Wilzin 25 mg hard capsules

1. Name Of The Medicinal Product

Wilzin25 mg hard capsules

2. Qualitative And Quantitative Composition

Each hard capsule contains 25 mg of zinc (corresponding to 83.92 mg of zinc acetate dihydrate).

For excipients, see section 6.1.

3. Pharmaceutical Form

Hard capsule.

Size 1 hard capsule with aqua blue opaque cap and body, imprinted "93-376”.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of Wilson's disease.

4.2 Posology And Method Of Administration

Wilzin treatment should be initiated under the supervision of a physician experienced in the treatment of Wilson's disease (see section 4.4). Wilzin is a life-long therapy.

There is no difference in dosage between symptomatic and presymptomatic patients.

Wilzin is available in hard capsules of 25 mg or 50 mg.

•Adults:

The usual dosage is 50 mg 3 times daily with a maximum dose of 50 mg 5 times daily.

•Children and adolescents:

Data are very limited in children under 6 years but since the disease is fully penetrant, prophylactic treatment should be considered as early as possible. The recommended dosage is as follows:

- from 1 to 6 years: 25 mg twice daily

- from 6 to 16 years if bodyweight under 57 kg: 25 mg three times daily

- from 16 years or if bodyweight above 57 kg: 50 mg three times daily.

•Pregnant women:

A dosage of 25 mg 3 times daily is usually effective but the dosage should be adjusted to copper levels (see section 4.4 and section 4.6).

In all cases, dosage should be adjusted according to therapeutic monitoring (see section 4.4.).

Wilzin must be taken on an empty stomach, at least 1 hour before or 2-3 hours after meals. In case of gastric intolerance, often occurring with the morning dose, this dose may be delayed to mid-morning, between breakfast and lunch. It is also possible to take Wilzin with a little protein, such as meat (see section 4.5).

In children who are unable to swallow capsules, these should be opened and their content suspended in a little water (possibly sugar or syrup flavoured water).

When switching a patient on chelating treatment to Wilzin for maintenance therapy, the chelating treatment should be maintained and co-administered for 2 to 3 weeks since this is the time it takes for the zinc treatment to induce maximum metallothionein induction and full blockade of copper absorption. The administration of the chelating treatment and Wilzin should be separated by at least 1 hour.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

Zinc acetate dihydrate is not recommended for the initial therapy of symptomatic patients because of its slow onset of action. Symptomatic patients must be initially treated with a chelating agent; once copper levels are below toxic thresholds and patients are clinically stable, maintenance treatment with Wilzin can be considered.

Nevertheless, while awaiting zinc induced duodenal metallothionein production and consequential effective inhibition of copper absorption, zinc acetate dihydrate could be administered initially in symptomatic patients in combination with a chelating agent.

Although rare, clinical deterioration may occur at the beginning of the treatment, as has also been reported with chelating agents. Whether this is related to mobilisation of copper stores or to natural history of the disease remains unclear. A change of therapy is recommended in this situation.

Caution should be exercised when switching patients with portal hypertension from a chelating agent to Wilzin, when such patients are doing well and the treatment is tolerated. Two patients of a series of 16 died from hepatic decompensation and advanced portal hypertension after being changed from penicillamine to zinc therapy.

Therapeutic monitoring

The aim of the treatment is to maintain the plasma free copper (also known as non-ceruloplasmin plasma copper) below 250 microgram/l (normal: 100-150 microgram/l) and the urinary copper excretion below 125 microgram/24 h (normal: < 50 microgram/24 h). The non-ceruloplasmin plasma copper is calculated by subtracting the ceruloplasmin-bound copper from the total plasma copper, given that each milligram of ceruloplasmin contains 3 micrograms of copper.

The urinary excretion of copper is an accurate reflection of body loading with excess copper only when patients are not on chelation therapy. Urinary copper levels are usually increased with chelation therapy such as penicillamine or trientine.

The level of hepatic copper cannot be used to manage therapy since it does not differentiate between potentially toxic free copper and metallothionein bound copper.

In treated patients, assays of urinary and/or plasma zinc may be a useful measure of treatment compliance. Values of urinary zinc above 2 mg/24 h and of plasma zinc above 1250 microgram/l generally indicate adequate compliance.

Like with all anti-copper agents overtreatment carries the risk of copper deficiency, which is especially harmful for children and pregnant women since copper is required for proper growth and mental development. In these patient groups, urinary copper levels should be kept a little above the upper limit of normal or in the high normal range (i.e. 40 – 50 microgram/24 h).

Laboratory follow-up including haematological surveillance and lipoproteins determination should also be performed in order to detect early manifestations of copper deficiency, such as anaemia and/or leukopenia resulting from bone marrow depression, and decrease in HDL cholesterol and HDL/total cholesterol ratio.

In case of gastric intolerance, often occurring with the morning dose, this dose may be delayed to mid-morning, between breakfast and lunch. It is also possible to take Wilzin with a little protein, such as meat (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Other anti-copper agents

Pharmacodynamic studies were conducted in Wilson's disease patients on the combination of Wilzin (50 mg three times daily) with ascorbic acid (1 g once daily), penicillamine (250 mg four times daily), and trientine (250 mg four times daily). They showed no significant overall effect on copper balance although mild interaction of zinc with chelators (penicillamine and trientine) could be detected with decreased faecal but increased urinary copper excretion as compared with zinc alone. This is probably due to some extent of complexion of zinc by the chelator, thus reducing the effect of both active substances.

