SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Vensir XL 225mg prolonged release capsules.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains venlafaxine hydrochloride equivalent to 225mg of venlafaxine Contains: 0.022 mg of carmoisine (E122). For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged release capsules, hard. The capsules are pink opaque / pink opaque / size ‘00’ hard gelatin capsules having thick and thin radial circular band on the body in blue ink and thick and thin radial circular band on the cap in blue ink filled with mini tablets.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

The treatment of major depressive disorder

The prevention of relapses of the initial episode of depression or for the prevention of the recurrence of new episodes.

All patients should be evaluated for the risk of suicidality and monitored for clinical worsening (see section 4.2 and 4.4).”

4.2 Posology and method of administration

For oral administration to adults only. The capsules should be swallowed unchewed and with liquid (e.g. a glass of water) and taken with food.

Major depressive disorder: Adults and the elderly: 75mg/day to 150mg/day. A dose of 75mg/day is recommended as the initial dose. Although there may be an increased potential for undesirable effects at higher doses, a dose increase may be considered after three weeks if there is no response.

In more severely depressed or hospitalised patients, and under close supervision of a physician, the daily dose may then be increased by up to 75mg every two or three days until the desired response is achieved. In those more severely depressed or hospitalised patients who require daily doses of 300 mg or more, treatment should be initiated under specialist supervision including shared care arrangements. The maximum recommended dose is 375mg/day.

The dose should then be gradually reduced, to the minimum effective dose consistent with patient response and tolerance. A limited amount of venlafaxine should be provided to reduce the risk from overdose (see section 4.4).

Prevention of relapse or for prevention of recurrence of a new episode: The dosage is similar to that used during the index episode. Patients should be re-assessed regularly in order to evaluate the benefit of long-term therapy.

Patients at increased risk for suicide (see also sections 4.4 and 4.9)

Patients with increased risk factors for suicide should be carefully evaluated for the presence or worsening of suicide-related behaviour (see sections 4.4 and 4.9) and a limited number of tablets should be provided to reduce the risk from overdose. A maximum of two weeks supply should be considered in these patients at initiation of treatment, during any dosage adjustment and until improvement occurs.

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 Vensir XL in these patients (see sections 4.4 and 4.8).

The efficacy and safety of Vensir XL for other indications in children and adolescents under the age of 18 have not yet 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. This dose may be given once daily due to the longer half-lives of venlafaxine and O-desmethylvenlafaxine (ODV) in these patients.

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 Vensir 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 Vensir XL at the nearest equivalent daily dosage. For example, venlafaxine immediate-release tablets 37.5 mg twice daily may be switched to Vensir XL 75 mg once daily. Individual dosage adjustments may be necessary.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI.

Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see sections 4.4 and 4.5).

4.4 Special warnings and precautions for use Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Vensir XL is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present

Use in children and adolescents under 18 years of age

Vensir 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 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, the development of a potentially life-threatening serotonin-syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions, may occur with venlafaxine treatment, particularly with concomitant use of other serotonergic agents (including SSRIs, SNRIs and triptans), with agents that impair metabolism of serotonin such as MAO-inhibitors, or with antipsychotics or other dopamine antagonists (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). 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 agents 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 venlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow-angle glaucoma (angle-closure glaucoma) be closely monitored.

Blood pressure

Dose-related increases in blood pressure have been commonly reported with venlafaxine. In some cases, severely elevated blood pressure requiring immediate treatment has been reported in postmarketing experience. All patients should be carefully screened for high blood pressure and pre-existing hypertension should be controlled before initiation of treatment. Blood pressure should be reviewed periodically, after initiation of treatment and after dose increases. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure, e.g., those with impaired cardiac function.

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 Undesirable effects). In clinical trials adverse events seen on treatment discontinuation (tapering and post-tapering) occurred in approximately 31% of patients treated with venlafaxine and in approximately 17% of placebo patients.

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 and electric shock sensations), sleep disturbances (including insomnia and abnormal dreams), agitation or anxiety, nausea and/or vomiting, tremor, sweating, headache, diarrhoea, palpitations and emotional instability are the most commonly reported withdrawal 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 selflimiting 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 "Withdrawal Symptoms Seen on Discontinuation of Venlafaxine", Section 4.2 Posology and Method of Administration).

