DAXAS 500 micrograms film-coated tablets

1. Name Of The Medicinal Product

Daxas ®

2. Qualitative And Quantitative Composition

Each tablet contains 500 micrograms of roflumilast.

Excipient: This product contains 199 mg lactose monohydrate per film-coated tablet.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet (tablet).

Yellow, D-shaped film-coated tablet, embossed with “D” on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Daxas is indicated for maintenance treatment of severe chronic obstructive pulmonary disease (COPD) (FEV1 post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment.

4.2 Posology And Method Of Administration

Posology

The recommended dose is one tablet of 500 micrograms roflumilast once daily.

Daxas may need to be taken for several weeks to achieve its effect (see section 5.1). Daxas has been studied in clinical trials for up to one year.

Special populations

Elderly (65 years and older)

No dose adjustment is necessary.

Renal impairment

No dose adjustment is necessary.

Hepatic impairment

The clinical data with Daxas in patients with mild hepatic impairment classified as Child-Pugh A are insufficient to recommend a dose adjustment (see section 5.2) and therefore Daxas should be used with caution in these patients.

Patients with moderate or severe hepatic impairment classified as Child-Pugh B or C should not take Daxas (see section 4.3).

Paediatric population

There is no relevant use of Daxas in the paediatric population (under 18 years).

Method of administration

For oral use.

The tablet should be swallowed with water and taken at the same time every day. The tablet can be taken with or without food.

4.3 Contraindications

Hypersensitivity to roflumilast or to any of the excipients (see section 6.1).

Moderate or severe hepatic impairment (Child-Pugh B or C).

4.4 Special Warnings And Precautions For Use

All patients should be informed about the risks of Daxas and the precautions for safe use and should be given a patient card before starting Daxas.

Rescue medicinal products

Roflumilast is an anti-inflammatory substance indicated for maintenance treatment of severe COPD associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment. It is not indicated as rescue medicinal product for the relief of acute bronchospasms.

Weight decrease

In 1-year studies (M2-124, M2-125), a decrease of body weight occurred more frequently in patients treated with Daxas compared to placebo-treated patients. After discontinuation of Daxas, the majority of patients had regained body weight after 3 months.

Body weight of underweight patients should be checked at each visit. Patients should be advised to check their body weight on a regular basis. In the event of an unexplained and clinically concerning weight decrease, the intake of Daxas should be stopped and body weight should be further followed-up.

Special clinical conditions

Due to lack of relevant experience, treatment with Daxas should not be initiated or existing treatment with Daxas should be stopped in patients with severe immunological diseases (e.g. HIV infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy), severe acute infectious diseases, cancers (except basal cell carcinoma), or patients being treated with immunosuppressive medicinal products (i.e. methotrexate, azathioprine, infliximab, etanercept, or oral corticosteroids to be taken long-term; except short-term systemic corticosteroids). Experience in patients with latent infections such as tuberculosis, viral hepatitis, herpes viral infection and herpes zoster is limited.

Patients with congestive heart failure (NYHA grades 3 and 4) have not been studied and therefore treatment of these patients is not recommended.

Psychiatric disorders

Daxas is associated with an increased risk of psychiatric disorders such as insomnia, anxiety, nervousness and depression. Rare instances of suicidal ideation and behaviour, including completed suicide, have been observed in clinical trials (see section 4.8). Therefore, the risks and benefits of starting or continuing treatment with Daxas should be carefully assessed if patients report previous or existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to cause psychiatric events is intended. Patients should be instructed to notify their prescriber of any changes in behaviour or mood and of any suicidal ideation. Moreover, Daxas is not recommended in patients with a history of depression associated with suicidal ideation or behaviour.

Persistent intolerability

While adverse reactions like diarrhoea, nausea, abdominal pain and headache mainly occur within the first weeks of therapy and mostly resolve on continued treatment, Daxas treatment should be reassessed in case of persistent intolerability. This might be the case in special populations that may have higher exposure, such as in black, non-smoking females (see section 5.2) or in patients concomitantly treated with the CYP1A2 inhibitor fluvoxamine or the dual CYP3A4/1A2 inhibitors enoxacin and cimetidine (see section 4.5).

Theophylline

There are no clinical data to support the concomitant treatment with theophylline for maintenance therapy. Therefore, the concomitant treatment with theophylline is not recommended.

Lactose

Daxas tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. Both roflumilast and roflumilast N-oxide have intrinsic phosphodiesterase 4 (PDE4) inhibitory activity. Therefore, following administration of roflumilast, the total PDE4 inhibition is considered to be the combined effect of both roflumilast and roflumilast N-oxide. Clinical interaction studies with CYP3A4 inhibitors erythromycin and ketoconazole showed increases of 9% of the total PDE4 inhibitory activity (i.e. total exposure to roflumilast and roflumilast N-oxide). Interaction studies with CYP1A2 inhibitor fluvoxamine, and the dual CYP3A4/1A2 inhibitors enoxacin and cimetidine resulted in increases of the total PDE4 inhibitory activity of 59%, 25% and 47%, respectively. A combination of Daxas with these active substances might lead to an increase of exposure and persistent intolerability. In this case, Daxas treatment should be reassessed (see section 4.4).

Administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in total PDE4 inhibitory activity by about 60%. Therefore, the use of strong cytochrome P450 inducers (e.g. phenobarbital, carbamazepine, phenytoin) may reduce the therapeutic efficacy of roflumilast.

Co-administration with theophylline resulted in an increase of 8% of the total PDE4 inhibitory activity (see section 4.4). In an interaction study with an oral contraceptive containing gestodene and ethinyl oestradiol, the total PDE4 inhibitory activity was increased by 17%.

No interactions were observed with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, warfarin, sildenafil and midazolam.

Co-administration with an antacid (combination of aluminium hydroxide and magnesium hydroxide) did not alter the absorption or pharmacokinetics of roflumilast or its N

4.6 Pregnancy And Lactation

Pregnancy

There are limited amount of data from the use of roflumilast in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). Daxas is not recommended during pregnancy and in women of childbearing potential not using contraception.

Roflumilast has been demonstrated to cross the placenta in pregnant rats.

Breastfeeding

Available pharmacokinetic data in animals have shown excretion of roflumilast or its metabolites in milk. A risk to the suckling child cannot be excluded. Daxas should not be used during breast-feeding.

Fertility

In a human spermatogenesis study, roflumilast 500 micrograms had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3

4.7 Effects On Ability To Drive And Use Machines

Daxas has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

In clinical COPD studies, approximately 16% of patients experienced adverse reactions with roflumilast (compared to 5% in placebo). The most commonly reported adverse reactions were diarrhoea (5.9%), weight decreased (3.4%), nausea (2.9%), abdominal pain (1.9%) and headache (1.7%). The majority of these adverse reactions were mild or moderate. These adverse reactions mainly occurred within the first weeks of therapy and mostly resolved on continued treatment.

Within the following table, adverse reactions are ranked under the MedDRA frequency classification:

Very common (

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions with roflumilast in clinical COPD studies

Frequency System Organ Class	Common	Uncommon	Rare
Immune system disorders		Hypersensitivity
Endocrine disorders			Gynaecomastia
Metabolism and nutrition disorders	Weight decreased Decreased appetite
Psychiatric disorders	Insomnia	Anxiety	Depression Nervousness
Nervous system disorders	Headache	Tremor Vertigo Dizziness	Dysgeusia
Cardiac disorders		Palpitations
Respiratory, thoracic and mediastinal disorders			Respiratory tract infections (excluding Pneumonia)
Gastrointestinal disorders	Diarrhoea Nausea Abdominal pain	Gastritis Vomiting Gastro-esophageal reflux disease Dyspepsia	Haematochezia Constipation
Hepatobiliary disorders			Gamma-GT increased Aspartate aminotransferase (AST) increased
Skin and subcutaneous tissue disorders		Rash	Urticaria
Musculoskeletal and connective tissue disorders		Muscle spasms and weakness Myalgia Back pain	Blood creatine phosphokinase (CPK) increased
General disorders and administration site conditions		Malaise Asthenia Fatigue

In clinical studies, rare instances of suicidal thinking and behaviour (including completed suicide) were reported. Patients should be instructed to notify their prescriber of any suicidal ideation (see also section 4.4).

4.9 Overdose

In Phase I studies, the following symptoms were observed at an increased rate after single oral doses of 2,500 micrograms and one single dose of 5,000 micrograms (ten times the recommended dose): headache, gastrointestinal disorders, dizziness, palpitations, light-headedness, clamminess and arterial hypotension.

In case of overdose, it is recommended that the appropriate supportive medical care is provided. Since roflumilast is highly protein bound, haemodialysis is not likely to be an efficient method of its removal. It is not known whether roflumilast is dialysable by peritoneal dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, Other systemic drugs for obstructive airway diseases, ATC code: R03DX07

Mechanism of action

Roflumilast is a PDE4 inhibitor, a non-steroid, anti-inflammatory agent designed to target both the systemic and pulmonary inflammation associated with COPD. The mechanism of action is the inhibition of PDE4, a major cyclic adenosine monophosphate (cAMP)-metabolizing enzyme found in structural and inflammatory cells important to the pathogenesis of COPD. Roflumilast targets the PDE4A, 4B and 4D splicing variants with similar potency in the nanomolar range. The affinity to the PDE4C splicing variants is 5 to 10-fold lower. This mechanism of action and the selectivity also apply to roflumilast N

Pharmacodynamic effects

Inhibition of PDE4 leads to elevated intracellular cAMP levels and mitigates COPD-related malfunctions of leukocytes, airway and pulmonary vascular smooth muscle cells, endothelial and airway epithelial cells and fibroblasts in experimental models. Upon in vitro stimulation of human neutrophils, monocytes, macrophages or lymphocytes, roflumilast and roflumilast N-oxide suppress the release of inflammatory mediators e.g. leukotriene B4, reactive oxygen species, tumor necrosis factor α, interferon γ and granzyme B.

In patients with COPD, roflumilast reduced sputum neutrophils. Furthermore, roflumilast attenuated influx of neutrophils and eosinophils into the airways of endotoxin challenged healthy volunteers.

Clinical efficacy

In two confirmative replicate one-year studies (M2-124 and M2-125) and two supplementary six-month studies (M2-127 and M2-128), a total number of 4,768 patients were randomised and treated of whom 2,374 were treated with Daxas. The design of the studies was parallel-group, double-blind and placebo-controlled.