When switching a patient on chelating treatment to Wilzin for maintenance therapy, the chelating treatment should be maintained and co-administered for 2 to 3 weeks since this is the time it takes for the zinc treatment to induce maximum metallothionein induction and full blockade of copper absorption. The administration of the chelating treatment and Wilzin should be separated by at least 1 hour.

Other medicinal products

The absorption of zinc may be reduced by iron and calcium supplements, tetracyclines and phosphorus-containing compounds, while zinc may reduce the absorption of iron, tetracyclines, fluoroquinolones.

Food

Studies of the co-administration of zinc with food performed in healthy volunteers showed that the absorption of zinc was significantly delayed by many foods (including bread, hard boiled eggs, coffee and milk). Substances in food, especially phytates and fibres, bind zinc and prevent it from entering the intestinal cells. However, protein appears to interfere the least.

4.6 Pregnancy And Lactation

Pregnancy:

Data on a limited number of exposed pregnancies in patients with Wilson's disease give no indication of harmful effects of zinc on embryo/foetus and mother. Five miscarriages and 2 birth defects (microcephaly and correctable heart defect) were reported in 42 pregnancies.

Animal studies conducted with different zinc salts do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

It is extremely important that pregnant Wilson's disease patients continue their therapy during pregnancy. Which treatment should be used, zinc or chelating agent should be decided by the physician. Dose adjustments to guarantee that the foetus will not become copper deficient must be done and close monitoring of the patient is mandatory (see section 4.4).

Lactation:

Zinc is excreted in human breast milk and zinc-induced copper deficiency in the breast-fed baby may occur. Therefore, breast-feeding should be avoided during Wilzin therapy.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Clinical experience of more than 1 000 patient-years with zinc (more than 500 with zinc acetate dihydrate) as well as post-marketing surveillance with zinc acetate dihydrate of more than 1 000 patient-years showed that the most common undesirable effect is gastric irritation. This is usually worst with the first morning dose and disappears after the first days of treatment. Delaying the first dose to mid-morning or taking the dose with a little protein may usually relieve the symptoms.

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common (> 1/10), common (>1/100, <1/10) and uncommon (>1/1,000, <1/100):

Blood and lymphatic system disorders	uncommon:	sideroblastic anaemia; leukopenia
Gastrointestinal disorders	common:	gastric irritation
Laboratory investigations	common:	blood amylase, lipase and alkaline phosphatase increased

Anaemia may be micro-, normo- or macrocytic and is often associated with leukopenia. Bone marrow examination usually reveals characteristic "ringed sideroblasts" (i.e. developing red blood cells containing iron-engorged paranuclear mitochondria). They may be early manifestations of copper deficiency and may recover rapidly following reduction of zinc dosage. However, they must be distinguished from haemolytic anaemia which commonly occurs where there is elevated serum free copper in uncontrolled Wilson's disease.

Elevations of serum alkaline phosphatase, amylase and lipase may occur after a few weeks of treatment, with levels usually returning to high normal within the first one or two years of treatment.

4.9 Overdose

Three cases of acute oral overdosage with zinc salts (sulphate or gluconate) have been reported in the literature. Death occurred in a 35 year-old woman on the fifth day after ingestion of 6 g of zinc (40 times the proposed therapeutic dose) and was attributed to renal failure and haemorrhagic pancreatitis with hyperglycaemic coma. The same dose did not produce any symptoms except for vomiting in an adolescent who was treated by whole-bowel irrigation. Another adolescent who ingested 4 g of zinc had serum zinc level of about 50 mg/l 5 hours later and only experienced severe nausea, vomiting and dizziness.

Treatment of overdose should be with gastric lavage or induced emesis as quickly as possible to remove unabsorbed zinc. Heavy metal chelation therapy should be considered if plasma zinc levels are markedly elevated (> 10 mg/l).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: various alimentary tract and metabolism product, ATC code: A16AX05.

Wilson's disease (hepatolenticular degeneration) is an autosomal recessive metabolic defect in hepatic excretion of copper in the bile. Copper accumulation in the liver leads to hepatocellular injury and eventual cirrhosis. When the liver capacity of storing copper is exceeded copper is released into the blood and is taken up in extra hepatic sites, such as the brain, resulting in motor disorders and psychiatric manifestations. Patients may present clinically with predominantly hepatic, neurologic, or psychiatric symptoms.

The active moiety in zinc acetate dihydrate is zinc cation, which blocks the intestinal absorption of copper from the diet and the reabsorption of endogenously secreted copper. Zinc induces the production of metallothionein in the enterocyte, a protein that binds copper thereby preventing its transfer into the blood. The bound copper is then eliminated in the stool following desquamation of the intestinal cells.

Pharmacodynamic investigations of copper metabolism in patients with Wilson's disease included determinations of net copper balance and radiolabelled copper uptake. A daily regimen of 150 mg of Wilzin in three administrations was shown to be effective in significantly reducing copper absorption and inducing a negative copper balance.

