Voltarol^® Tablets 25mg and 50mg

The active substance is sodium-[o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate (diclofenac sodium).

Each enteric coated tablet contains 25mg or 50mg diclofenac sodium Ph.Eur.

Enteric coated tablet.

Adults and Elderly

Relief of all grades of pain and inflammation in a wide range of conditions,

including:

(i) arthritic conditions: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gout,

(ii) acute musculo-skeletal disorders such as periarthritis (for example frozen shoulder), tendinitis, tenosynovitis, bursitis,

(iii) other painful conditions resulting from trauma, including fracture, low back pain, sprains, strains, dislocations, orthopaedic, dental and other minor surgery.

Children (aged 1-12 years)

Juvenile chronic arthritis (25mg tablet only).

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4 Special warnings and special precautions for use).

For oral administration

75-150mg daily in two or three divided doses.

The recommended maximum daily dose of Voltarol is 150mg.

Children (aged 1-12 years)

1-3mg/kg per day in divided doses. (25mg tablet only)

Elderly

Although the pharmacokinetics of Voltarol are not impaired to any clinically relevant extent in elderly patients, non-steroidal anti-inflammatory drugs should be used with particular caution in such patients who generally are more prone to adverse reactions. In particular it is recommended that the lowest effective dosage be used in frail elderly patients or those with a low body weight (see also precautions) and the patient should be monitored for GI bleeding during NSAID therapy.

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

• Patients with active, or a history of, Gastrointestinal ulcers, bleeding or perforation (two or more distinct episodes of proven ulceration or bleeding).

• Patients who have previously shown hypersensitivity reactions (e.g. asthma, angioedema, urticaria or acute rhinitis) to ibuprofen, aspirin or other non-steroidal anti-inflammatory drugs.

• Severe hepatic, renal and heart failure (see section 4.4 Special warnings and precautions for use).

• During the last trimester of pregnancy (see section 4.6 Pregnancy and lactation).

• History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy.

Warnings

In all patients

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 Posology and method of administration and GI and cardiovascular risks below).

The use of Voltarol with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5 Interactions with other medicaments and other forms of interaction).

Elderly

The elderly have increased frequency of adverse reactions to NSAIDs especially gastro intestinal bleeding and perforation which may be fatal (see section 4.2 Posology and method of administration).

Gastrointestinal

Close medical surveillance is imperative in patients with symptoms indicative of Gastrointestinal disorders, with a history suggestive of gastric or intestinal ulceration, with ulcerative colitis, or with Crohn's disease as these conditions may be exacerbated (see section 4.8 Undesirable effects).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding).

Gastrointestinal bleeding or ulceration/perforation

Haematemesis, melaena, ulceration or perforation which can be fatal has been reported with all NSAIDs. They can occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. In the rare instances when Gastrointestinal bleeding or ulceration occurs in patients receiving Voltarol, the drug should be withdrawn.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3 Contraindications), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, other drugs likely to increase gastrointestinal risk (see below and section 4.5 Interactions with other medicaments and other forms of interaction).

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral, corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as aspirin (see section 4.5 Interaction with other medicaments and other forms of interaction).

Hepatic

Close medical surveillance is also imperative in patients suffering from impairment of hepatic function.

Hypersensitivity reactions

As with other non-steroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug (see section 4.8 Undesirable effects).

Like other NSAIDs, Voltarol may mask the signs and symptoms of infection due to its pharmacodynamic properties.

Precautions

Renal

Patients with renal, cardiac or hepatic impairment and the elderly should be kept under surveillance, since the use of NSAIDs may result in deterioration of renal function. The lowest effective dose should be used and renal function monitored.

The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, those being treated with diuretics or recovering from major surgery. Effects on renal function are usually reversible on withdrawal of Voltarol.

Hepatic

If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Voltarol should be discontinued. Hepatitis may occur without prodromal symptoms.

Use of Voltarol in patients with hepatic porphyria may trigger an attack.

Haematological

Voltarol may reversibly inhibit platelet aggregation (see anticoagulants in section 4.5 Interaction with other medicaments and other forms of interactions). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Long term treatment

All patients who are receiving non-steroidal anti-inflammatory agents should be monitored as a precautionary measure e.g. renal function, hepatic function (elevation of liver enzymes may occur) and blood counts. This is particularly important in the elderly.

