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Summary of the product characteristics

SUMMARY OF THE PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT

Tifaxin XL 75 mg prolonged-release capsules, hard
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
One capsule contains venlafaxine hydrochloride, equivalent to 75 mg of venlafaxine. Excipients: sucrose max. 92.69 mg sunset yellow FCF (E110) 0.0006 mg For a full list of excipients, see section 6.1. PHARMACEUTICAL FORM

Prolonged-release capsules, hard.
White to off-white granules in a capsule size “1” with a yellow cap and transparent body.
4.
CLINICAL PARTICULARS
Therapeutic indications

Treatment of major depressive episodes.
For prevention of recurrence of major depressive episodes.
Treatment of generalised anxiety disorder.
Treatment of social anxiety disorder.
Treatment of panic disorder, with or without agoraphobia.
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 ad-
verse 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 suffi-
cient period of time, usually several months or longer. Treatment should be reassessed regu-
larly 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 epi-sode. Antidepressive medicinal products should continue for at least six months following remis-sion. Generalised anxiety disorder
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 225 mg/day. 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.
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 inter-
vals 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.
Panic disorder
It is recommended that a dose of 37.5 mg/day of prolonged-release venlafaxine be used for
7 days. Dosage should then be increased to 75 mg/day. Patients not responding to the 75
mg/day dose may benefit from dose increases up to a maximum dose of 225 mg/day. Dos-
age 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 possibil-
ity 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 sec-
tions 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, individualisa-
tion 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 re-
duce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms oc-
cur 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 ap-
proximately 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 spheroids, which release the active sub-
stance 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 contraindi-
cated 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 irre-
versible 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 sui-
cide 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 sui-cidal 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 antidepres-sants 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 be-haviour or thoughts and unusual changes in behaviour and to seek medical advice immedi-ately if these symptoms present. Use in children and adolescents under 18 years of age
Tifaxin XL should not be used in the treatment of children and adolescents under the age of
18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility
(predominantly aggression, oppositional behaviour and anger) were more frequently ob-
served in clinical trials among children and adolescents treated with antidepressants com-
pared to those treated with placebo. If, based on clinical need, a decision to treat is neverthe-
less taken; the patient should be carefully monitored for the appearance of suicidal symp-
toms. 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 potential 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 change, (e.g. agitation, hallucina-
tions, coma) autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia),
neuromuscular aberrations (e.g. hyperflexia, incoordination) and /or gastrointestinal symp-
toms (e.g. nausea, vomiting, diarrhoea).
Narrow angle glaucoma
Mydriasis may occur in association with venlafaxine. It is recommended that patients with
raised intra-ocular pressure or patients at a risk of narrow angle glaucoma (angle-closure
glaucoma) be monitored closely.
Blood pressure
Dose-related increases in blood pressure have been reported commonly with venlafaxine. In
some cases, severely elevated blood pressure requiring immediate treatment has been re-
ported in post-marketing 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 also be exercised in patients whose underlying condition 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 evaluation 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 if
venlafaxine, especially in overdose. The balance of risks and benefits should be considered
before prescribing venlafaxine to patients at high risk of serious cardiac arrthymias.