5.2 Pharmacokinetic Properties

Since the mechanism of action of zinc is an effect on copper uptake at the level of the intestinal cell, pharmacokinetic evaluations based on blood levels of zinc do not provide useful information on zinc bioavailability at the site of action.

Zinc is absorbed in the small intestine and its absorption kinetics suggest a tendency to saturation at increasing doses. Fractional zinc absorption is negatively correlated with zinc intake. It ranges from 30 to 60% with usual dietary intake (7-15 mg/d) and decreases to 7% with pharmacological doses of 100 mg/d.

In the blood, about 80% of absorbed zinc is distributed to erythrocytes, with most of the remainder being bound to albumin and other plasma proteins. The liver is the main storage for zinc and hepatic zinc levels are increased during maintenance therapy with zinc.

The plasma elimination half-life of zinc in healthy subjects is around 1 hour after a dose of 45 mg. The elimination of zinc results primarily from faecal excretion with relatively little from urine and sweat. The faecal excretion is in the greatest part due to the passage of unabsorbed zinc but it is also due to endogenous intestinal secretion.

5.3 Preclinical Safety Data

Preclinical studies have been conducted with zinc acetate and with other zinc salts. Pharmacological and toxicological data available showed large similarities between zinc salts and among animal species.

The oral LD50 is approximately 300 mg zinc/kg body weight (about 100 to 150 times the human therapeutic dose). Repeat-dose toxicity studies have established that the NOEL (No Observed Effect Level) is about 95 mg zinc/kg body weight (about 48 times the human therapeutic dose).

The weight of evidence, from in vitro and in vivo tests, suggests that zinc has no clinically relevant genotoxic activity.

Reproduction toxicology studies performed with different zinc salts showed no clinically relevant evidence of embryotoxicity, foetotoxicity or teratogenicity.

No conventional carcinogenicity study has been conducted with zinc acetate dihydrate.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule content:

maize starch

magnesium stearate

Capsule shell:

gelatin

titanium dioxide (E171)

brilliant blue FCF (E133)

Printing ink:

black iron oxide (E172)

shellac

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

White HDPE bottle which is equipped with a polypropylene and HDPE closure and contains a filler (cotton coil). Each bottle contains 250 capsules.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Orphan Europe SARL

Immeuble “Le Wilson”

F-92058 Paris-La-Défense - France

8. Marketing Authorisation Number(S)

EU/1/04/286/001

9. Date Of First Authorisation/Renewal Of The Authorisation

13 October 2004

10. Date Of Revision Of The Text

Winfex XL 150mg Prolonged Release Capsules

1. Name Of The Medicinal Product

Winfex XL 150mg Prolonged Release Capsules

2. Qualitative And Quantitative Composition

Each prolonged release capsule contains venlafaxine hydrochloride equivalent to 150mg of venlafaxine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged Release capsules

Winfex XL 150mg Capsules are opaque scarlet capsules containing three 50mg tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depressive episodes.

For prevention of recurrence of major depressive episodes.

Treatment of social anxiety disorder.

4.2 Posology And Method Of Administration

Major depressive episodes

The recommended starting dose for prolonged-release venlafaxine is 75mg given once daily. Patients not responding to the initial 75mg/day dose may benefit from dose increases up to a maximum dose of 375mg/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.

Social anxiety disorder

The recommended dose for prolonged-release venlafaxine is 75mg given once daily. There is no evidence that higher doses confer any additional benefit.

However, in individual patients not responding to the initial 75mg/day, increases up to a maximum dose of 225mg/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.

Use in elderly patients

No specific dose adjustments of venlafaxine are considered necessary based on patient age alone. However, caution should be exercised in treatment the elderly (e.g., due to the possibility of renal impairment, the potential for changes in neurotransmitter sensitivity and affinity occurring with aging). The lowest effective dose should always be used, and patients should be carefully monitored when an increase in the dose is required.

Use in children and adolescents under the age of 18 years

Venlafaxine is not recommended for use in children and adolescents.

Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy and do not support the use of venlafaxine in these patients (see sections 4.4 and 4.8).

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

Use in patients with hepatic impairment

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

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

Use in patients with renal impairment

Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 30-70ml/minute, caution is advised. For patients that require haemodialysis and in patients with severe renal impairment (GFR <30ml/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 venlafaxine prolonged-release capsules be taken with food, at approximately the same time each day. Capsules must by swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

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

4.3 Contraindications

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

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

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

4.4 Special Warnings And Precautions For Use

Suicide/suicidal thoughts or clinical worsening

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

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

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

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

Use in children and adolescents under 18 years of age

Venlafaxine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents, such as MAO-inhibitors, that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

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

Narrow-angle glaucoma

Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow-angle glaucoma (angle-closure glaucoma) be closely monitored.

Blood pressure

Dose-related increases in blood pressure have been commonly reported with venlafaxine. In some cases, severely elevated blood pressure requiring immediate treatment has been reported in postmarketing experience. All patients should be carefully screened for high blood pressure and pre-existing hypertension should be controlled before 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 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during long-term treatment.

Co-administration with weight loss agents

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.

Mania/hypomania

Mania/hypomania may occur in a small proportion of patients with mood disorders who have received antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used cautiously in patients with a history or family history of bipolar disorder.

