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RANFAXINE XL 75 MG PROLONGED RELEASE CAPSULES HARD

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Ranfaxine XL 75 mg prolonged release capsules, hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Ranfaxine XL 75 mg prolonged release capsule , hard contains 84.85 mg
venlafaxine hydrochloride, equivalent to 75mg Venlafaxine
For a full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Prolonged- Release Capsule, hard
Ranfaxine XL 75 mg prolonged release capsules, hard are Size “1” capsule with pink
opaque cap and body imprinted with RVn on the cap and 75 on the body in black ink

4

CLINICAL PARTICULARS

4.1
Therapeutic indications
Treatment of major depressive episodes.
For prevention of recurrence of major depressive episodes.

4.2

Posology and method of administration

Major depressive episodes
The recommended starting dose for Ranfaxine XL 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. Longerterm 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.

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 Ranfaxine 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
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.
Ranfaxine XL contain spheroids, which release the active substance slowly into the
digestive tract. The insoluble portion of these spheroids is eliminated and may be seen
in faeces.

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 again 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 a
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 25mg Tablets 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).

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 initation 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 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
levels should be considered during long-term treatment.
Co-administration with weight loss agents
The safety and efficacy of venlafaxine therapy in combination with weight loss
agents, including phentermine, have not been established. Co-administration of
venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated
for weight loss alone or in combination with other products.
Mania/hypomania
Mania/hypomania may occur in a small proportion of patients with mood disorders
who have received antidepressants, including venlafaxine. As with other
antidepressants, venlafaxine should be used cautiously in patients with a history or
family history of bipolar disorder.
Aggression
Aggression may occur in a small number of patients who have received
antidepressants, including venlafaxine. This has been reported under initiation, dose
changes and discontinuation of treatment.
As with other antidepressants, venlafaxine should be used cautiously in patients with
a history of aggression.
Discontinuation of treatment
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.

Diabetes
In patients with diabetes, treatment with an SSRI or venlafaxine may alter glycaemic
control. Insulin and/or oral antidiabetic dosage may need to be adjusted.

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

Effect of venlafaxine on other medicinal products

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-OH-imipramine.
There was a dose-dependent increase of 2-OH-desipramine AUC by 2.5 to 4.5-fold
when venlafaxine 75 mg to 150 mg daily was administered. Imipramine did not affect
the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical
significance of this interaction is unknown. Caution should be exercised with
co-administration of venlafaxine and imipramine.
Haloperidol
A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral
clearance, a 70% increase in AUC, an 88% increase in Cmax, but no change in half-life
for haloperidol. This should be taken into account in patients treated with haloperidol
and venlafaxine concomitantly. The clinical significance of this interaction is
unknown.
Risperidone
Venlafaxine increased the risperidone AUC by 50%, but did not significantly alter the
pharmacokinetic profile of the total active moiety (risperidone plus
9-hydroxyrisperidone). The clinical significance of this interaction is unknown.
Metoprolol
Concomitant administration of venlafaxine and metoprolol to healthy volunteers in a
pharmacokinetic interaction study for both medicinal products resulted in an increase
of plasma concentrations of metoprolol by approximately 30-40% without altering the
plasma concentrations of its active metabolite, α-hydroxymetoprolol. The clinical
relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter
the pharmacokinetic profile of venlafaxine or its active metabolite,
O-desmethylvenlafaxine. Caution should be exercised with co-administration of
venlafaxine and metoprolol.

Indinavir
A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a
36% decrease in Cmax for indinavir. Indinavir did not affect the pharmacokinetics of
venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction
is unknown.

4.6

Fertility, Pregnancy and lactation
Pregnancy
There are no adequate data from the use of venlafaxine in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential
risk for humans is unknown. Venlafaxine must only be administered to pregnant
women if the expected benefits outweigh any possible risk.
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 Ranfaxiran XL taking
into account the related mechanism of action (inhibition of the re-uptake of
serotonin).
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.
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 breastfeeding. A risk to the suckling child cannot be excluded. Therefore, a decision to
continue/discontinue breast-feeding or to continue/discontinue therapy with
Ranfaxine XL should be made, taking into account the benefit of breast-feeding to the
child and the benefit of Ranfaxine XL 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).