The one-year studies included patients with a history of severe to very severe COPD [FEV₁ (forced expiratory volume in one second)

In a pooled analysis of the one-year studies M2-124 and M2-125, Daxas 500 micrograms once daily significantly improved lung function compared to placebo, on average by 48 ml (pre-bronchodilator FEV₁, primary endpoint, p<0.0001), and by 55 ml (post-bronchodilator FEV₁, p<0.0001). The improvement in lung function was apparent at the first visit after 4 weeks and was maintained up to one year (end of treatment period). The rate (per patient per year) of moderate exacerbations (requiring intervention with systemic glucocorticosteroids) or severe exacerbations (resulting in hospitalisation and/or leading to death) after 1 year was 1.142 with roflumilast and 1.374 with placebo corresponding to a relative risk reduction of 16.9% (95% CI: 8.2% to 24.8%) (primary endpoint, p=0.0003). Effects were similar, independent of previous treatment with inhaled corticosteroids or underlying treatment with LABAs. In the subgroup of patients with history of frequent exacerbations (at least 2 exacerbations during the last year), the rate of exacerbations was 1.526 with roflumilast and 1.941 with placebo corresponding to a relative risk reduction of 21.3% (95% CI: 7.5% to 33.1%). Roflumilast did not significantly reduce the rate of exacerbations compared with placebo in the subgroup of patients with moderate COPD.

The reduction of moderate or severe exacerbations with Daxas and LABA compared to placebo and LABA was on average 21% (p=0.0011). The respective reduction in exacerbations seen in patients without concomitant LABAs was on average 15% (p=0.0387). The numbers of patients who died due to any reason were equal for those treated with placebo or roflumilast (42 deaths each group; 2.7% each group; pooled analysis).

A total of 2,690 patients were included and randomized in two supportive 1-year studies (M2₁, p<0.0001), and by 53 ml (post-bronchodilator FEV₁, p<0.0001). The rate of exacerbations (as defined in the protocols) were not significantly reduced by roflumilast in the individual studies (relative risk reduction: 13.5% in study M2-111 and 6.6% in study M2-112; p= not significant). Adverse events rates were independent of concomitant treatment with inhaled corticosteroids.

Two six-month supportive studies (M2-127 and M2-128) included patients with a history of COPD for at least 12 months prior to baseline. Both studies included moderate to severe patients with a non-reversible airway obstruction and a FEV₁ of 40% to 70% of predicted. Roflumilast or placebo treatment was added to continuous treatment with a long-acting bronchodilator, in particular salmeterol in study M2-127 or tiotropium in study M2₁ was significantly improved by 49 ml (primary endpoint, p<0.0001) beyond the bronchodilator effect of concomitant treatment with salmeterol in study M2

No study has been conducted to compare Daxas to the combination of LABA plus inhaled corticosteroids or on top of the combination of LABA plus inhaled corticosteroids.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Daxas in all subsets of the paediatric population in chronic obstructive pulmonary disease (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic Properties

Roflumilast is extensively metabolised in humans, with the formation of a major pharmacodynamically active metabolite, roflumilast N-oxide. Since both roflumilast and roflumilast N-oxide contribute to PDE4 inhibitory activity in vivo, pharmacokinetic considerations are based on total PDE4 inhibitory activity (i.e. total exposure to roflumilast and roflumilast N-oxide).

Absorption

The absolute bioavailability of roflumilast following a 500 micrograms oral dose is approximately 80%. Maximum plasma concentrations of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state. Maximum concentrations of the N_max) of roflumilast by one hour and reduces C_max by approximately 40%. However, C_max and t_max of roflumilast N-oxide are unaffected.

Distribution

Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single dose of 500 micrograms roflumilast is about 2.9 l/kg. Due to the physico-chemical properties, roflumilast is readily distributed to organs and tissues including fatty tissue of mice, hamster and rat. An early distribution phase with marked penetration into tissues is followed by a marked elimination phase out of fatty tissue most probably due to pronounced break-down of parent compound to roflumilast N-oxide. These studies in rats with radiolabeled roflumilast also indicate low penetration across the blood-brain barrier. There is no evidence for a specific accumulation or retention of roflumilast or its metabolites in organs and fatty tissue.

Biotransformation

Roflumilast is extensively metabolised via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the major metabolite observed in the plasma of humans. The plasma AUC of the Nin vivo.

In vitro studies and clinical interaction studies suggest that the metabolism of roflumilast to its Nin vitro results in human hepatic microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is a low probability of relevant interactions with substances metabolised by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.

Elimination

The plasma clearance after short-term intravenous infusion of roflumilast is about 9.6 l/h. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days for roflumilast N-oxide following once-daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 20% of the radioactivity was recovered in the faeces and 70% in urine as inactive metabolites.

Linearity/Non-linearity

The pharmacokinetics of roflumilast and its N-oxide metabolite are dose-proportional over a range of doses from 250 micrograms to 1,000 micrograms.

Special populations

In elderly, females and in non-Caucasians, total PDE4 inhibitory activity was increased. Total PDE4 inhibitory activity was slightly decreased in smokers. None of these changes were considered to be clinically meaningful. No dose adjustment is recommended in these patients. A combination of factors, such as in black, non-smoking females, might lead to an increase of exposure and persistent intolerability. In this case, Daxas treatment should be reassessed (see section 4.4).

