SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Sunveniz XL 75 mg prolonged-release tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Sunveniz XL 75 mg: Each prolonged-release tablet contains 75 mg of venlafaxine (as venlafaxine hydrochloride).

Excipients with known effect:

Each prolonged-release tablet contains 83.26 mg of lactose.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release tablet.

The prolonged-release tablet is round, pink and white coloured bilayer coated tablet imprinted with “759” with black ink on one side and plain on other side.

4    CLINICAL PARTICULARS

4.1    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

Posology

Major depressive episodes

The recommended starting dose for prolonged-release Sunveniz XL is 75 mg given once daily. Patients not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 375 mg/day. Dosage increases can be made at intervals of 2 weeks or more. If clinically warranted due to symptom severity, dose increases can be made at more frequent intervals, but not less than 4 days.

Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained.

Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly on a case-by-case basis. 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 episode.

Antidepressive medicinal products should continue for at least six months following remission.

Generalised anxiety disorder

The recommended starting dose for prolonged-release Sunveniz XL is 75 mg given once daily. Patients not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 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 Sunveniz XL 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 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.

Panic disorder

It is recommended that a dose of 37.5 mg/day of prolonged-release Sunveniz XL 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. 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.

Use in patients with hepatic impairment

In patients with mild and moderate hepatic impairment, in general a 50 % dose reduction should be considered. However, due to inter-individual variability in clearance, individualisation of dosage may be desirable.

There are limited data in patients with severe hepatic impairment. Caution is advised, and a dose reduction by more than 50 % should be considered. The potential benefit should be weighed against the risk in the treatment of patients with severe hepatic impairment.

Use in patients with renal impairment

Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 30-70 ml/minute, caution is advised. For patients that require haemodialysis and in patients with severe renal impairment (GFR < 30 ml/min), the dose should be reduced by 50%. Because of inter-individual variability in clearance in these patients, individualisation of dosage may be desirable.

Use in elderly patients

No specific dose adjustments of Sunveniz XL 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.

Paediatric population

The safety and efficacy of Sunveniz XL for other indications in children and adolescents under the age of 18 have not been established.

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

Withdrawal symptoms seen on discontinuation of Sunveniz XL

Abrupt discontinuation should be avoided. When stopping treatment with Sunveniz XL, 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.

Method of administration

For oral use.

It is recommended that Sunveniz XL prolonged-release tablets be taken with food, at approximately the same time each day. Tablets must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

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

Sunveniz XL prolonged-release tablets contain granules, which release the active substance slowly into the digestive tract. The insoluble portion of these granules is eliminated and may be seen in faeces.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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. Sunveniz XL must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI.

Sunveniz XL 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 Sunveniz 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.

Paediatric population

Sunveniz 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

Serotonin syndrome, a potentially life-threatening condition, may occur with Sunveniz XL treatment, particularly with concomitant use of other medicinal products, such as MAO-inhibitors, that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea).

Narrow-angle glaucoma

Mydriasis may occur in association with Sunveniz XL. 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 Sunveniz XL. 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

Sunveniz XL 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 Sunveniz XL, especially in overdose. The balance of risks and benefits should be considered before prescribing Sunveniz XL to patients at high risk of serious cardiac arrhythmia.

Convulsions

Convulsions may occur with venlafaxine therapy. Sunveniz XL 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 Sunveniz XL. 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 Sunveniz XL. Sunveniz XL 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 Sunveniz XL and weight loss agents is not recommended. Sunveniz XL 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 Sunveniz XL. Sunveniz XL 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 Sunveniz XL. This has been reported under initiation, dose changes and discontinuation of treatment.

Sunveniz XL should be used cautiously in patients with a history of aggression. Discontinuation of treatment

Withdrawal symptoms, when treatment is discontinued, are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation (tapering and post-tapering) occurred in approximately 31% of patients treated with Sunveniz XL and 17% of patients taking placebo.

The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that

Sunveniz XL should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient’s needs (see section 4.2).

Akathisia/psychomotor restlessness

The use of Sunveniz XL has been associated with development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by 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 Sunveniz XL. This may increase the risk of caries, and patients should be advised upon the importance of dental hygiene.

Lactose intolerance

Sunveniz XL contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.