Aggression

Aggression may occur in a small number of patients who have received antidepressants, including venlafaxine. This has been reported under initiation, dose changes and discontinuation of treatment.

As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.

Discontinuation of treatment

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

The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that venlafaxine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see section 4.2).

Akathisia/psychomotor restlessness

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

Dry mouth

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

Diabetes

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Monoamine Oxidase Inhibitors (MAOI)

Irreversible non-selective MAOIs

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

Reversible, selective MAO-A inhibitor (moclobemide)

Due to the risk of serotonin syndrome, the combination of venlafaxine with a reversible and selective MAOI, such as moclobemide, is not recommended. Following treatment with a reversible MAO-inhibitor, a shorter withdrawal period than 14 days may be used before initiation of venlafaxine treatment. It is recommended that venlafaxine should be discontinued for at least 7 days before starting treatment with a reversible MAOI (see section 4.4).

Reversible, non-selective MAOI (linezolid)

The antibiotic linezolid is a weak reversible and non-selective MAOI and should not be given to patients treated with venlafaxine (see section 4.4).

Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI and started on venlafaxine, or have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, lithium, sibutramine, tramadol, or St. John's Wort [Hypericum perforatum]), with medicinal agents which impair metabolism of serotonin (including MAOIs), or with serotonin precursors (such as tryptophan supplements).

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

CNS-active substances

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

Ethanol

Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active substances, patients should be advised to avoid alcohol consumption.

Effect of other medicinal products on venlafaxine

Ketoconazole (CYP3A4 inhibitor)

A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and poor metabolisers (PM) resulted in higher AUC of venlafaxine (70% and 21% in CYP2D6PM 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 75mg to 150mg 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, α-hydroxymetoprolol. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Caution should be exercised with co-administration of venlafaxine and metoprolol.

Indinavir

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

4.6 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.

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.

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 the 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).

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 breast-feeding. A risk to the suckling child cannot be excluded. Therefore, a decision to continue/discontinue breast-feeding or to continue/discontinue therapy with venlafaxine should be made, taking into account the benefit of breast-feeding to the child and the benefit of Winfex XL therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Any psychoactive medicinal product may impair judgement, thinking, and motor skills. Therefore, any patient receiving venlafaxine should be cautioned about their ability to drive or operate hazardous machinery.

4.8 Undesirable Effects

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

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

Frequencies are defined as: very common (

Body System	Very Common	Common	Uncommon	Rare	Not Known
Haematological / Lymphatic			Ecchymosis, Gastrointestinal haemorrhage		Mucous membrane bleeding, Prolonged bleeding time, Thrombocytopenia, Blood dyscrasias, (including agranulocytosis, aplastic anaemia, neutropenia and pancytopenia)
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, Paraesthesia, 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) [12.2%]		Rash, Alopecia		Erythema multiforme, Toxic epidermal necrolysis, Stevens-Johnson syndrome, Pruritus, Urticaria
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 (figure), 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 of early after treatment discontinuation (see section 4.4.).

***See section 4.4.

Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraethesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, 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 the 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 post-marketing 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 electrocardigraphic 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 limited absorption of the active substance. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antidepressants – ATC code: NO6A X16.

The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are inhibitors of serotonin and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its active metabolite reduce ß-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, H₁-histaminergic or α₁-adrenergic receptors in vitro. Pharmacological activity at these receptors may be related to various side effects seen with other antidepressant medicinal products, such as anticholinergic, sedative and cardiovascular side effects.

Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.

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

Major depressive episodes

The efficacy of venlafaxine immediate-release as a treatment for major depressive episodes was demonstrated in five randomised, double-blind, placebo-controlled, short-term trials ranging from 4 to 6 weeks duration, for doses up to 375mg/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 225mg/day.

In one longer-term study, adult outpatients who had responded during an 8-week open trial on venlafaxine prolonged-release (75, 150, or 225mg) 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 200mg/day, on a b.i.d. schedule) on the last episode of depression.

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, multi-center, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients. Patients received doses in a range of 75 to 225mg/day. There was no evidence for any greater effectiveness of the 150 to 225mg/day group compared to the 75mg /day group in the 6-month study.

5.2 Pharmacokinetic Properties

Venlafaxine is extensively metabolised, primarily to the active metabolite, O-desmethylvenlafaxine (ODV). Mean ± SD plasma half-lives of venlafaxine and ODV are 5±2 hours and 11±2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75mg to 450mg/day.

Absorption

At least 92% of venlafaxine is absorbed following single oral doses of immediate-release venlafaxine. Absolute bioavailability if 40% to 45% due to presystemic metabolism. After immediate-release venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively. Following the administration of venlafaxine prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. When equal daily doses of venlafaxine are administered as either an immediate-release tablet or prolonged-release capsule, the prolonged-release capsule provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Food does not affect the bioavailability of venlafaxine and ODV.