Renal impairment

Total PDE4 inhibitory activity decreased by 9% in patients with severe renal impairment (creatinine clearance 10-30 ml/min). No dose adjustment is necessary.

Hepatic impairment

The pharmacokinetics of Daxas 250 micrograms once-daily was tested in 8 patients with mild to moderate hepatic impairment classified as Child

5.3 Preclinical Safety Data

There is no evidence for an immunotoxic, skin sensitising or phototoxic potential.

A slight reduction in male fertility was seen in conjunction with epididymal toxicity in rats. No epididymal toxicity or changes in semen parameters were present in any other rodent or non-rodent species including monkeys in spite of higher exposures.

In one of two rat embryofetal development studies, a higher incidence of incomplete skull bone ossification was seen at a dose producing maternal toxicity. In one of three rat studies on fertility and embryofetal development, post-implantation losses were observed. Post-implantation losses were not seen in rabbits. Prolongation of gestation was seen in mice.

The relevance of these findings to humans is unknown.

Most relevant findings in safety pharmacology and toxicology studies occurred at higher doses and exposure than that intended for clinical use. These findings consisted mainly of gastrointestinal findings (i.e. vomiting, increased gastric secretion, gastric erosions, intestine inflammation) and cardiac findings (i.e. focal haemorrhages, haemosiderin deposits and lympho-histiocytic cell infiltration in the right atria in dogs, and decreased blood pressure and increased heart rate in rats, guinea pigs and dogs).

Rodent-specific toxicity in the nasal mucosa was observed in repeat-dose toxicity and carcinogenicity studies. This effect seems to be due to an ADCP (4-Amino-3,5-dichloro-pyridine) N-oxide intermediate specifically formed in rodent olfactory mucosa, with special binding affinity in these species (i.e. mouse, rat and hamster).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Core

Lactose monohydrate

Maize starch

Povidone (K90)

Magnesium stearate

Coating

Hypromellose 2910

Macrogol 4000

Titanium dioxide (E171)

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

PVC/PVDC aluminium blisters in packs of 10, 30, or 90 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Nycomed GmbH

Byk-Gulden-Straße 2

D-78467 Konstanz

Germany

8. Marketing Authorisation Number(S)

EU/1/10/636/001: 10 tablets pack

EU/1/10/636/002: 30 tablets pack

EU/1/10/636/003: 90 tablets pack

9. Date Of First Authorisation/Renewal Of The Authorisation

July 2010

10. Date Of Revision Of The Text

July 2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

© Merck Sharp & Dohme Limited, 2010. All rights reserved.

SPC.DAX.10.UK.3281

Depo-Medrone with Lidocaine

1. Name Of The Medicinal Product

Depo-Medrone with Lidocaine

2. Qualitative And Quantitative Composition

Methylprednisolone BP 4%, Lidocaine Hydrochloride BP 1%

3. Pharmaceutical Form

White, sterile aqueous suspension for injection

4. Clinical Particulars

4.1 Therapeutic Indications

Corticosteroid (glucocorticoid). Depo-Medrone with Lidocaine is indicated in conditions requiring a glucocorticoid effect: e.g. anti-inflammatory or anti-rheumatic. It is recommended for local use where the added anaesthetic effect would be considered advantageous.

Depo

Intra

Rheumatoid arthritis

Osteo-arthritis with an inflammatory component

Periarticular administration

Epicondylitis

Intrabursal administration

Subacromial bursitis

Prepatellar bursitis

Olecranon bursitis

Tendon sheath administration

Tendinitis

Tenosynovitis

Epicondylitis

Therapy with Depo-Medrone with Lidocaine does not obviate the need for the conventional measures usually employed. Although this method of treatment will ameliorate symptoms, it is in no sense a cure and the hormone has no effect on the cause of the inflammation.

4.2 Posology And Method Of Administration

Depomust not be used by the intrathecal or intravenous routes (see Contra

Adults

Intra Rheumatoid arthritis, osteo-arthritis. The dose of Depo

Periarticular: Epicondylitis. Infiltrate 0.1 - 0.75 ml (4 - 30 mg of steroid) into the affected area.

Intrabursal: Subdeltoid bursitis, prepatellar bursitis, olecranon bursitis. For administration directly into bursae, 0.1 - 0.75 ml (4 - 30 mg of steroid). In most acute cases, repeat injections are not needed.

Into the tendon sheath: Tendinitis, tenosynovitis, epicondylitis. For administration directly into the tendon sheath, 0.1

Children:

For infants and children, the recommended dosage should be reduced, but dosage should be governed by the severity of the condition rather than by strict adherence to the ratio indicated by age or body weight.

Elderly:

When used according to instructions, there is no information to suggest that a change in dosage is warranted in the elderly. However, treatment of elderly patients, particularly if long-term, should be planned bearing in mind the more serious consequences of the common side-effects of corticosteroids in old age and close clinical supervision is required (see Other special warnings and precautions).

Special precautions should be observed when administering Depo

Intra

After injection the joint is moved slightly to aid mixing of the synovial fluid and the suspension. Subsequent to therapy care should be taken for the patient not to overuse the joint in which benefit has been obtained. Negligence in this matter may permit an increase in joint deterioration that will more than offset the beneficial effects of the steroid.