Respiratory disorders

Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking).

SLE and mixed connective tissue disease

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8 Undesirable effects).

Dermatological

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with he use of NSAIDs, including Voltarol (see section 4.8 Undesirable effects). Patients appear to be at the highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Voltarol should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

Female fertility

The use of Voltarol may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Voltarol should be considered.

Lithium and digoxin

Voltarol may increase plasma concentrations of lithium and digoxin.

Anticoagulants

Although clinical investigations do not appear to indicate that Voltarol has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage with the combined use of diclofenac and anticoagulant therapy (see section 4.4 Special warnings and precautions for use). Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other non-steroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.

Antidiabetic agents

Clinical studies have shown that Voltarol can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects which have required adjustment to the dosage of hypoglycaemic agents.

Methotrexate

Cases of serious toxicity have been reported when methotrexate and NSAIDs are given within 24 hours of each other. This interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.

Quinolone antimicrobials

Convulsions may occur due to an interaction between quinolones and NSAIDs. This may occur in patients with or without a previous history of epilepsy or convulsions. Therefore, caution should be exercised when considering the use of a quinolone in patients who are already receiving an NSAID.

Other NSAIDs including cyclooxygenase-2 selective inhibitors and corticosteroids

Co-administration of Voltarol with aspirin or corticosteroids may increase the risk of Gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs (see section 4.4 Special warnings and precautions for use).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding (see section 4.4 Special warnings and precautions for use).

Diuretics

Like other NSAIDs, Voltarol may inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently.

Cardiac glycosides

Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Mifepristone

NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Antihypertensives

Concomitant use of NSAIDs with antihypertensive drugs (i.e. beta-blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics) may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.

Ciclosporin and Tacrolimus

Cases of nephrotoxicity have been reported in patients receiving concomitant ciclosporin and NSAIDs, including diclofenac sodium. Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through renal antiprostagladin effects of both NSAID and calcineurin inhibitor.

Pregnancy

Congenital abnormalities have been reported in association with the administration of NSAIDs in man, however, these are low in frequency and do not appear to follow any discernible pattern.

In view of the known effects of NSAIDs on the foetal cardiovascular system (e.g. a premature closure of the ductus arteriosus) and in causing uterine inertia, use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3 Contraindications). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit outweighs the potential risk to foetus. The lowest effective dose should be used and duration kept as short as possible.

Lactation

Following doses of 50mg enteric coated tablets every 8 hours, traces of active substance have been detected in breast milk, but in quantities so small that no adverse effects on the breast fed infant are to be expected.

NSAIDs should if possible be avoided when breast feeding.

See section 4.4 Special warnings and precautions for use, regarding female fertility.

Patients who experience dizziness, drowsiness, fatigue or visual disturbances, while taking NSAIDs should refrain from driving or operating machinery.

If serious side-effects occur, Voltarol should be withdrawn.

Frequency estimate: frequent:>10 %, occasional:> 1 - 10 %, rare:> 0.001 - 1 %, isolated cases: < 0.001 %.

Gastrointestinal tract

Occasional: Epigastric pain, other Gastrointestinal disorders (e.g. nausea, vomiting, diarrhoea, abdominal cramps, dyspepsia, flatulence, anorexia).

Rare: Gastritis, Gastrointestinal bleeding (haematemesis, melaena, and bloody diarrhoea), Gastrointestinal ulcers with or without bleeding or perforation (sometimes fatal, particularly in the elderly) may occur (see section 4.4 Special warnings and precautions for use).

In isolated cases: Aphthous stomatitis, glossitis, oesophageal lesions, lower gut disorders (e.g. non-specific haemorrhagic colitis and exacerbations of ulcerative colitis or Crohn's proctocolitis, colonic damage and stricture formation), pancreatitis, constipation.

Central Nervous System disorders

Occasional: Headache, dizziness, or vertigo.

Rare: Drowsiness, tiredness, hypotension.

In isolated cases: Disturbances of sensation, paraesthesia, memory disturbance, disorientation, insomnia, irritability, convulsions, depression, confusion, hallucinations, malaise, anxiety, nightmares, tremor, psychotic reactions, aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus and mixed tissue disease), with symptoms such as fever, stiff neck, headache, nausea and vomiting.