Distribution

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

Metabolism

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

Elimination

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

Special populations

Age and gender

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

CYP2D6 extensive/poor metabolisers

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

Patients with hepatic impairment

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

Patients with renal impairment

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

5.3 Preclinical Safety Data

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

Animal studies regarding reproductive toxicity have found in rats a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation. The cause of these deaths is unknown. These effects occurred at 30 mg/kg/day, 4 times the human daily dose of 375mg 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 375mg/day. The human relevance of this finding is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hypromellose

Eudragit RS 100 powder

Sodium lauril sulfate

Magnesium stearate

Coating

Eudragit E 12.5 (dry weight)

Composition of the capsule shell

Titanium dioxide (E171)

Erythrosine (E127)

Indigo carmine (E132)

Gelatin QS

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

The medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Opaque white PVC/PE/PVDC/ aluminium foil blisters.

Pack size 28, 42, 56, 60 and 100

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS, UK .

8. Marketing Authorisation Number(S)

PL 17780/0232

9. Date Of First Authorisation/Renewal Of The Authorisation

18/04/2008

10. Date Of Revision Of The Text

07/01/2011

POM

Warticon Solution

1. Name Of The Medicinal Product

Warticon

2. Qualitative And Quantitative Composition

Podophyllotoxin 5 mg/ml (0.5% w/v). The quality of podophyllotoxin fulfills in-house specification.

3. Pharmaceutical Form

Topical solution

4. Clinical Particulars

4.1 Therapeutic Indications

For the topical treatment of condylomata acuminata affecting the penis and the external female genitalia.

4.2 Posology And Method Of Administration

The affected area should be thoroughly washed with soap and water, and dried prior to application.

Warticon is applied twice daily for 3 days. If residual warts persist, this 3-day treatment may be repeated weekly, if necessary, for a total of 4 weeks of treatment.

Where lesions are greater than 4 cm², it is recommended that treatment takes place under the direct supervision of medical staff.

4.3 Contraindications

Open wounds following surgical procedures should not be treated with podophyllotoxin.

Hypersensitivity to podophyllotoxin is a contra-indication.

Use in children.

Concomitant use with other podophyllotoxin containing preparations.

Pregnancy and lactation.

4.4 Special Warnings And Precautions For Use

Avoid contact with eyes. Should the solution accidentally come into contact with the eye, the eye should be thoroughly rinsed with water.

The hands should be thoroughly washed after each application. Prolonged contact with healthy skin must be avoided since the solution contains an active pharmaceutical substance which could be harmful on healthy skin.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None presently known.

4.6 Pregnancy And Lactation

The product is not for use in pregnancy or lactation.

Reproduction toxicity studies in animals have not given evidence of an increased incidence of foetal damage or other deleterious effects on the reproductive process. However, since podophyllotoxin is a mitosis inhibitor, Warticon Solution should not be used during pregnancy or lactation.

It is not known if the substance is excreted into breast milk.

Observations in man indicate that podophyllin, a crude mixture of lignans, can be harmful to pregnancy. Such observations have not been reported in patients treated with podophyllotoxin.

4.7 Effects On Ability To Drive And Use Machines

None presently known.

4.8 Undesirable Effects

Local irritation may occur on the second or third day of application associated with the start of wart necrosis. In most cases the reactions are mild. Tenderness, itching, smarting, erythema, superficial epithelial ulceration and balanoposthitis have been reported. Local irritation decreases after treatment.

4.9 Overdose

There have been no reported overdosages with Warticon Solution. However, excessive use of podophyllotoxin 0.5% solution has been reported as causing two cases of severe local reactions. In cases of excessive use of Warticon Solution resulting in severe local reaction, the treatment should be stopped, the area washed and symptomatic treatment introduced. No specific antidote is known. In the event of accidental ingestion, give emetic or stomach washout. Treatment should be symptomatic and in severe oral overdose ensure the airway is clear and give fluids. Check and correct electrolyte balance, monitor blood gases and liver function. Blood count should be monitored for at least 5 days.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmaco-therapeutic group: D06B B Antivirals

Podophyllotoxin is a metaphase inhibitor in dividing cells binding to at least one binding site on tubulin. Binding prevents tubulin polymerisation required for microtubule assembly. At higher concentrations podophyllotoxin also inhibits nucleoside transport through the cell membrane.

The chemotherapeutic action of podophyllotoxin is assumed to be due to inhibition of growth and the ability to invade the tissue of the viral infected cells.

5.2 Pharmacokinetic Properties

Topical Administration of a 0.5% solution of ethanolic podophyllotoxin in the majority of cases only requires volumes in the range of 0.1 ml to 0.2 ml. Studies monitoring serum drug level reveal that topical application of a twice daily dose of 100MCL to the penile preputial cavity in 10 patients resulted in a maximum serum concentration of 0.25 ng/ml.

5.3 Preclinical Safety Data

No relevant findings

6. Pharmaceutical Particulars

6.1 List Of Excipients

Phosphoric acid Ph Eur

Ethanol BP

Purified Water Ph Eur

Patent Blue V (E131)

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Should be stored below 25^oC.

6.5 Nature And Contents Of Container

An amber glass bottle with plastic child-proof cap. Each bottle contains 3 ml of Warticon Solution. The outer carton also includes a tube containing plastic applicators. Each loop will carry approximately 5μl Warticon Solution.

6.6 Special Precautions For Disposal And Other Handling

The solution is applied by the plastic applicators provided.