Intrabursal injections should be made as follows: the area around the injection site is prepared in a sterile way and a wheal at the site made with 1 percent procaine hydrochloride solution. A 20 to 24 gauge needle attached to a dry syringe is inserted into the bursa and the fluid aspirated. The needle is left in place and the aspirating syringe changed for a small syringe containing the desired dose. After injection, the needle is withdrawn and a small dressing applied. In the treatment of tenosynovitis and tendinitis, care should be taken to inject Depo

4.3 Contraindications

Depo-Medrone with Lidocaine is contra-indicated where there is known hypersensitivity to components or to any local anaesthetics of the amide type and in systemic infection unless anti-infective therapy is employed.

Due to its potential for neurotoxicity, Depomust not be given by the intrathecal route. In addition, as the product is a suspension it must not be given by the intravenous route (see Side-effects).

4.4 Special Warnings And Precautions For Use

1. Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to appropriately titrate the dose against disease activity (see Dosage and administration).

2. Patients should carry 'Steroid Treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

3. Depo

4. Depo-Medrone with Lidocaine is not recommended for epidural, intranasal, intra-ocular, or any other unapproved route of administration. See Side-effects section for details of side-effects reported from some non-recommended routes of administration.

5. Due to the absence of a true tendon sheath, the Achilles tendon should not be injected with Depo-Medrone with Lidocaine.

6. While crystals of adrenal steroids in the dermis suppress inflammatory reactions, their presence may cause disintegration of the cellular elements and physiochemical changes in the ground substance of the connective tissue. The resultant infrequently occurring dermal and/or subdermal changes may form depressions in the skin at the injection site and the possibility of depigmentation. The degree to which this reaction occurs will vary with the amount of adrenal steroid injected. Regeneration is usually complete within a few months or after all crystals of the adrenal steroid have been absorbed. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Multiple small injections into the area of the lesion should be made whenever possible. The technique of intra-articular injection should include precautions against injection or leakage into the dermis.

7. Systemic absorption of methylprednisolone occurs following intra-articular injection of Depo-Medrone with Lidocaine. Systemic as well as local effects can therefore be expected.

8. Intra-articular corticosteroids are associated with a substantially increased risk of inflammatory response in the joint, particularly bacterial infection introduced with the injection. Charcot-like arthropathies have been reported particularly after repeated injections. Appropriate examination of any joint fluid present is necessary to exclude any bacterial infection, prior to injection.

9 Following a single dose of Depo-Medrone with Lidocaine, plasma cortisol levels are reduced and there is evidence of hypothalamic-pituitary-adrenal axis (HPA) suppression. This suppression lasts for a variable period of up to 4 weeks. The usual dynamic tests of HPA axis function can be used to diagnose evidence of impaired activity (e.g. Synacthen test).

10. Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of 6 mg methylprednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.

• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).

• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.

• Patients receiving doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.

• Patients repeatedly taking doses in the evening.

11. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.

12. Because rare instances of anaphylactic reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of drug allergy.

13. Corticosteroids may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised.

14. Chickenpox is of serious concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

15. Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

16. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

17. This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.

18. Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see Side-effects).

19. The following precautions apply for parenteral corticosteroids: Following intra-articular injection, a marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.

No additional benefit derives from the intramuscular administration of Depo-Medrone with Lidocaine. Where parenteral corticosteroid therapy for sustained systemic effect is desired, plain Depo-Medrone should be used.

Local injection of a steroid into a previously infected joint is to be avoided.

Corticosteroids should not be injected into unstable joints.

Sterile technique is necessary to prevent infections or contamination.

Special precautions:

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

1. Osteoporosis (post-menopausal females are particularly at risk).

2. Hypertension or congestive heart failure.

3. Existing or previous history of severe affective disorders (especially previous steroid psychosis).

4. Diabetes mellitus (or a family history of diabetes).

5. History of tuberculosis.

6. Glaucoma (or a family history of glaucoma).

7. Previous corticosteroid-induced myopathy.

8. Liver failure or cirrhosis.

9. Renal insufficiency.

10. Epilepsy.

11. Peptic ulceration.

12. Fresh intestinal anastomoses.

13. Predisposition to thrombophlebitis.

14. Abscess or other pyogenic infections.

15. Ulcerative colitis.

16. Diverticulitis.

17. Myasthenia gravis.

18. Ocular herpes simplex, for fear of corneal perforation.

19. Hypothyroidism.

20. Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 Interaction with Other Medicaments and Other Forms of Interaction that can increase the risk of side effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Use in children: Corticosteroids cause growth retardation in infancy, childhood and adolescence which may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time.

Use in the elderly: The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Since concurrent administration of these agents results in a mutual inhibition of metabolism, it is possible that convulsions and other adverse effects associated with the individual use of either drug may be more apt to occur.

2. Drugs that induce hepatic enzymes, such as rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced.

3. Drugs such as erythromycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance.

4. Steroids may reduce the effects of anticholinesterases in myasthenia gravis. The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.

5. The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

6. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication. Salicylates and non-steroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids in hypothrombinaemia.

7. Steroids have been reported to interact with neuromuscular blocking agents such as pancuronium with partial reversal of the neuromuscular block.

