac E904
Propylene glycol E1520
Sodium hydroxide E524
Povidone E1201
Titanium dioxide E171

6.2

Incompatibilities
Not applicable

6.3

Shelf life
36 months

6.4

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

6.5

Nature and contents of container
PVC-ACLAR/aluminium foil blister strips containing 14 capsules. Two of such
strips are packaged in a carton.

6.6

Special precautions for disposal
Not applicable

7

MARKETING AUTHORISATION HOLDER
Forum Products Limited
Betchworth House
57-65 Station Road
Redhill
Surrey
RH1 1DL
UK
FORAVEN XL 150mg modified release capsules are marketed in a trading style
(Quantum Generics) of the MA holder.

8

MARKETING AUTHORISATION NUMBER(S)
PL 05928/0027

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/02/2009

10

DATE OF REVISION OF THE TEXT
26/05/2011

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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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