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

Irreversible non-selective MAOIs

Sunveniz XL must not be used in combination with irreversible non-selective MAOIs . Sunveniz XL must not be initiated for at least 14 days after discontinuation of treatment with an irreversible non-selective MAOI. Sunveniz XL must be discontinued for at least 7 days before starting treatment with an irreversible nonselective MAOI (see sections 4.3 and 4.4).

Reversible, selective MAO-A inhibitor (moclobemide)

Due to the risk of serotonin syndrome, the combination of Sunveniz XL 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 Sunveniz XL treatment. It is recommended that Sunveniz XL 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 Sunveniz XL (see section 4.4).

Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI and started on Sunveniz XL 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

Serotonin syndrome may occur with Sunveniz XL 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 products which impair metabolism of serotonin (including MAOIs), or with serotonin precursors (such as tryptophan supplements).

If concomitant treatment of Sunveniz XL with an SSRI, an SNRI or a serotonin receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Sunveniz XL with serotonin precursors (such as tryptophan supplements) is not recommended (see section 4.4).

CNS-active substances

The risk of using Sunveniz XL in combination with other CNS-active substances has not been systematically evaluated. Consequently, caution is advised when Sunveniz XL is taken in combination with other CNS-active substances.

Ethanol

Sunveniz XL has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, patients should be advised to avoid alcohol consumption.

Effect of other medicinal products on Sunveniz XL

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-desmethyl venlafaxine (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 Sunveniz XL may increase levels of venlafaxine and O-desmethylvenlafaxine. Therefore, caution is advised if a patient’s therapy includes a CYP3A4 inhibitor and Sunveniz XL concomitantly.

Effect of Sunveniz XL on other medicinal products

Lithium

Serotonin syndrome may occur with the concomitant use of Sunveniz XL and lithium (see Serotonin syndrome).

Diazepam

Sunveniz XL 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

Sunveniz XL or O-desmethylvenlafaxine. It is unknown whether a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines exists.

Imipramine

Sunveniz XL 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 Sunveniz XL 75 mg to 150 mg daily was administered. Imipramine did not affect the pharmacokinetics of Sunveniz XL and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised with co-administration of Sunveniz XL 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 Sunveniz XL concomitantly. The clinical significance of this interaction is unknown.

Sunveniz XL 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 Sunveniz XL 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 Sunveniz XL or its active metabolite, O-desmethylvenlafaxine. Caution should be exercised with co-administration of Sunveniz XL 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 Sunveniz XL and O-desmethylvenlafaxine . The clinical significance of this interaction is unknown.

4.6 Fertility, pregnancy and lactation Pregnancy

There are no or limited amount of data from the use of Sunveniz XL in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Sunveniz XL is not recommended during pregnancy and in women of childbearing potential not using contraception.

Discontinuation symptoms may occur in the newborns if Sunveniz XL is used until or shortly before birth. Some newborns exposed to Sunveniz XL 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 venlafaxine 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.

Breastfeeding

Sunveniz XL and its active metabolite, O-desmethylvenlafaxine, are excreted in human milk to such an extent that effects on the breastfed newborns are likely. A decision must be made whether to discontinue breast feeding or to discontinue/abstain from Sunveniz XL therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

4.7    Effects on ability to drive and use machines

Sunveniz XL has minor to moderate influence on the ability to drive and use machines.

Any psychoactive medicinal product may impair judgment, thinking and motor skills. Therefore, any patient receiving Sunveniz XL 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).

System organ class	Very common	Common	Uncommon	Rare	Not known
Blood and lymphatic system disorders			Ecchymosis, Gastrointestinal haemorrhage		Mucous membrane bleeding, Prolonged bleeding time, Thrombocytopaenia, Blood dyscrasias, (including agranulocytosis, aplastic anaemia, neutropaenia a pancytopaenia)
Immune system			Photosensitivity reaction		Anaphylaxis

