Venlor XR capsules

VENLOR XR TABLET is indicated for the treatment of depression, including depression with associated anxiety. VENLOR XR TABLET is indicated for the prevention of relapses of an episode of depression in patients responding to an initial six to eight weeks of treatment. In patients responding to six months of relapse prevention, VENLOR XR TABLET may be used to prevent recurrence. Safety and efficacy beyond one year have not been demonstrated. When VENLOR XR TABLET is used for long-term, it should periodically be re-evaluated for the usefulness of the product in individual patients. VENLOR XR TABLET is also indicated for the treatment of generalised anxiety disorder and for the treatment of Social Anxiety Disorder. The effectiveness of VENLOR XR TABLET in the treatment of Social Anxiety Disorder for more than 12 weeks has not been demonstrated.

Posology
The usual recommended dose of VENLOR XR TABLET is 75 mg, given once daily. If after several weeks further clinical improvement is required, the dose may be increased to 150 mg, given once daily. If needed, the dose can be further increased up to 225 mg given once daily. Dose increments should be made at intervals of approximately 2 weeks or more, but not less than 4 days. The dose for depressed patients may be further increased, if needed, up to 375 mg, given once daily.

VENLOR XR TABLET should be administered once daily, at approximately the same time either in the morning or in the evening.

Maintenance, continuation and extended treatment
The need for long-term therapy with VENLOR XR TABLET must be periodically reassessed. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Discontinuing VENLOR XR TABLET
Dose tapering is recommended whenever possible when discontinuing VENLOR XR TABLET therapy (see section 4.4). Tapering over at least a two-week period is recommended if VENLOR XR TABLET has been used for more than 6 weeks. Tapering can be achieved by reducing the daily dose by 75 mg at 1-week intervals. The period required for tapering may depend on the dose, duration of therapy and the individual patient. Patients should be advised to consult their doctor before abruptly discontinuing VENLOR XR TABLET (see section 4.4).

Special populations
Patients with renal impairment
Patients with renal impairment should receive lower doses of VENLOR XR TABLET. The total daily dose should be reduced by 25 to 50 % for patients with renal impairment with a glomerular filtration rate (GFR) of 10 to 70 mL/min. The total daily dose should be reduced by 50 % in haemodialysis patients. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable.

Patients with hepatic impairment
The total daily dose of VENLOR XR TABLET should be reduced by 50 % in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been studied; therefore, caution should be used if considering treating these patients with VENLOR XR TABLET and a further reduction should be considered. Since there is a variability in clearance between patients with hepatic impairment, individualisation of dosing, including further dose reductions (> 50 %), may be desirable in some patients.

Due to individual variability in clearance in these patients, individualisation of dosage may be desirable.

Elderly patients
No specific dosage adjustments of VENLOR XR TABLET are recommended based on patient age.

Paediatric population
VENLOR XR TABLET is contraindicated in children under 18 years of age (see section 4.3).

Method of administration
It is recommended that VENLOR XR TABLET be taken with food. Each tablet should be swallowed whole with fluid. Do not divide, crush, chew or place the tablet in water.

VENLOR XR TABLET is contraindicated in:

• patients with known hypersensitivity to venlafaxine hydrochloride or to any of the excipients of VENLOR XR TABLET (see section 6.1)
• patients taking monoamine oxidase inhibitors (MAOIs)
• patients who have discontinued treatment with a MAOI in less than 14 days (see section 4.5)
• children under 18 years of age (see section 4.4)
• pregnancy and lactation (see section 4.6).

VENLOR XR TABLET must be discontinued for at least 7 days before starting treatment with a MAOI. Severe adverse reactions have been reported when venlafaxine therapy is initiated soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of VENLOR XR TABLET.

Suicide/suicidal thoughts or clinical worsening:
All patients treated with VENLOR XR TABLET should be monitored appropriately and observed closely for clinical worsening and suicidality. Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restless), hypomania, mania, other unusual changes in behaviour, worsening of depression, and suicidal ideation, especially when initiating therapy or during any change in dose or dosage regimen. The risk of suicide attempt must be considered especially in depressed patients, and the smallest quantity of medicine, consistent with good patient management, should be provided to reduce the risk of overdose. Risk assessment for suicide should be performed regularly. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are strong predictors of suicide.