7. Marketing Authorisation Holder

Stiefel Laboratories (UK) Ltd

Eurasia Headquarters

Concorde Road

Maidenhead

SL6 4BY

UK

8. Marketing Authorisation Number(S)

PL0174/0211

9. Date Of First Authorisation/Renewal Of The Authorisation

21^st June 1999 / 8^th October 2003

10. Date Of Revision Of The Text

August 2009

WAXSOL Ear Drops, Docusate sodium BP 0.5% w / v

1. Name Of The Medicinal Product

WAXSOL Ear Drops, Ducosate sodium BP 0.5% w/v

2. Qualitative And Quantitative Composition

WAXSOL Ear Drops contain the following active ingredient:

Docusate Sodium BP 0.5% w/v.

3. Pharmaceutical Form

Ear drops.

4. Clinical Particulars

4.1 Therapeutic Indications

WAXSOL Ear Drops are indicated as an aid in the removal of ear wax.

4.2 Posology And Method Of Administration

Recommended dose and dosage schedules:

Adults (including the elderly): The application of ear drops sufficient to fill the affected ear on not more than two consecutive nights, prior to attending for syringing if this is necessary. If the problem persists patients should consult their doctor.

Children: As for adult dose.

4.3 Contraindications

Perforation of the ear drum or inflammation of the ear.

4.4 Special Warnings And Precautions For Use

If pain or inflammation is experienced, treatment should be discontinued.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

There is no evidence to suggest that WAXSOL Ear Drops should not be used during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Immune system disorders: hypersensitivity/allergic reactions

Skin disorders: contact dermatitis and allergic skin reactions

General disorders: Application site reactions rarely including transient stinging or irritation may occur. Injuries or inflammation in the auditory canal may result in painful symptoms.

4.9 Overdose

Excess WAXSOL may seep from the ear and treatment of any resulting adverse events, such as skin irritation should be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

The so-called "wax" which often obstructs the external auditory meatus of the ear contains less than 50% of fatty matter derived from secretions of the sebaceous ceruminous glands. The majority of the wax consists of desquamated epithelium, foreign matter and shed hairs. This non-fatty material forms a matrix holding together the granules of fatty matter to form the ceruminous mass.

The addition of oils or solvents binds the mass more firmly together, but aqueous solutions, if they are able to penetrate the matrix, cause a disintegration of the ceruminous mass.

WAXSOL Ear Drops, because of their low surface tension and miscibility, rapidly penetrate the dry matrix of the ceruminous mass, reducing the solid material to a semi-solid debris. This can be syringed away readily, or in less severe or chronic cases, is ejected by normal physiological processes.

5.2 Pharmacokinetic Properties

There are no available data on systemic absorption following instillation into the ear. However, any absorption which may occur is likely to be of an extremely low magnitude.

5.3 Preclinical Safety Data

Although no toxicity studies via application to the ear are available, oral repeated dose toxicity studies with docusate sodium did not identify any clinically relevant information.

However, in cosmetic testing work, docusate sodium produced irritation under severe occluded conditions of a patch test and it has been cautioned that it is a cumulative irritant.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glycerin

Phenonip (solution of esters of 4-hydroxybenzoic acid in phenoxetol)

Water

6.2 Incompatibilities

None known.

6.3 Shelf Life

The shelf life is 3 years.

6.4 Special Precautions For Storage

Store below 25ºC.

6.5 Nature And Contents Of Container

Amber glass bottle with a dropper applicator, containing 10 or 11 ml of WAXSOL solution.

6.6 Special Precautions For Disposal And Other Handling

The dropper applicator must be filled before dripping WAXSOL Ear Drops into the affected ear.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

8. Marketing Authorisation Number(S)

PL 15142/0243

9. Date Of First Authorisation/Renewal Of The Authorisation

27/09/2006

10. Date Of Revision Of The Text

18 June 2011

LEGAL CATEGORY

P

11. DOSIMETRY (IF APPLICABLE)

Not applicable.

12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUITCALS (IF APPLICABLE)

Not applicable.

Wind-Eze Tablets

1. Name Of The Medicinal Product

Wind-Eze

2. Qualitative And Quantitative Composition

Simeticone [Equivalent to Poly(Dimethylsiloxane)], 11.57% w/w, approx. 125.00mg

3. Pharmaceutical Form

Chewable tablets for oral administration.

4. Clinical Particulars

4.1 Therapeutic Indications

Antiflatulent defoaming agent for the symptomatic relief of flatulence, wind pains, bloating, abdominal distension and other similar symptoms associated with gastrointestinal gas.

4.2 Posology And Method Of Administration

Adults, elderly and children over 12 years:

One tablet to be taken three or four times daily or as required for relief, after meals and upon retiring. The tablets are to be chewed before swallowing.

Not recommended for children under 12 years.

4.3 Contraindications

The product should not be used in patients with known hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

If symptoms persist or worsen, medical advice should be sought.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Since simeticone is not absorbed by the gastro intestinal tract, Wind-Eze may be taken during pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Rarely hypersensitivity reactions such as rash, pruritus, facial oedema, tongue oedema, respiratory difficulty.

4.9 Overdose

In the unlikely event of deliberate or accidental overdosage, treat symptoms on appearance. There are no special procedures recommended.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Physiologically simeticone is extremely inert, and therefore it will not be pharmacologically active.