disorders
Metabolism and nutrition disorders		Serum cholesterol increased, Weight loss	Weight gain,		Abnormal liver function tests, Hyponatraemia, Hepatitis, Syndrome of Inappropriate Antidiuret Hormone Secretion (SIADH), Prolactin increased
Nervous system disorders	Dry mouth (10.0%), Headach e (30.3%)*	Abnormal dreams, Decreased libido, Dizziness, Increased muscle tonus (hypertonia), Insomnia, Nervousness, Paresthesia, Sedation, Tremor, Confusion, Depersonalisat ion	Apathy, Hallucinations, Myoclonus, Agitation, Impaired coordination and balance	Akathisia/ Psychomo tor restlessnes s, Convulsio n, Manic reaction	Neuroleptic Malignant Syndrome (NMS), Serotonergic syndrome, Delirium, Extrapyramid reactions (including dystonia and dyskinaesi; Tardive dyskinaesia, Suicidal ideation and behaviours**
Eye disorders		Abnormality of accommodatio n, Mydriasis, Visual disturbance			Angle-closure glaucoma
Ear and labyrinth disorders			Tinnitus
Cardiac disorders		Hypertension, Vasodilatation (mostly hot flashes/flushes ), Palpitations	Postural hypotension, Syncope, Tachycardia		Hypotension, QT prolongation, Ventricula fibrillation, Ventricular tachycardia (including torsade de pointes)
Respiratory, thoracic and mediastinal disorders		Yawning			Pulmonary eosinophilia
Gastro intestinal disorders	Nausea (20.0%)	Appetite decreased (anorexia), Constipation, Vomiting	Altered taste sensation, Bruxism, Diarrhoea		Pancreatitis
Skin and subcutaneous	Sweating (includin	Chills	Rash, Alopecia		Erythema multiforme, Toxic epidermal

tissue disorders	g night sweats) [12.2%]				necrolysis, Stevens-Johnson syndrome, Pruritus, Urticaria
Musculoskeletal and connective tissue disorders					Rhabdomyolysis
Renal and urinary disorders		Urination impaired (mostly hesitancy), Pollakiuria	Urinary retention
Reproductive system and breast disorders		Abnormal ejaculation/org asm (males), Anorgasmia, Erectile dysfunction (impotence), Menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g., menorrhagia, metrorrhagia)	Abnormal orgasm (females),
General disorders and administratio n site conditions		Asthenia (fatigue)

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

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

Discontinuation of Sunveniz XL (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraethesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, 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 Sunveniz XL treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

Paediatric population

In general, the adverse reaction profile of Sunveniz XL (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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In post marketing experience, overdose with Sunveniz XL 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 Sunveniz XL should be written for the smallest quantity of the medicinal product consistent with good patient management in order to reduce the risk of overdose.

Recommended treatment

General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs must be monitored. When there is a risk of aspiration, induction of emesis is not recommended. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Administration of activated charcoal may also limit absorption of the active substance. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for Sunveniz XL are known.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nervous system; psychoanaleptics; antidepressants; Other antidepressants. ATC code: N06A X16

The mechanism of Sunveniz 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 (ODV), are inhibitors of serotonin and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its active metabolite reduce P-adrenergic responsiveness after both acute (single dose) and chronic administration. Venlafaxine and ODV are very similar with respect to their overall action on neurotransmitter reuptake and receptor binding.

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

Sunveniz XL does not possess monoamine oxidase (MAO) inhibitory activity.

In vitro studies revealed that venlafaxine has virtually no affinity for opiate or benzodiazepine sensitive receptors.

Major depressive episodes

The efficacy of venlafaxine immediate-release as a treatment for major depressive episodes was demonstrated in five randomised, double-blind, placebo-controlled, short-term trials ranging from 4 to 6 weeks duration, for doses up to 375 mg/day. The efficacy of venlafaxine prolonged-release as a treatment for major depressive episodes was established in two placebo-controlled, short-term studies for 8 and 12 weeks duration, which included a dose range of 75 to 225 mg/day.

In one longer-term study, adult outpatients who had responded during an 8-week open trial on venlafaxine prolonged-release (75, 150, or 225 mg) were randomised to continuation of their same venlafaxine prolonged-release dose or to placebo, for up to 26 weeks of observation for relapse.

In a second longer-term study, the efficacy of venlafaxine in prevention of recurrent depressive episodes for a 12-month period was established in a placebo-controlled double-blind clinical trial in adult outpatients with recurrent major depressive episodes who had responded to venlafaxine treatment (100 to 200 mg/day, on a b.i.d. schedule) on the last episode of depression.

Generalised anxiety disorder

The efficacy of venlafaxine prolonged-release capsules as a treatment for generalised anxiety 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 outpatients.