Patients with major depressive disorder may experience worsening of their depression and/or emergence of suicidal ideation and behaviour, whether or not they are taking antidepressant medicines. This risk may persist until significant remission occurs. A causal role, however, for antidepressant medicines in inducing such behaviour has not been established. Patients being treated with VENLOR XR TABLET should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy, or at any time of dose changes, either increases or decreases.

Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders.

The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness, impulsivity, akathisia, hypomania, and mania). Although a causal link between the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing VENLOR XR TABLET, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patientu2019s presenting symptoms. If the decision is made to discontinue treatment, VENLOR XR TABLET should be tapered (see section 4.2).

Serotonin syndrome
Serotonin syndrome, a potentially life-threatening condition, may occur with VENLOR XR TABLET treatment, particularly with concomitant use of other medicines that may affect the serotonergic neurotransmitter systems (including triptans, SSRIs, SNRIs, amphetamines, lithium, sibutramine, St.John's Wort [Hypericum perforatum], fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicines that impair metabolism of serotonin (such as MAOIs e.g. methylene blue), with serotonin precursors (such as tryptophan supplements) or with antipsychotics or other dopamine antagonists (see section 4.3 and section 4.5). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Serotonin syndrome in its most severe form, can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes. If concomitant treatment with venlafaxine and other medicines that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.

Narrow-angle glaucoma
Mydriasis may occur in association with VENLOR XR TABLET. It is recommended that patients with raised intra-ocular pressure or patients at risk for acute narrow angle glaucoma (angle closure glaucoma) be closely monitored.

Cardiac disease and risk of dysrhythmia
VENLOR XR TABLET should not be used in patients with an identified very high risk of serious ventricular dysrhythmia or uncontrolled hypertension. VENLOR XR TABLET has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. It should therefore be used with caution in these patients. Cases of QTc prolongation, Torsade de Pointes (TdP), ventricular tachycardia, and fatal cardiac dysrhythmias have been reported with the use of venlafaxine, especially in overdose or in patients with other risk factors for QTc prolongation/TdP. The balance of risks and benefits should be considered before prescribing venlafaxine to patients at high risk of serious cardiac dysrhythmia or QTc prolongation.

Blood pressure
Dose-related increases in blood pressure have been reported in some patients treated with VENLOR XR TABLET. Regular blood pressure monitoring is recommended for patients receiving VENLOR XR TABLET. Pre-existing hypertension should be controlled before treatment with VENLOR XR TABLET. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure.

Heart rate
Increases in heart rate may occur, particularly with higher doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.

Convulsions
Convulsions may occur with VENLOR XR TABLET therapy. VENLOR XR TABLET should be introduced with care in patients with a history of convulsions. VENLOR XR TABLET should be discontinued in any patient who develops seizures.

Mania/hypomania
Mania/hypomania may occur in a small proportion of patients with mood disorders who have received VENLOR XR TABLET. VENLOR XR TABLET should therefore be used cautiously in patients with a history or family history of bipolar disorder.

Aggression
Aggression may occur in a small proportion of patients who have received VENLOR XR TABLET treatment, dose reduction or discontinuation. VENLOR XR TABLET should be used cautiously in patients with a history of aggression.

Hyponatraemia
Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with VENLOR XR TABLET, usually 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
Medicines that inhibit serotonin uptake may lead to abnormalities of platelet aggregation. The risk of skin and mucous membrane bleeding, including gastrointestinal haemorrhage, may be increased in patients taking VENLOR XR TABLET. VENLOR XR TABLET should be used cautiously in patients predisposed to bleeding, including patients on anti-coagulants and platelet inhibitors.

Postpartum haemorrhage
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs), such as VENLOR XR TABLET, may increase the risk of postpartum haemorrhage (see section 4.6 and 4.8).

Allergic reactions
Patients should be advised to notify their doctor if they develop a rash, hives, or a related allergic phenomenon.

Co-administration with weight loss medicines
The safety and efficacy of VENLOR XR TABLET therapy in combination with weight loss medicines, including phentermine, have not been established. Co-administration of VENLOR XR TABLET and weight loss medicines is not recommended. VENLOR XR TABLET is not indicated for weight loss alone or in combination with other medicines.

Serum cholesterol
Increases in serum cholesterol may occur in patients treated with VENLOR XR TABLET. Measurement of serum cholesterol levels should be considered during long-term treatment.