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 and SIADH
Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone Secre-
tion (SIADH 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 mucosal bleeding, including gastrointestinal haemorrhage, may be increased
in patients taking venlafaxine. As with other serotonin uptake inhibitors, venlafaxine should
be used with caution in patients predisposed to bleeding, including patients on anticoagu-
lants 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 for at least 3 months in placebo con-
trolled clinical trial. 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, includ-
ing phentermine, have not been established. Co-administration of venlafaxine and weight
loss agents is not recommended. Venlafaxine in indicated for weight loss alone or in combi-
nation with other products.
Mania/hypomania
Mania/hypomania may occur in a small number of patients who have received antidepres-
sants, including venlafaxine.
As with other antidepressants, venlafaxine should be used with caution in patients with a
history of mania or a family history of bipolar disorder
Aggression
Aggression may occur in a small proportion of patients with mood disorder who have re-
ceived antidepressants, including venlafaxine. This has been reported under initiation, dose
changes and discontinuation of treatment.
As with other antidepressants, venlafaxine should be used with caution in patients with a
history of aggression.
Discontinuation of treatment
Withdrawal symptoms when treatment is discontinued are common, particularly if discon-
tinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment dis-
continuation (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 (includ-
ing paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or
anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported re-
actions. 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 in-
advertently 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 treat-
ment 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 accompa-
nied 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 on 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.
The excipient sunset yellow FCF (E110) included in the capsules shell may cause allergic
reactions. Since the capsules contain sucrose, patients with rare hereditary problems of fruc-
tose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency
should not take this medicine.
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. Venla-
faxine must not be initiated for at least 14 days after discontinuation of treatment with an irre-
versible non-selective MAOI. Venlafaxine must be discontinued for at least 7 days before
starting treatment with an irreversible MAO inhibitor (see section 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 re-
versible MAO-inhibitor, a short 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 inpatients who have recently been discontin-
ued from an MAOI and started on venlafaxine, or have recently had velafaxine therapy dis-
continued prior to the initiation of an MAOI.
These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing,
dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures
and death.
Serotonin syndrome
As with other serotonergic agents, serotonin syndrome may occur with venlafaxine treat-
ment, particularly with concomitant use of other agents that may affect the serotonergic neu-
rotransmitter system (including tryptans, SSRIs, SNRIs, lithium , sibutramine, tramadol or St
Johns wort [Hypericum perforatum], with medicinal agents which impair metabolism of sero-
tonin (including MAOIS) or with serotonin precursors (such as tryptophan supplements).
If concomitant treatment of venlafaxine with an SSRI, an SNRI or a serotonin receptor ago-
nist (triptan) is clinically warranted, careful observation of the patient is advised, particularly
during treatment initiation and dose increases. The concomitant use of venlafaxine with sero-
tonin 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 or 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 of ketoconazole in CYP2D6 extensive (EM) and poor metabolisers
(PM) resulted in higher AUC if venlafaxine (70% and 21% in CYP2D6 PM and EM subjects,
respectively) and O-desmethylvenlafaxine 933% 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, ketoco-
nazole, nelfinavir, ritonavir, saquinavir, telithromycin) and venlafaxine may increase levels of
venlafaxine and o-desmethylvenlafaxine. Therefore caution is advised of a patients 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 Se-
rotonin 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 benzodiazipines exists.
Imipramine
Venlafaxine does not affect the pharmacokinetic properties of imipramine and 2-OH-
imipramine is not affected by venlafaxine. There was a dose-dependant increase of 2-OH-
desipramine AUC by 2.5 to 4.5 fold when venlafaxine 75mg to 150mg daily was adminis-
tered. Imipramine does 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, and 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 con-
comitantly. The clinical significance of this interaction is unknown.
Risperidone
Venlafaxine increased the risperidone AUC by 50%, but did not significantly alter the phar-
macokinetic 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 pharma-
cokinetic interaction study for both medicinal products resulted in a n increase of plasma
concentrations of metoprolol by approximately 30-40% without altering the plasma concen-
tration 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 metabolites, 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% de-
crease 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 on 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 ex-
pected 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 after birth. Some newborns ex-
posed to venlafaxine late in the third trimester have developed complications requiring tube-
feeding, respiratory support or prolonged hospitalisation. Such complications can arise im-
mediately upon delivery.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late
pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn
(PPHN). Although no studies have investigated an association of PPHN to SNRI treatment,
this potential risk cannot be ruled out with venlafaxine taking into account the related me-
chanism 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 into breast milk.
There have been post-marketing reports of breast-fed infants who experienced crying, irrita-
bility, and abnormal sleep patterns. Symptoms consistent with venlafaxine drug discontinua-
tion have also been reported after stopping breast-feeding. A risk to the suckling child cannot
be excluded. Therefore, a decision should be made whether to continue/discontinue breast-
feeding or to continue/discontinue therapy with venlafaxine, taking into account the benefit of
breast-feeding to the child and the benefit of venlafaxine therapy to the mother.

4.7 Effects on ability to drive and use machines

Any psychoactive medicinal products may impair judgement, thinking or motor skills. There-
fore any patient receiving venlafaxine should be cautioned about their ability to drive or oper-
ate 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
Uncommon
Not Known
bleeding, prolonged bleeding time, throm-bocytopenia, blood dyscrasias, (including agranulocy-tosis, aplas-tic anaemia, neutropenia and pancy-topaenia) tions tests, hypona-traemia, hepatitis, syndrome of inappropri-ate antidiu-retic hor-mone secre-tion (SIADH), prolactin increased tion, impaired vulsion, manic (NMS), sero- dyskinaesia, suicidal ideation and behav-iours**, ver-tigo, aggres-sion*** fibrillation, ventricular tachycardia (including torsade de pointes) crolysis, Stevens-Johnson syndrome, pruritis, utri-caria gamia, erectile dysfunction (impotence), urination im-paired (mostly hesitancy), menstrual dis-orders associ-ated with in-creased bleed-ing creased irregu-lar bleeding (e.g. menor-rhagia, matre-orrhagia), pol-lakiuria
* In pooled clinical trials, the incidence of headache was 30.3% with venlafaxine versus 31.3% with
placebo.
** Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or
early after treatment discontinuation (see section 4.4).
*** See section 4.4.
Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal
symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances
(including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting,
tremor, vertigo, headache and flu syndrome are the most commonly reported reactions.
Generally these events are mild to moderate and are self-limiting; however, in some patients
they may be severe and/or prolonged. It is therefore advised that when venlafaxine treat-
ment 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 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 ob-
served (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, epitaxis and myalgia.