4.6 Pregnancy And Lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, methylprednisolone does cross the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate in man, however, when administered for long periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory, occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

The use of local anaesthetics such as lidocaine during labour and delivery may be associated with adverse effects on mother and foetus. Lidocaine readily crosses the placenta.

Lactation

Corticosteroids are excreted in small amounts in breast milk, however, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression, but the benefits of breastfeeding are likely to outweigh any theoretical risk.

It is not known whether lidocaine is excreted in human breast milk.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

The incidence of predictable undesirable side-effects associated with the use of corticosteroids, including hypothalamic-pituitary-adrenal suppression correlates with the relative potency of the drug, dosage, timing of administration and duration of treatment (See other special warnings and precautions).

Side-effects for the Depo-Medrone component may be observed including:

PARENTERAL CORTICOSTEROID THERAPY - Anaphylactic reaction or allergic reactions, hypopigmentation or hyperpigmentation, subcutaneous and cutaneous atrophy, sterile abscess, post injection flare (following intra-articular use), charcot-like arthropathy.

GASTRO-INTESTINAL - Dyspepsia, peptic ulceration with perforation and haemorrhage, abdominal distension, oesophageal ulceration, oesophageal candidiasis, acute pancreatitis, perforation of bowel.

Increases in alanine transaminase (ALT, SGPT) aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome and are reversible upon discontinuation.

ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE EFFECTS - Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, may suppress reactions to skin tests, recurrence of dormant tuberculosis (see Other special warnings and precautions).

MUSCULOSKELETAL - Proximal myopathy, osteoporosis, vertebral and long bone fractures, avascular osteonecrosis, tendon rupture, aseptic necrosis, muscle weakness.

FLUID AND ELECTROLYTE DISTURBANCE - Sodium and water retention, potassium loss, hypertension, hypokalaemic alkalosis, congestive heart failure in susceptible patients.

DERMATOLOGICAL - Impaired healing, petechiae and ecchymosis, thin fragile skin, skin atrophy, bruising, striae, telangiectasia, acne.

ENDOCRINE/METABOLIC - Suppression of the hypothalamo-pituitary-adrenal axis; growth suppression in infancy, childhood and adolescence; menstrual irregularity and amenorrhoea. Cushingoid facies, hirsutism, weight gain, impaired carbohydrate tolerance with increased requirement for antidiabetic therapy, negative nitrogen and calcium balance. Increased appetite.

NEUROPSYCHIATRIC

OPHTHALMIC - Increased intra-ocular pressure, glaucoma, papilloedema, cataracts with possible damage to the optic nerve, corneal or scleral thinning, exacerbation of ophthalmic viral or fungal disease, exophthalmos.

GENERAL - Leucocytosis, hypersensitivity including anaphylaxis, thrombo-embolism, nausea, vertigo.

WITHDRAWAL SYMPTOMS - Too rapid a reduction of corticosteroid dosage following prolonged treatment can lead to acute adrenal insufficiency, hypotension and death. However, this is more applicable to corticosteroids with an indication where continuous therapy is given (see Other special warnings and precautions).

A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

Side-effects for the Lidocaine component include:

CENTRAL NERVOUS SYSTEM - Lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensation of heat, cold, numbness, twitching, tremors, convulsions, loss of consciousness, respiratory depression, respiratory arrest.

CARDIOVASCULAR SYSTEM - Bradycardia, hypotension, cardiovascular collapse, cardiac arrest.

ALLERGIC REACTIONS - Cutaneous lesions, urticaria, oedema, anaphylactic reactions.

CERTAIN SIDE-EFFECTS REPORTED WITH SOME NON RECOMMENDED ROUTES OF ADMINISTRATION:

Intrathecal: Usual systemic corticoid adverse reactions, headache, meningismus, meningitis, paraplegia, spinal fluid abnormalities, nausea, vomiting, sweating, arachnoiditis, convulsions.

Extradural: Wound dehiscence, loss of sphincter control.

Intranasal: Permanent/temporary blindness, allergic reactions, rhinitis.

Ophthalmic (Subconjunctival): Redness and itching, abscess, slough at injection site, residue at injection site, increased intra-ocular pressure, decreased vision - blindness, infection.

Miscellaneous: Scalp, tonsillar fauces, sphenopalatine ganglion: blindness.

4.9 Overdose

There is no clinical syndrome of acute overdosage with Depo

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Methylprednisolone acetate is a synthetic glucocorticoid with the actions and use of natural corticosteroids. However the slower metabolism of the synthetic corticosteroid with their lower protein-binding affinity may account for their increased potency compared with the natural corticosteroids.

Lidocaine has the actions of a local anaesthetic.

5.2 Pharmacokinetic Properties

Administration of methylprednisolone acetate 40 mg intramuscularly produced measurable plasma concentrations of methylprednisolone for 11-17 days. The average peak plasma concentration was 14.8 ng per ml and occurred after 6-8 hours.

Plasma concentrations of lidocaine decline rapidly after an intravenous dose with an initial half life of less than 30 minutes; the elimination half life is 1-2 hours.

5.3 Preclinical Safety Data

Due to the age and well established safety nature of this product, preclinical data has not been included.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium chloride, myristyl-gamma-picolinium chloride, benzyl alcohol, macrogol, sodium hydroxide, hydrochloric acid and water for injection.