Special senses

Isolated cases: Disturbances of vision (blurred vision, optic neuritis, diplopia), impaired hearing, tinnitus, taste disturbances.

Skin

Occasional: Rashes or skin eruptions.

Rare: Urticaria.

In isolated cases: Bullous eruptions, eczema, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome, (acute toxic epidermolysis), erythroderma (exfoliative dermatitis), loss of hair, photosensitivity reactions, purpura including allergic purpura.

Kidney

Rare: Oedema.

In isolated cases: Acute renal insufficiency, urinary abnormalities (e.g. haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, papillary necrosis.

Liver

Occasional: Elevation of serum aminotransferase enzymes (ALT, AST).

Rare: Liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice.

Blood

In isolated cases: Thrombocytopenia, leucopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.

Vascular

Isolated cases: Vasculitus.

Respiratory

Isolated cases: Pneumonitis.

Cardiovascular system

Isolated cases: Palpitations, chest pain, hypertension, congestive heart failure.

Other organ systems

Isolated cases: Impotence.

Hypersensitivity

Hypersensitivity reactions have been reported following treatment with NSAIDs. These consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising of asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necroylsis and etheryma multiforme).

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4 Special warnings and special precautions for use).

Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, tinnitus, fainting, occasionally convulsions. In rare cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures

Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults gastric lavage should be considered within one hour of ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patients clinical condition.

Non-steroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

Voltarol is a non-steroidal agent with marked analgesic/anti- inflammatory properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase).

Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

Absorption

Absorption is complete but onset is delayed until passage through the stomach, which may be affected by food which delays stomach emptying. The mean peak plasma diclofenac concentration reached at about 2 hours (50mg dose produces 1.48 ± 0.65µg/ml (1.5µg/ml 5µmol/l)).

Bioavailability

About half of the administered diclofenac is metabolised during its first passage through the liver ("first-pass" effect), the area under the concentrations curve (AUC) following oral administration is about half that following an equivalent parenteral dose.

Pharmacokinetic behaviour does not change on repeated administration. Accumulation does not occur, provided the recommended dosage intervals are observed. The plasma concentrations attained in children given equivalent doses (mg/kg, b.w.) are similar to those obtained in adults.

Distribution

The active substance is 99.7% protein bound, mainly to albumin (99.4%).

Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma and remain higher for up to 12 hours.

Metabolism

Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.

Elimination

The total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours.

About 60% of the administered dose is excreted in the urine in the form of the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

Characteristics in patients

Elderly

No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed, other than the finding that in five elderly patients, a 15 minute iv infusion resulted in 50% higher plasma concentrations than expected with young healthy subjects.

Patients with renal impairment

In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of < 10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Patients with hepatic disease

In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.

None stated.

The enteric-coated tablets also contain

• aerosil 200 standard

• lactose

• maize starch

• sodium starch glycollate

• povidone (K30)

• avicel PH 102

• magnesium stearate

• hydroxypropyl methylcellulose

• cremophor RH40

• yellow iron oxide (E.172)

• red iron oxide (E.172) 50mg tablet only

• purified talc special

• titanium dioxide (E.171)

• eudragit L30D-55

• polyethylene glycol 8000 flakes

• silicone antifoam emulsion SE2

• ammonia 25% and purified water.

None known.

5 years.

Protect from moisture. Store below 30°C.

Medicines should be kept out of the reach of children.

The 25mg tablets are yellow, round, biconvex, film coated tablets, impressed GEIGY on one face and VOLTAROL 25 on the other, and come in PVC/PVdC blister packs of 84.

The 50mg tablets are light brown, round, biconvex, film coated tablets, impressed GEIGY on one face and VOLTAROL 50 on the other, and come in PVC/PVdC blister packs of 14 and 84.

The enteric-coated tablets should be swallowed whole, preferably before meals.

Novartis Pharmaceuticals UK Ltd.

Trading as Geigy Pharmaceuticals

Frimley Business Park

Frimley

Camberley

Surrey, GU16 7SR.

25mg: PL 00101/0476

50mg: PL 00101/0477

11 July 1997

May 2007

POM