4.9 Overdose

In post-marketing experience, overdose with venlafaxine was reported predominantly with,
alcohol and/or other medicinal products. The most commonly reported events in overdose
include tachycardia, changes in level of consciousness (from somnolence to coma), mydria-
sis, convulsion and vomiting. Other reported events include electrocardiographic changes
(e.g. prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachy-
cardia, bradycardia, hypotension, vertigo and death.
Published retrospective studies report that venlafaxine overdosage may be associated with
an increased risk of fatal outcomes compared to tat observes 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 that
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 fir
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 should be closely 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: N06A X16
The mechanism of venlafaxine 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 inhib-
its dopamine uptake. Venlafaxine den its active metabolite reduce β-adrenergic responsive-
ness after both acute (single dose) and chronic administration. Venlafaxine and ODV are
very similar with respect of their overall action on neurotransmitter reuptake and receptor
binding
Venlafaxine has virtually no affinity for rat brain muscarinic, cholinergic, H1-histamine or α1
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
ad cardiovascular side effects.
Venlafaxine does not have any 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 375mg/day. The efficacy of venlafaxine
prolonged release as a treatment for major depressive episodes was established in two pla-
cebo-controlled, short-term studies for 8 and 12 weeks duration, which included a dose
range of 75 to 225mg/day
One longer term study, adult outpatients who had responded during a 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 depres-
sive 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 de-
pression.
Generalised anxiety disorder
The efficacy of venlafaxine prolonged-release capsules as a treatment for generalised anxi-
ety disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75
to 225 mg/day), one 6-month, placebo-controlled, fixed-dose study (75 to 225 mg/day), and
one 6-month, placebo-controlled, flexible-dose study (37.5, 75, and 150 mg/day) in adult out-
patients.
While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this
dose was not as consistently effective as the higher doses.
Social anxiety disorder
The efficacy of venlafaxine prolonged-release capsules as a treatment for social anxiety dis-
order 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.
Panic disorder
The efficacy of venlafaxine prolonged-release capsules as a treatment for panic disorder was
established in two double-blind, 12-week, multi-center, placebo-controlled studies in adult
outpatients with panic disorder, with or without agoraphobia. The initial dose in panic disorder
studies was 37.5 mg/day for 7 days. Patients then received fixed doses of 75 or 150 mg/day
in one study and 75 or 225 mg/day in the other study.
Efficacy was also established in one long-term double-blind, placebo-controlled, parallel-
group study of the long-term safety, efficacy, and prevention of relapse in adult outpatients
who responded to open-label treatment. Patients continued to receive the same dose of
venlafaxine prolonged-release that they had taken at the end of the open-label phase (75,
150, or 225 mg).
5.2 Pharmacokinetic properties
Venlafaxine is extensively metabolised, primarily to the active metabolite, o-
desmethylvenlafaxine (ODV). Mean ± SD plasma half lives of venlafaxine and ODV are 5 ± 2
hours and 11 ± 2 hours, respectively. Steady-state concentrations of venlafaxine and ODV
are attained within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibit linear
kinetics over the dose range of 75mg to 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
prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are at-
tained 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 pro-
longed-release capsule provides a slower rate of absorption, but the same extent of absorp-
tion 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 exten- sive 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 im-
paired) subjects, venlafaxine and ODV half-lives were prolonged compared to normal sub- jects. The oral clearance of both venlafaxine and ODV was reduced. A large degree of inter- subject variability was noted. There are limited data in patients with severe hepatic impair- ment (see section 4.2)

Patients with renal impairment
In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clear- ance 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. Venla-
faxine 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 lacta-
tion. 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
Contents of the capsule:
Sugar spheres (contains sucrose)
Ethyl cellulose (E462)
Hydroxypropylcellulose
Hypromellose (E464)
Talc (E553b)
Dibutyl sebacate
Oleic acid
Colloidal anhydrous silica.
Capsule shell:
Gelatin
Sodium lauryl sulphate
Pigments:
sunset yellow FCF (E110)
quinoline yellow (E104)
titanium dioxide (E171).
6.2
Incompatibilities

Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container

20, 28, 30, 50, 98 and 100 capsules packed in blisters (PVC/ aluminium).
50 and 100 capsules in a HDPE bottle with HDPE screw cap and a sachet of silica gel (des-
iccant).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
MARKETING AUTHORISATION HOLDER

Genus Pharmaceuticals
Park View House
65 London Road
Newbury
Berkshire
RG14 1JN, UK
8.
MARKETING AUTHORISATION NUMBER(S)

PL 06831/0218
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25 November 2008
10. DATE OF REVISION OF THE TEXT
06/2011

Source: http://www.genuspharma.com/assets/Tifaxin-XL-75mgV5220611PL068310218.pdf

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