6.2 Incompatibilities

None

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Store at room temperature. Protect from freezing.

6.5 Nature And Contents Of Container

Glass vials with rubber cap containing 1 or 2 ml of suspension.

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data

7. Marketing Authorisation Holder

Pharmacia Limited,

Ramsgate Road,

Sandwich,

Kent CT13 9NJ

U.K.

8. Marketing Authorisation Number(S)

PL 0032/0076

9. Date Of First Authorisation/Renewal Of The Authorisation

MA granted: 03 March 1981

MA renewed: 25 November 1991

10. Date Of Revision Of The Text

October 2009

11. Legal category

POM

Ref: DML5_0 UK

Dequadin (Reckitt Benckiser Healthcare (UK) Ltd)

1. Name Of The Medicinal Product

Dequadin

2. Qualitative And Quantitative Composition

Each lozenge contains 0.25 mg dequalinium chloride BP

3. Pharmaceutical Form

Lozenge

4. Clinical Particulars

4.1 Therapeutic Indications

For the local therapy of most of the common infections of the mouth including: Vincents angina, pharyngitis, sore throats, tonsillitis, stomatitis, aphthous ulcers, thrush, glossitis.

4.2 Posology And Method Of Administration

For oral administration.

Adults and children over 10 years: One lozenge to be sucked every 2 to 3 hours, up to a maximum of eight in one day.

Elderly

There is no need for a dosage reduction in the elderly.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

The label states:

Keep all medicines out of the reach of children. If symptoms persist, consult your doctor.

Warning: Do not exceed the stated dose.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant drug interactions known.

4.6 Pregnancy And Lactation

The safety of Dequadin during pregnancy and lactation has not been established, but it is not considered to constitute a hazard.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

Occasional hypersensitivity reactions and soreness of the tongue are possible.

4.9 Overdose

Overdosage should not present a problem other than gastrointestinal discomfort. Treatment should be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Dequalinium chloride is a quaternary ammonium antiseptic active against many gram-positive and gram-negative bacteria, yeasts and fungi.

5.2 Pharmacokinetic Properties

Not available.

5.3 Preclinical Safety Data

There are no preclinical safety data of relevance to the consumer.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Icing sugar,

Citric acid monohydrate,

Liquid glucose,

Sodium saccharin,

Camphor,

Magnesium stearate,

Gelatin,

Sunset yellow,

Lime flavour,

Peppermint oil.

Purified water not detected in final formulation.

6.2 Incompatibilities

None.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

PVC/PVDC blister strips sealed with aluminium foil enclosed in a cardboard carton to give packs of 20 or 40 lozenges.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Reckitt Benckiser healthcare (UK) Limited

Dansom Lane

Hull

East Yorkshire

HU8 7DS

United Kingdom

8. Marketing Authorisation Number(S)

PL 00063/0402

9. Date Of First Authorisation/Renewal Of The Authorisation

01/08/2008

10. Date Of Revision Of The Text

August 2008

Depefex 75mg & 150mg XL Capsules

1. Name Of The Medicinal Product

Depefex 75 mg XL Capsules

Depefex 150 mg XL Capsules

2. Qualitative And Quantitative Composition

Each prolonged release capsule contains 75 mg or 150 mg of venlafaxine as venlafaxine hydrochloride.

Venlafaxine is chemically defined as (R/S)-1-[(2-dimethylamino)-1-(4-methoxy phenyl) ethyl] cyclohexanol hydrochloride.

Depefex Capsules contain sucrose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged-release capsules, hard.

Depefex 75 mg XL Capsules are white opaque capsules containing white or whitish pellets.

Depefex 150 mg XL Capsules are natural transparent capsules containing white or whitish pellets.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depressive episodes.

For prevention of recurrence of major depressive episodes.

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.

Use in elderly patients

No specific dose adjustments of venlafaxine are considered necessary based on patient age alone. However, caution should be exercised in treating the elderly (e.g., due to the 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 be swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

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

Venlafaxine prolonged-release capsules contain spheroids, which release the active substance slowly into the digestive tract. The insoluble portion of these spheroids is eliminated and may be seen in faeces.

4.3 Contraindications

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

Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is 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

Depefex 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 preexisting hypertension should be controlled before initation of treatment. Blood pressure should be reviewed periodically, after initiation of treatment and after dose increases. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure, e.g., those with impaired cardiac function.

Heart rate

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

Cardiac disease and risk of arrhythmia

Venlafaxine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, it should be used with caution in these patients.

In postmarketing experience, fatal cardiac arrhythmias have been reported with the use of venlafaxine, especially in overdose. The balance of risks and benefits should be considered before prescribing venlafaxine to patients at high risk of serious cardiac arrhythmia.

Convulsions

Convulsions may occur with venlafaxine therapy. As with all antidepressants, venlafaxine should be introduced with caution in patients with a history of convulsions, and concerned patients should be closely monitored. Treatment should be discontinued in any patient who develops seizures.

Hyponatraemia

Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with venlafaxine. This has most frequently been reported in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volume-depleted may be at greater risk for this event.

Abnormal bleeding

Medicinal products that inhibit serotonin uptake may lead to reduced platelet function. The risk of skin and mucous membrane bleeding, including gastrointestinal haemorrhage, may be increased in patients taking venlafaxine. As with other serotonin-reuptake inhibitors, venlafaxine should be used cautiously in patients predisposed to bleeding, including patients on anticoagulants and platelet inhibitors.