5.2 Pharmacokinetic Properties

Simeticone (activated dimeticone) is not absorbed following oral administration. It acts by changing the surface tension of gas bubbles, causing them to coalesce.

5.3 Preclinical Safety Data

Simeticone is physiologically inert and considered to be non-toxic. It is not absorbed following oral administration, nor is it pharmacologically active. Preclinical data reveal no hazard for humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Dextrates (hydrated) USNF

Sorbitol Crystalline EP

Tribasic Calcium Phosphate (Powder) USNF

Citric Acid Anhydrous (Powder) EP

Natural and artificial peppermint flavour No. 517

(Spray dried) HSE

Talc (purified) EP

Non-pareil seeds (Starch/Sucrose) HSE

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years in PVC/PVDC Al foil blister packs. 3 years in PVC/PE/Aclar Al. foil blister packs.

6.4 Special Precautions For Storage

Store below 25^oC.

Store in a dry place.

6.5 Nature And Contents Of Container

Blister packs of construction 190 μm PVC (product contact side)/51μm PE/38μm aclar and 25μm aluminium foil with vinyl sealing coat (product contact side).

or

Blister packs of construction 250μm PVC (product contact side)/PVDC 60 g/m² and 20 μm aluminium foil with vinyl heat sealing coat (product contact side).

Pack sizes: 4, 10, 20, 30, 50.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Stafford-Miller Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

Trading as GlaxoSmithKline Consumer Healthcare, Brentford TW8 9GS, U.K.

8. Marketing Authorisation Number(S)

PL 00036/0084

9. Date Of First Authorisation/Renewal Of The Authorisation

25th May 2001

10. Date Of Revision Of The Text

February 2008

Winfex XL 75mg Prolonged Release Capsules

1. Name Of The Medicinal Product

Winfex XL 75mg Prolonged Release Capsules

2. Qualitative And Quantitative Composition

Each prolonged release capsule contains venlafaxine hydrochloride equivalent to 75mg of venlafaxine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged Release capsules

Winfex XL 75mg Capsules are opaque flesh capsules containing two 37.5mg tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depressive episodes.

For prevention of recurrence of major depressive episodes.

Treatment of social anxiety disorder.

4.2 Posology And Method Of Administration

Major depressive episodes

The recommended starting dose for prolonged-release venlafaxine is 75mg given once daily. Patients not responding to the initial 75mg/day dose may benefit from dose increases up to a maximum dose of 375mg/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.

Social anxiety disorder

The recommended dose for prolonged-release venlafaxine is 75mg given once daily. There is no evidence that higher doses confer any additional benefit.

However, in individual patients not responding to the initial 75mg/day, increases up to a maximum dose of 225mg/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.

Use in elderly patients

No specific dose adjustments of venlafaxine are considered necessary based on patient age alone. However, caution should be exercised in treatment the elderly (e.g., due to the possibility of renal impairment, the potential for changes in neurotransmitter sensitivity and affinity occurring with aging). The lowest effective dose should always be used, and patients should be carefully monitored when an increase in the dose is required.

Use in children and adolescents under the age of 18 years

Venlafaxine is not recommended for use in children and adolescents.

Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy and do not support the use of venlafaxine in these patients (see sections 4.4 and 4.8).

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

Use in patients with hepatic impairment

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

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

Use in patients with renal impairment

Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 30-70ml/minute, caution is advised. For patients that require haemodialysis and in patients with severe renal impairment (GFR <30ml/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 venlafaxine prolonged-release capsules be taken with food, at approximately the same time each day. Capsules must by swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

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

4.3 Contraindications

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

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

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

4.4 Special Warnings And Precautions For Use

Suicide/suicidal thoughts or clinical worsening

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

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

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

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

Use in children and adolescents under 18 years of age

Venlafaxine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents, such as MAO-inhibitors, that may affect the serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

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

Narrow-angle glaucoma

Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow-angle glaucoma (angle-closure glaucoma) be closely monitored.

Blood pressure

Dose-related increases in blood pressure have been commonly reported with venlafaxine. In some cases, severely elevated blood pressure requiring immediate treatment has been reported in postmarketing experience. All patients should be carefully screened for high blood pressure and pre-existing hypertension should be controlled before 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 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during long-term treatment.

Co-administration with weight loss agents

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.

Mania/hypomania

Mania/hypomania may occur in a small proportion of patients with mood disorders who have received antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used cautiously in patients with a history or family history of bipolar disorder.

Aggression

Aggression may occur in a small number of patients who have received antidepressants, including venlafaxine. This has been reported under initiation, dose changes and discontinuation of treatment.

As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.

Discontinuation of treatment

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

The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that venlafaxine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see section 4.2).

Akathisia/psychomotor restlessness

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

Dry mouth

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

Diabetes

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Monoamine Oxidase Inhibitors (MAOI)

Irreversible non-selective MAOIs

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

Reversible, selective MAO-A inhibitor (moclobemide)

Due to the risk of serotonin syndrome, the combination of venlafaxine with a reversible and selective MAOI, such as moclobemide, is not recommended. Following treatment with a reversible MAO-inhibitor, a shorter withdrawal period than 14 days may be used before initiation of venlafaxine treatment. It is recommended that venlafaxine should be discontinued for at least 7 days before starting treatment with a reversible MAOI (see section 4.4).