Akathisia/psychomotor restlessness

The use of venlafaxine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Dry mouth

Dry mouth is reported in 10% of patients treated with venlafaxine. This may increase the risk of caries, and patients should be advised upon the importance of dental hygiene.

Diabetes

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

4.5 Interaction with other medicinal products and other forms of interaction Monoamine Oxidase Inhibitors (MAOI)

Irreversible non-selective MAOIs

Venlafaxine must not be used in combination with irreversible non-selective MAOIs. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible non-selective MAOI. Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible 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, a potentially life-threatening condition, 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 that impair metabolism of serotonin (such as MAOIs), or with serotonin precursors (such as tryptophan supplements).

If concomitant treatment with venlafaxine and 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.

Drugs that Prolong the QT Interval

The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of other medicinal products which prolong the QTc interval. Co-administration of such medicinal products should be avoided (see section 4.4).

Relevant classes include:

•    class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)

•    some antipsychotics (e.g. thioridazine)

•    some macrolides (e.g. erythromycin)

•    some antihistamines

•    some quinolone antibiotics (e.g. moxifloxacin)

The above list is not exhaustive and other individual medicinal products known to significantly increase QT interval should be avoided.

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 C_max, 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, a-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 C_max for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown.

Clozapine

Increased levels of clozapine, that were temporally associated with adverse events, including seizures, have been reported following the addition of venlafaxine.

ECT

There is little clinical experience of the concurrent use of venlafaxine with ECT. As prolonged seizure activity has been reported with concomitant SSRI antidepressants, caution is advised.

4.6 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.

As with other serotonin reuptake inhibitors (SSRIs/SNRIs), discontinuation symptoms may occur in the newborns if venlafaxine is used until or shortly before birth. Some newborns exposed to venlafaxine late in the third trimester have developed complications requiring tube-feeding, respiratory support or prolonged hospitalisation. Such complications can arise immediately upon delivery.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated an association of PPHN to SNRI treatment, this potential risk cannot be ruled out with Vensir XL, taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).

The following symptoms may be observed in neonates if the mother has used an SSRI/SNRI late in pregnancy: irritability, tremor, hypotonia, persistent crying, and difficulty in sucking or in sleeping. These symptoms may be due to either serotonergic effects or exposure symptoms. In the majority of cases, these complications are observed immediately or within 24 hours after partus.

Lactation

Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are excreted in breast milk. 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 Vensir XL should be made, taking into account the benefit of breast-feeding to the child and the benefit of Vensir XL therapy to the woman.

4.7 Effects on ability to drive and use machines

Although venlafaxine has been shown not to affect psychomotor, cognitive, or complex behaviour performance in healthy volunteers, any psychoactive drug may impair judgement, thinking or motor skills. Therefore patients should be cautioned about their ability to drive or operate hazardous machinery.

4.8 Undesirable effects

The most commonly (>1/10) reported adverse reactions in clinical studies were nausea, dry mouth, headache and sweating (including night sweats).

Adverse reactions are listed below by system organ class and frequency.

Frequencies are defined as: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), not known (cannot be estimated from the available data).

Body System	Very Common	Common	Uncommon	Rare	Not Known
Haematological/ Lymphatic			Ecchymosis, Gastrointestinal haemorrhage		Mucous membrane bleeding, Prolonged bleeding time, Thrombocytopaenia, Blood dyscrasias, (including agranulocytosis, aplastic anaemia, neutropaenia and pancytopaenia)
Metabolic/ Nutritional		Serum cholesterol increased, Weight loss	Weight gain		Abnormal liver function tests, Hyponatraemia, Hepatitis, Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), Prolactin increased
Nervous	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	Neuroleptic Malignant Syndrome (NMS), Serotonergic syndrome, Delirium, Extrapyramidal reactions (including dystonia and dyskinesia), Tardive dyskinesia, Suicidal ideation and behaviours**, Vertigo, Aggression***
Special Senses		Abnormality of accommodation, Mydriasis, Visual disturbance,	Altered taste sensation, Tinnitus		Angle-closure glaucoma
Cardiovascular		Hypertension, Vasodilatation (mostly hot flashes/flushes), Palpitations	Postural hypotension, Syncope, Tachycardia		Hypotension, QT prolongation, Ventricular fibrillation, Ventricular tachycardia (including torsade de pointes)
Respiratory		Yawning			Pulmonary eosinophilia
Digestive	Nausea (20.0%)	Appetite decreased (anorexia), Constipation, Vomiting	Bruxism, Diarrhoea		Pancreatitis
Skin	Sweating (including night sweats)		Rash, Alopecia		Erythaema multiforme, Toxic epidermal necrolysis, Stevens-Johnson syndrome, Pruritus, Urticaria