Sexual dysfunction
Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as VENLOR XR TABLET may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SNRIs.

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.

Medicine-Laboratory test interactions
False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of VENLOR XR TABLET therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

Discontinuation of treatment
Discontinuation effects are well-known to occur. It is therefore recommended that VENLOR XR TABLET be tapered gradually, and the patient be monitored (see section 4.2). The following symptoms have been reported in association with abrupt discontinuation or dose reduction, or tapering of VENLOR XR TABLET treatment: Hypomania, anxiety, agitation, nervousness, confusion, insomnia or other sleep disturbances, fatigue, somnolence, paraesthesia, dizziness, convulsion, vertigo, headache, flu-like symptoms, tinnitus, impaired coordination and balance, tremor, sweating, dry mouth, anorexia, diarrhoea, nausea and vomiting. 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 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 to 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). In some patients, discontinuation could take months or longer.

Use in elderly patients
VENLOR XR TABLET appears to pose no exceptional safety problems for healthy elderly patients.

Abuse and dependence
Clinical studies did not show evidence of drug-seeking behaviour, development of tolerance, or dose escalation over time. VENLOR XR TABLET has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP) or N-methyl-D-aspartic acid (NMDA) receptors. Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate medicine discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.

Mannitol and lactose
VENLOR XR TABLET contains mannitol which may have a mild laxative effect. VENLOR XR TABLET contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take VENLOR XR TABLET.

Paediatric population
Safety and efficacy in individuals below 18 years of age have not been established. In clinical trials in Major Depressive Disorder, there were increased reports of hostility and suicide-related adverse events such as suicidal ideation and self-harm (see section 4.3).

Monoamine oxidase inhibitors
Severe adverse reactions have been reported in patients who have recently been discontinued from a MAOI and started on VENLOR XR TABLET or have recently had VENLOR XR TABLET therapy discontinued prior to initiation of a MAOI (see section 4.3). These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.

CNS active medicines
The risk of using VENLOR XR TABLET in combination with other CNS-active medicines has not been systematically evaluated. Consequently, caution is advised when VENLOR XR TABLET is taken in combination with other CNS-active medicines.

Serotonin syndrome
Serotonin syndrome, a potentially life threatening condition which may occur with VENLOR XR TABLET treatment, particularly with concomitant use of other medicines that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, lithium, sibutramine, tramadol, or St. Johnu2019s Wort [Hypericum perforatum]), with medicines which impair metabolism of serotonin (such as MAOIs; including linezolid [an antibiotic which is a reversible non-selective MAOI], (see section 4.3), or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms (see section 4.3 and section 4.4). If concomitant treatment of VENLOR XR TABLET with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of VENLOR XR TABLET with serotonin precursors (such as tryptophan supplements) is not recommended (see section 4.4).

Indinavir
A pharmacokinetic study with indinavir has shown a 28 % decrease in AUC and a 36 % decrease in C max for indinavir. Indinavir did not affect the pharmacokinetics of VENLOR XR TABLET and O-desmethylvenlafaxine (ODV). The clinical significance of this interaction is unknown.

Ethanol
VENLOR XR TABLET has not been shown to increase the impairment of mental and motor skills caused by ethanol. However, patients should be advised to avoid alcohol consumption while taking VENLOR XR TABLET.

Haloperidol
A pharmacokinetic study with haloperidol has shown for haloperidol a 42 % decrease in total oral clearance, a 70 % increase in AUC, an 88 % increase in C max, but no change in half-life. This should be taken into account in patients treated with haloperidol and VENLOR XR TABLET concomitantly.

Cimetidine
At steady-state, cimetidine has been shown to inhibit first-pass metabolism of venlafaxine; however, cimetidine had no effect on the pharmacokinetics of ODV. The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly in most patients. In the elderly and in patients with hepatic or renal dysfunction this interaction may be more pronounced.

Imipramine
Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, C max and C min increased by about 35 % in the presence of venlafaxine. There was an increase of 2-OH-desipramine AUC by 2,5 to 4,5-fold. Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. This should be taken into account in patients treated with imipramine and VENLOR XR TABLET concomitantly.

Ketoconazole
A pharmacokinetic study with ketoconazole in extensive (EM) and poor metabolisers (PM) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in subjects 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 ODV. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and VENLOR XR TABLET concomitantly.