Common

Haematological/
Lymphatic

Metabolic/
Nutritional



Very
Common

Uncommon



Body System

Rare

Not Known

Ecchymosis,
Gastrointestinal
haemorrhage

Serum cholesterol
increased, Weight
loss

Mucous membrane
bleeding, Prolonged
bleeding time,
Thrombocytopaenia,
Blood dyscrasias,
(including
agranulocytosis,
aplastic anaemia,
neutropaenia and
pancytopaenia)

Weight gain

Abnormal liver
function tests,
Hyponatraemia,
Hepatitis, Syndrome
of Inappropriate
Antidiuretic
Hormone Secretion
(SIADH), Prolactin
increased

Body System

Very
Common

Common

Uncommon

Rare

Not Known

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

Akathisia/
Psychomotor
restlessness,
Convulsion,
Manic
reaction

Special Senses

Abnormality of
accommodation,
Mydriasis, Visual
disturbance,

Altered taste
sensation,
Tinnitus

Neuroleptic
Malignant
Syndrome (NMS),
Serotonergic
syndrome, Delirium,
Extrapyramidal
reactions (including
dystonia and
dyskinaesia),
Tardive dyskinaesia,
Suicidal ideation
and behaviours**,
Vertigo,
Aggression***
Angle-closure
glaucoma

Cardiovascular

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

Postural
hypotension,
Syncope,
Tachycardia

Respiratory

Yawning

Nervous

Digestive

Nausea
(20.0%)

Skin

Sweating
(including
night
sweats)
[12.2%]

Musculoskeletal

Appetite
decreased
(anorexia),
Constipation,
Vomiting

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

Bruxism,
Diarrhoea

Pancreatitis

Rash, Alopecia

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

Body System
Urogenital

Body as a
Whole

Common

Very
Common

Abnormal
ejaculation/orgasm
(males),
Anorgasmia,
Erectile
dysfunction
(impotence),
Urination
impaired (mostly
hesitancy),
Menstrual
disorders
associated with
increased bleeding
or increased
irregular bleeding
(e.g., menorrhagia,
metrorrhagia),
Pollakiuria

Uncommon
Abnormal
orgasm
(females),
Urinary
retention

Rare

Not Known

Urinary
incontinence

Anaphylaxis
Angioedema,
Photosensitivity
reaction
*In pooled clinical trials, the incidence of headache was 30.3% with venlafaxine
versus 31.3% with placebo.
Asthenia (fatigue),
Chills

**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.

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 placebo-controlled, 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 8-week 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.

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 immediaterelease venlafaxine. Absolute bioavailability is 40% to 45% due to presystemic
metabolism. After immediate-release venlafaxine administration, the peak plasma
concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively.
Following the administration of venlafaxine prolonged-release capsules, peak plasma

concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours,
respectively. When equal daily doses of venlafaxine are administered as either an
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, N-desmethylvenlafaxine, by CYP3A4. In vitro and in
vivo studies indicate that venlafaxine is a weak inhibitor of CYP2D6. Venlafaxine did
not inhibit CYP1A2, CYP2C9, or CYP3A4.
Elimination
Venlafaxine and its metabolites are excreted primarily through the kidneys.
Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as
either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV
(26%), or other minor inactive metabolites (27%). Mean ± SD plasma steady-state
clearances of venlafaxine and ODV are 1.3±0.6 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 half-life was prolonged by about 142% and clearance reduced by about
56%. Dosage adjustment is necessary in patients with severe renal impairment and in
patients that require haemodialysis (see section 4.2).

5.3
Preclinical safety data
Studies with venlafaxine in rats and mice revealed no evidence of carcinogenesis.
Venlafaxine was not mutagenic in a wide range of in vitro and in vivo tests.
Animal studies regarding reproductive toxicity have found in rats a decrease in pup
weight, an increase in stillborn pups, and an increase in pup deaths during the first
5 days of lactation. The cause of these deaths is unknown. These effects occurred at
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

Core Spheroid Composition
Cellulose, microcrystalline
Hypromellose
Modified Release coating
Ethyl cellulose
Povidone (K 30)
Triacetin
Talc

Capsule Shell: Pink Opaque
Body
Iron Oxide Red (E 172)
Titanium Dioxide (E171)
Gelatin
Sodium Lauryl Sulfate
Cap
Iron Oxide Red (E 172)
Titanium Dioxide (E171)
Gelatin
Sodium Lauryl Sulfate
Black Printing Ink:
Shellac
Propylene glycol
Strong ammonia solution
Black iron oxide (E172)
Potassium hydroxide

6.2
Incompatibilities
Not applicable.

6.3
Shelf life
2 Years

6.4
Special precautions for storage
This medicinal product does not require any special storage conditions

6.5
Nature and contents of container
PVC Blister pack

White opaque PVC film with the backing of hard tempered, heat sealable aluminum
foil of printable quality coated with heat sealed lacquer on inner side.
7, 10, 14 20, 28, 30, 50, 56, 60, 100
For healthcare professions only
HDPE bottle pack: 100
White opaque high-density polyethylene bottle (HDPE) with fine ribbed screw cap
with induction seal liner
Not all pack sizes may be marketed

6.6

Special precautions for disposal

No special requirements

7

MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited
Building 4, Chiswick Park
566 Chiswick High Road
London, W4 5YE
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)

PL 14894/0523

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
03/11/2008

10

DATE OF REVISION OF THE TEXT
19/07/2011

+ Expand Transcript

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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