	[12.2%]
Musculoskeletal					Rhabdomyolysis
Urogenital		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	Abnormal orgasm (females), Urinary retention	Urinary incontinence
Body as a Whole		Asthenia (fatigue), Chills	Angioedema, Photosensitivity reaction		Anaphylaxis

*In pooled clinical trials, the incidence of headache was 30.3% with venlafaxine versus 31.3% with placebo.

**Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment discontinuation (see section 4.4).

***See section 4.4

Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including 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 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, haemoperfusion 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: Venlafaxine.

ATC code: N06AX16

Vensir XL is a structurally novel antidepressant which is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is a racemate with two active enantiomers.

The mechanism of Vensir XL’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, are potent neuronal serotonin and noradrenaline re-uptake inhibitors (SNRI) and weak inhibitors of dopamine reuptake. In addition, venlafaxine and O-desmethylvenlafaxine reduce P-adrenergic responsiveness in animals after both acute (single dose) and chronic administration. Venlafaxine and its major metabolite appear to be equipotent with respect to their overall action on neurotransmitter reuptake.

Venlafaxine has virtually no affinity for rat brain muscarinic, histaminergic or adrenergic receptors in vitro. Pharmacologic activity at these receptors may be related to various side effects seen with other antidepressant drugs, such as anticholinergic, sedative and cardiovascular effects.

5.2 Pharmacokinetic properties Absorption:

Venlafaxine is well absorbed and undergoes extensive first-pass metabolism. Mean peak plasma concentrations of venlafaxine range from approximately 33 to 172ng/ml after 25 to 150mg single doses, and are reached in approximately 2.4 hours.

Distribution:

Venlafaxine and O-desmethylvenlafaxine are 27% and 30% bound to plasma proteins respectively.

Metabolism:

Venlafaxine is extensively metabolised in the liver. O-desmethylvenlafaxine is the major active metabolite of venlafaxine. The mean disposition half-life of venlafaxine and O-desmethylvenlafaxine is approximately 5 and 11 hours, respectively. Mean peak O-desmethylvenlafaxine plasma concentrations range from approximately 61 to 325ng/ml and are reached in approximately 4.3 hours. Plasma concentrations of venlafaxine and O-desmethylvenlafaxine generally correlated well with dose levels.

Elimination:

O-desmethylvenlafaxine, other minor venlafaxine metabolites, and non-metabolised venlafaxine are excreted primarily through the kidneys.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity reproduction.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

•    Microcrystalline cellulose

•    Co-povidone

•    Ethyl cellulose

•    Magnesium stearate

•    Povidone

•    Colloidal Silicon Dioxide

•    Talc

Capsule shell components

•    Gelatin

•    Carmoisin (E122)

•    Titanium dioxide (E171)

Printing ink

•    Shellac

•    Propylene glycol

•    Strong Ammonia Solution (E527)

•    FD & C Blue # 2 Aluminium Lake (E132)

6.2 Incompatibilities

Not Applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25 °C

Store in the original container to protect from moisture

6.5 Nature and contents of container

PVC/ACLAR (White opaque ) film and Aluminium lidding foil. PVC/PVdC (White opaque) film and Aluminium foil. OPA/Alu/PVC foil and aluminium foil.

Blister packs of 10, 14, 15 20, 28, 30, 56, 60 and 100 capsules. Not all pack sizes may be marketed

Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Morningside Healthcare Ltd 115 Narborough Road Leicester LE30PA United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 20117/0157

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/03/2016

10    DATE OF REVISION OF THE TEXT

01/03/2016