Metoprolol
Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to healthy volunteers in a pharmacokinetic interaction study for both medicines resulted in an increase of plasma concentrations of metoprolol by approximately 30 to 40 % without altering the plasma concentrations of its active metabolite, u03b1-hydroxymetoprolol. Venlafaxine as in VENLOR XR TABLET appeared to reduce the blood pressure lowering effect of metoprolol in this study of healthy volunteers. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of Venlafaxine or its active metabolite, ODV. Caution should be exercised with co-administration of VENLOR XR TABLET and metoprolol.

Risperidone
Venlafaxine as in VENLOR XR TABLET increased the risperidone AUC by 32 % 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.

Diazepam
Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or ODV. VENLOR XR TABLET has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam. It is unknown whether a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines exists.

Lithium
The steady-state pharmacokinetics of venlafaxine and ODV are not affected when lithium is co-administered. Venlafaxine as in VENLOR XR TABLET also has no effects on the pharmacokinetics of lithium. Serotonin syndrome may occur with the concomitant use of venlafaxine and lithium (see serotonin syndrome).

Pregnancy
VENLOR XR TABLET must not be administered to pregnant women. Safety during human pregnancy has not been established (see section 4.3). Some neonates exposed to venlafaxine as in VENLOR XR TABLET late in the third trimester have developed complications requiring tube-feeding, respiratory support, or prolonged hospitalisation. Such complications can arise immediately upon delivery. Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth (see section 4.4 and 4.8). Patients should be advised to notify their doctor if they become pregnant or intend to become pregnant during therapy.

Breastfeeding
Venlafaxine and ODV are excreted in human milk; therefore, mothers on treatment with VENLOR XR TABLET should not breastfeed.

Fertility
Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of VENLOR XR TABLET, ODV. This ODV exposure was approximately 2 to 3 times that of a human VENLOR XR TABLET dose of 225 mg/day. The human relevance of this finding is unknown.

VENLOR XR TABLET may impair judgement, thinking and motor skills. Therefore, patients should be cautioned about their ability to drive or operate hazardous machines.

a. Summary of the safety profile
The most frequently observed adverse events associated with the use of VENLOR XR TABLET are nervous system complaints. The occurrence of many frequently observed adverse events is dose related.

b. Tabulated list of adverse reactions
The following adverse effects have been classified as either being frequent, less frequent, or of an unknown frequency.

MedDRA system organ class Frequency Side Effects Blood and lymphatic system disorders Less frequent Ecchymosis, haemorrhage including gastrointestinal bleeding. Frequency unknown Mucous membrane bleeding, prolonged bleeding time, thrombocytopenia, blood dyscrasias (including agranulocytosis, aplastic anaemia, neutropenia, pancytopenia). Metabolism and nutrition disorders Frequent Increased serum cholesterol (particularly with prolonged administration and possibly with higher doses), weight loss, decreased appetite. Less frequent Altered taste, hyponatremia, weight gain. Endocrine disorders Frequency unknown Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion, increased prolactin.

MedDRA system organ class Frequency Side Effects Psychiatric disorders Frequent Abnormal dreams, nervousness, insomnia, decreased libido, anxiety, agitation, depersonalisation. Less frequent Apathy, hallucinations, manic reaction, activation of mania or hypomania, derealisation. Frequency unknown Delirium, abnormal thinking, aggression, amnesia, depression, emotional lability, suicidal ideation, and behaviours. Nervous system disorders Frequent Dizziness, hypertonia, paraesthesia, tremor, headache, somnolence, sedation, akathisia, dysgeusia. Less frequent Myoclonus, convulsion, dysarthria, syncope, balance disorder, abnormal co-ordination. Frequency unknown Neuroleptic Malignant Syndrome (NMS), serotonin syndrome, tardive dyskinesia, hypoesthesia, trismus. Eye disorders Frequent Abnormality of accommodation, mydriasis, visual disturbances. Frequency unknown Angle closure glaucoma.