Reversible, non-selective MAOI (linezolid)

The antibiotic linezolid is a weak reversible and non-selective MAOI and should not be given to patients treated with venlafaxine (see section 4.4).

Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI and started on venlafaxine, or have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, lithium, sibutramine, tramadol, or St. John's Wort [Hypericum perforatum]), with medicinal agents which impair metabolism of serotonin (including MAOIs), or with serotonin precursors (such as tryptophan supplements).

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

CNS-active substances

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

Ethanol

Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active substances, patients should be advised to avoid alcohol consumption.

Effect of other medicinal products on venlafaxine

Ketoconazole (CYP3A4 inhibitor)

A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and poor metabolisers (PM) resulted in higher AUC of venlafaxine (70% and 21% in CYP2D6PM 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 75mg to 150mg 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, α-hydroxymetoprolol. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Caution should be exercised with co-administration of venlafaxine and metoprolol.

Indinavir

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

4.6 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.

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.

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 the 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).

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 breast-feeding. A risk to the suckling child cannot be excluded. Therefore, a decision to continue/discontinue breast-feeding or to continue/discontinue therapy with venlafaxine should be made, taking into account the benefit of breast-feeding to the child and the benefit of Winfex XL therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Any psychoactive medicinal product may impair judgement, thinking, and motor skills. Therefore, any patient receiving venlafaxine should be cautioned about their ability to drive or operate hazardous machinery.

4.8 Undesirable Effects

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

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

Frequencies are defined as: very common (

Body System	Very Common	Common	Uncommon	Rare	Not Known
Haematological / Lymphatic			Ecchymosis, Gastrointestinal haemorrhage		Mucous membrane bleeding, Prolonged bleeding time, Thrombocytopenia, Blood dyscrasias, (including agranulocytosis, aplastic anaemia, neutropenia and pancytopenia)
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, Paraesthesia, 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) [12.2%]		Rash, Alopecia		Erythema multiforme, Toxic epidermal necrolysis, Stevens-Johnson syndrome, Pruritus, Urticaria
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 (figure), 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 of early after treatment discontinuation (see section 4.4.).

***See section 4.4.

Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraethesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, 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 the 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 post-marketing 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 electrocardigraphic 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 limited absorption of the active substance. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antidepressants – ATC code: NO6A X16.

The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are inhibitors of serotonin and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its active metabolite reduce ß-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, H₁-histaminergic or α₁-adrenergic receptors in vitro. Pharmacological activity at these receptors may be related to various side effects seen with other antidepressant medicinal products, such as anticholinergic, sedative and cardiovascular side effects.

Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.

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

Major depressive episodes

The efficacy of venlafaxine immediate-release as a treatment for major depressive episodes was demonstrated in five randomised, double-blind, placebo-controlled, short-term trials ranging from 4 to 6 weeks duration, for doses up to 375mg/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 225mg/day.

In one longer-term study, adult outpatients who had responded during an 8-week open trial on venlafaxine prolonged-release (75, 150, or 225mg) 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 200mg/day, on a b.i.d. schedule) on the last episode of depression.

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, multi-center, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients. Patients received doses in a range of 75 to 225mg/day. There was no evidence for any greater effectiveness of the 150 to 225mg/day group compared to the 75mg /day group in the 6-month study.

5.2 Pharmacokinetic Properties

Venlafaxine is extensively metabolised, primarily to the active metabolite, O-desmethylvenlafaxine (ODV). Mean ± SD plasma half-lives of venlafaxine and ODV are 5±2 hours and 11±2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75mg to 450mg/day.

Absorption

At least 92% of venlafaxine is absorbed following single oral doses of immediate-release venlafaxine. Absolute bioavailability if 40% to 45% due to presystemic metabolism. After immediate-release venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively. Following the administration of venlafaxine prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. When equal daily doses of venlafaxine are administered as either an immediate-release tablet or prolonged-release capsule, the prolonged-release capsule provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Food does not affect the bioavailability of venlafaxine and ODV.

Distribution

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

Metabolism

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

Elimination

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

Special populations

Age and gender

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

CYP2D6 extensive/poor metabolisers

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

Patients with hepatic impairment

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

Patients with renal impairment

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

5.3 Preclinical Safety Data

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

Animal studies regarding reproductive toxicity have found in rats a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation. The cause of these deaths is unknown. These effects occurred at 30 mg/kg/day, 4 times the human daily dose of 375mg 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 375mg/day. The human relevance of this finding is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hypromellose

Eudragit RS 100 powder

Sodium lauril sulfate

Magnesium stearate

Coating

Eudragit E 12.5 (dry weight)

Composition of the capsule shell

Titanium dioxide (E171)

Red iron oxide (E172)

Gelatin QS

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

The medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Opaque white PVC/PE/PVDC/ aluminium foil blisters.

Pack size 28, 42, 56, 60 and 100

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS, UK .

8. Marketing Authorisation Number(S)

PL 17780/0231

9. Date Of First Authorisation/Renewal Of The Authorisation

18/04/2008

10. Date Of Revision Of The Text

07/01/2011

LICENSING STATUS

POM