Serum cholesterol

Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during long-term treatment.

Co-administration with weight loss agents

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

Mania/hypomania

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

Aggression

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

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

Discontinuation of treatment

Withdrawal symptoms, when treatment is discontinued, are common, particularly if discontinuation is abrupt (see section 4.8). 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 at least 14 days after discontinuation of treatment with an irreversible nonselective 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 CYP2D6 PM and EM subjects, respectively) and O-desmethylvenlafaxine (33% and 23% in CYP2D6 PM and EM subjects, respectively) following administration of ketoconazole. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) and venlafaxine may increase levels of venlafaxine and O-desmethylvenlafaxine. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.

Effect of venlafaxine on other medicinal products

Lithium

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

Diazepam

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

Imipramine

Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. There was a dose-dependent increase of 2-OH-desipramine AUC by 2.5 to 4.5-fold when venlafaxine 75 mg to 150 mg daily was administered. Imipramine did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised with co-administration of venlafaxine and imipramine.

Haloperidol

A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, a 70% increase in AUC, an 88% increase in Cmax, 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 Cmax 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). Venlafaxine must only be administered to pregnant women if the expected benefits outweigh any possible risk.

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

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.

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 Depefex should be made, taking into account the benefit of breast-feeding to the child and the benefit of Depefex therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Any psychoactive medicinal product may impair judgment, 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, Thrombocytopaenia, Blood dyscrasias, (including agranulocytosis, aplastic anaemia, neutropaenia and pancytopaenia)
Metabolic/Nutritional		Serum cholesterol increased, Weight loss	Weight gain		Abnormal liver function tests, Hyponatraemia, Hepatitis, Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), Prolactin increased
Nervous	Dry mouth (10.0%), Headache (30.3%)*	Abnormal dreams, Decreased libido, Dizziness, Increased muscle tonus (hypertonia), Insomnia, Nervousness, Paresthesia, Sedation, Tremor, Confusion, Depersonalisation	Apathy, Hallucinations, Myoclonus, Agitation, Impaired coordination and balance	Akathisia/Psychomotor restlessness, Convulsion, Manic reaction	Neuroleptic Malignant Syndrome (NMS), Serotonergic syndrome, Delirium, Extrapyramidal reactions (including dystonia and dyskinaesia), Tardive dyskinaesia, 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 (fatigue), Chills	Angioedema, Photosensitivity reaction		Anaphylaxis

*In pooled clinical trials, the incidence of headache was 30.3% with venlafaxine versus 1.3% with placebo.

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

*** see section 4.4

Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including 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 that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed (see section 4.4).

In paediatric clinical trials the adverse reaction suicidal ideation was observed. There were also increased reports of hostility and, especially in major depressive disorder, self-harm.

Particularly, the following adverse reactions were observed in paediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

4.9 Overdose

In postmarketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other medicinal products. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other reported events include electrocardiographic changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, vertigo, and death.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine treated patients have a higher burden of suicide risk factors than SSRI patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristics of venlafaxine-treated patients, is not clear. Prescriptions for venlafaxine should be written for the smallest quantity of the medicinal product consistent with good patient management in order to reduce the risk of overdose.

Recommended treatment

General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs must be monitored. When there is a risk of aspiration, induction of emesis is not recommended. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Administration of activated charcoal may also limit absorption of the active substance. Forced diuresis, dialysis, 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 β-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 375 mg/day. The efficacy of venlafaxine prolonged-release as a treatment for major depressive episodes was established in two placebo-controlled, short-term studies for 8 and 12 weeks duration, which included a dose range of 75 to 225 mg/day.

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

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

5.2 Pharmacokinetic Properties

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

Absorption

At least 92% of venlafaxine is absorbed following single oral doses of immediate-release venlafaxine. Absolute bioavailability is 40% to 45% due to presystemic metabolism. After immediate-release venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively. Following the administration of venlafaxine prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are 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 30mg/kg/day, 4 times the human daily dose of 375 mg of venlafaxine (on an mg/kg basis). The no-effect dose for these findings was 1.3 times the human dose. The potential risk for humans is unknown.

Reduced fertility was observed in a study in which both male and female rats were exposed to ODV. This exposure was approximately 1 to 2 times that of a human venlafaxine dose of 375 mg/day. The human relevance of this finding is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Stearic acid

Ethylcellulose

Talc

Sugar spheres 20:

Sucrose

Maize Starch

Capsule shell:

Gelatin

Titanium dioxide [only in 75 mg XL capsules]

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 Months.

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package.

6.5 Nature And Contents Of Container

Al/PVDC - clear PVC/PVDC blister packs of 28 capsules

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Chiesi Limited, Cheadle Royal Business Park, Highfield, Cheadle, SK8 3GY, UK.

8. Marketing Authorisation Number(S)

Depefex 75 mg XL Capsules: PL 8829/0171

Depefex 150 mg XL Capsules: PL 8829/0172

9. Date Of First Authorisation/Renewal Of The Authorisation

15/02/2008

10. Date Of Revision Of The Text

15/02/2011

11 LEGAL CATEGORY

POM