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 disorder was established in four double-blind, parallel-group, 12-week, multicenter, 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 75 mg 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 Sunveniz XL prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. When equal daily doses of venlafaxine are administered as either an immediate-release tablet or prolonged-release capsule, the prolonged-release capsule provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Food does not affect the bioavailability of venlafaxine and ODV.

Distribution

Venlafaxine and ODV are minimally bound at therapeutic concentrations to human plasma proteins (27% and 30%, respectively). The volume of distribution for venlafaxine at steady-state is 4.4±1.6 L/kg following intravenous administration.

Biotransformation

Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that venlafaxine is biotransformed to its major active metabolite, ODV, by CYP2D6. In vitro and in vivo studies indicate that venlafaxine is metabolised to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. In vitro and in vivo studies indicate that venlafaxine is a weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9, or CYP3A4.

Elimination

Venlafaxine and its metabolites are excreted primarily through the kidneys. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Mean ± SD plasma steady-state clearances of venlafaxine and ODV are 1.3±0.6 L/h/kg and 0.4±0.2 L/h/kg, respectively.

Special populations

Age and gender

Subject age and gender do not significantly affect the pharmacokinetics of venlafaxine and ODV.

CYP2D6 extensive/poor metabolisers

Plasma concentrations of venlafaxine are higher in CYP2D6 poor metabolisers than extensive metabolisers. Because the total exposure (AUC) of venlafaxine and ODV is similar in poor and extensive metabolisers, there is no need for different venlafaxine dosing regimens for these two groups.

Patients with hepatic impairment

In Child-Pugh A (mildly hepatically impaired) and Child-Pugh B (moderately hepatically impaired) subjects, venlafaxine and ODV half-lives were prolonged compared to normal subjects. The oral clearance of both venlafaxine and ODV was reduced. A large degree of intersubject variability was noted. There are limited data in patients with severe hepatic impairment (see section 4.2).

Patients with renal impairment

In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance reduced by about 57% compared to normal subjects, while ODV elimination half-life was prolonged by about 142% and clearance reduced by about 56%. Dosage adjustment is necessary in patients with severe renal impairment and in patients that require haemodialysis (see section 4.2).

5.3 Preclinical safety data

Studies with venlafaxine in rats and mice revealed no evidence of carcinogenesis. Venlafaxine was not mutagenic in a wide range of in vitro and in vivo tests.

Animal studies regarding reproductive toxicity have found in rats a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation. The cause of these deaths is unknown. These effects occurred at 30 mg/kg/day, 4 times a 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

Tablet core:

Sustained release layer: hypromellose, povidone(K-30), lactose monohydrate,

methacrylic acid-ethyl acrylate (1:1) co-polymer, talc,

magnesium stearate.

Openable layer:

silicified microcrystalline cellulose,

crospovidone Type A,

colloidal anhydrous silica,

sodium lauryl sulphate,

lake allura red (E129)

talc,

magnesium stearate.

Coating:

ethyl cellulose aqueous dispersion,

mannitol,

povidone (K-30)

dibutyl sebacate,

triethyl citrate,

polysorbate 20,

opadry II 85F 19250 clear which consists of: talc,

macrogol 3350, polysorbate 80, polyvinyl alcohol.

Printing ink (opacode-s-1-17823 black) shellac,

black iron oxide (E172), propylene glycol.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Blister: Store in the original package, in order to protect from moisture.

HDPE tablet container: Keep the tablet container tightly closed, in order to protect from moisture.

6.5 Nature and contents of container

Blister consisting of an OPA (oriented Poly Amide) / Aluminium / PVC (Polyvinyl chloride) film and Paper / PET (Polyethylene terephthalate) / Aluminium / Peelable lidding foil with heat seal lacquer.

Pack sizes: 14, 15, 20, 28, 30, 50 or 100 prolonged-release tablets.

HDPE tablet container along with silica gel canister closed with child resistant closure.

Pack sizes: 30 or 1000 (for dispensing only) prolonged release tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87 2132 JH Hoofddorp The Netherlands

MARKETING AUTHORISATION NUMBER(S)

PL31750/0026

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/12/2010

10    DATE OF REVISION OF THE TEXT

12/02/2015