MedDRA system organ class Frequency Side Effects Ear and labyrinth disorders Frequent Tinnitus. Frequency unknown Vertigo. Cardiac disorders Frequent Palpitations, tachycardia. Less frequent Dysrhythmias, electrocardiogram QT prolongation, ventricular fibrillation, ventricular tachycardia (including torsade de pointes). Vascular disorders Frequent Less frequent Hypertension, vasodilation (hot flushes/flashes), dose related increases in blood pressure. Orthostatic or postural hypotension, syncope. Frequency unknown Hypotension.

MedDRA system organ class Frequency Side Effects Respiratory, thoracic and mediastinal disorders Frequent Dyspnoea, yawning. Less frequent Interstitial lung disease, pulmonary eosinophilia. Frequency unknown Pharyngitis, rhinitis.

MedDRA system organ class Frequency Side Effects Gastrointestinal disorders Frequent Decreased appetite, constipation, nausea, vomiting, anorexia, diarrhoea, dyspepsia, abdominal pain, dry mouth. Less frequent Bruxism, pancreatitis, gastrointestinal haemorrhage (see blood and lymphatic disorders). Frequency unknown Increased appetite, eructation, flatulence.

MedDRA system organ class Frequency Side Effects Hepatobiliary disorders Less frequent Reversible increases in liver enzymes, hepatitis. Frequency unknown Abnormal liver function test.

MedDRA system organ class Frequency Side Effects Skin and subcutaneous tissue disorders Frequent Sweating, pruritus, hyperhidrosis (including night sweats), rash. Less frequent Angioedema, alopecia, erythema multiforme, Stevens-Johnson syndrome, urticaria, photosensitivity reaction (see general disorders and administrative site conditions), toxic epidermal necrolysis, ecchymosis (see blood and lymphatic system disorders).

MedDRA system organ class Frequency Side Effects Musculoskeletal, connective tissue and bone disorders Frequent Arthralgia, hypertonia, paraesthesia, myalgia. Less frequent Ataxia, muscle spasm, rhabdomyolysis.

MedDRA system organ class Frequency Side Effects Renal and urinary disorders Frequent Urinary hesitation, urinary frequency, pollakiuria. Less frequent Urinary retention, urinary incontinence.

MedDRA system organ class Frequency Side Effects Reproductive system and breast disorders Frequent Less frequent Frequency unknown Abnormal ejaculation/orgasms (male), anorgasmia, erectile dysfunction, sexual dysfunction. Abnormal orgasm (female), galactorrhoea, menstrual changes, menorrhagia. Menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g. menorrhagia, metrorrhagia), post-partum haemorrhage.

MedDRA system organ class Frequency Side Effects General disorders and administrative site conditions Frequent Asthenia/fatigue, headache, pain, abdominal pain, back pain, chest pain, chills, fever. Frequency unknown Photosensitivity reactions, anaphylaxis, mucosal haemorrhage, angioedema.

MedDRA system organ class Frequency Side Effects Investigations Frequent Increased blood cholesterol.

c. Description of selected adverse reactions
Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment, discontinuation (see section 4.4).

d. Paediatric population
Children and adolescents up to 18 years: The side effect profile of venlafaxine in children and adolescents was similar to that seen in adults. In paediatric clinical trials, there were increased reports of hostility and, especially in Major Depressive Disorders, suicide-related adverse events such as suicidal ideation and self-harm. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed. Particularly, the following adverse reactions were observed: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia. (see section 4.3 and 4.4).

Discontinuation of treatment
Discontinuation of venlafaxine as in VENLOR XR TABLET (particularly when abrupt) commonly leads to withdrawal symptoms. Fatigue, somnolence, anorexia, palpitations, dizziness, dry mouth, diarrhoea, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nervousness, confusion, hypomania, nausea and/or vomiting, tremor, vertigo, headache, flu syndrome, visual impairment and hypertension 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 as in VENLOR XR TABLET treatment is no longer required, gradual discontinuation by dose tapering should be carried out. However, in some patientu2019s, severe aggression, and suicidal ideation occurred when the dose was reduced or during discontinuation (see section 4.2 and section 4.4).

VENLOR XR TABLET overdose is reported predominantly in combination with alcohol and/or other medicines. The most frequent events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other events reported include electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, hypoglycaemia, vertigo, and death. VENLOR XR TABLET overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant medicines, 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 VENLOR XR TABLET should be written for the smallest quantity of medicine consistent with good patient management, in order to reduce the risk of overdose.

Management of overdose
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. 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 VENLOR XR TABLET are known.