Volsaid

VOLSAID RETARD 100

Each modified-release tablet contains 100 mg diclofenac sodium.

Modified-release tablet

Pale red, round, biconvex tablet. One side is marked "DIC 100" and the reverse side is plain.

Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) recommended for the treatment of:

- rheumatoid arthritis, osteoarthritis and ankylosing spondylitis

- acute gout

- low back pain

- the relief of pain in fractures

- acute musculo-skeletal disorders and trauma including periarthritis (particularly frozen shoulder), bursitis, tendinitis, tenosynovitis, dislocations, sprains and strains

- the control of pain and inflammation in orthopaedic, dental and other minor surgery

Route of Administration

For oral administration

Dosage Recommendations

Adults

One tablet to be taken once a day swallowed whole, preferably with or after food.

Children

Diclofenac sodium is not suitable for use in children.

The Elderly

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

Hypersensitivity to diclofenac sodium or to any of the excipients.

Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding.

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, urticaria), in response to aspirin, ibuprofen or other non-steroidal anti-inflammatory drugs.

Porphyria.

Severe heart failure, hepatic failure and renal failure.

During the last trimester of pregnancy.

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

The use of Volsaid with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.

Elderly

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory disorders

Caution is required if administered to patients suffering from, or with a previous history of bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, Renal and Hepatic Impairment

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure.). On stopping diclofenac, effects on renal function are usually reversible.

Diclofenac should be stopped if liver function tests show abnormalities that persist or worsen, or if liver disease develops or if other symptoms such as eosinophilia or rash occur.

Diclofenac sodium may trigger an attack in patients with hepatic porphyria.

Monitoring of renal function, hepatic function (elevation of liver enzymes may occur) and blood counts should be performed on long-term NSAID patients, as a precautionary measure.

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 (150 mg 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 significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration. As the cardiovascular effects of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.

Gastrointestinal bleeding, ulceration and perforation

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

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 , and in the elderly.).

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

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 or anti-platelet agents such as aspirin.

When GI bleeding or ulceration occurs in patients receiving diclofenac, the treatment should be withdrawn.

NSAIDs should be given with care in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease, haematemesis, melaena, haematological abnormalities, or bleeding diathesis) as these conditions may be exacerbated.

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.

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 the use of NSAIDs. Patients appear to be at highest risk for these early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first appearance of skin rash, mucosal lesions, or any signs of hypersensitivity.

Impaired female fertility

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

Care should be taken in patients treated with any of the drugs mentioned below because, as with other NSAIDs, diclofenac sodium has the potential to induce the following interactions.

Other analgesics including cyclooxygenase-2 selective inhibitors

Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects.

Anti-hypertensives

Reduced anti-hypertensive effect.

Diuretics

Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Increased serum potassium levels may result when diclofenac is given concomitantly with potassium-sparing diuretics. Serum potassium levels should therefore be monitored.

Cardiac Glycosides

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium

Decreased elimination of lithium.

Methotrexate

Decreased elimination of methotrexate. Methotrexate and NSAIDs should only be administered within 24 hours of each other if given with extreme caution.

Ciclosporin

Increased risk of nephrotoxicity. Ciclosporin may increase the bioavailability of diclofenac.

Quinolone Antibiotics

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Anticoagulants and anti-platelet agents: Caution is recommended since concomitant administration could increase the risk of bleeding. Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.

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

Increased risk of gastrointestinal bleeding.

Oral Hypoglycaemic Agents

It has been reported that hypo- and hyperglycaemic effects have occurred rarely when diclofenac and oral antidiabetic agents have been given together and adjustment of the hypoglycaemic may be required.

Inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia have also been reported.

Aminoglycosides

Reduction in renal function in susceptible individuals, decreased elimination of aminoglycosides and increased plasma concentrations have been reported.

Probenecid

Reduction in metabolism and elimination of NSAID and metabolites occurs with probenecid.

Mifepristone

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

Corticosteroids

Increased risk of gastrointestinal ulceration or bleeding..

Tacrolimus

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Congenital abnormalities have been reported in association with NSAID administration 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 (risk of closure of the ductus arteriosus), use in the last trimester is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

Undesirable effects such as dizziness, drowsiness, fatigue, visual disturbances and headaches are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

Gastrointestinal

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, constipation, anorexia, dyspepsia, flatulence and abdominal pain, melaena, haematemesis, ulcerative stomatitis, glossitis, oesophageal lesions, aphthous stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Ischaemic colitis has been reported with a frequency not known.

Cardiovascular

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Hypersensitivity Reactions

Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of:

- non-specific allergic reactions and anaphylaxis

- respiratory tract reactivity comprising of asthma, aggravated asthma, bronchospasm or dyspnoea

- assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely Stevens-Johnson syndrome, Lyell's syndrome, eczema, erythroderma, hair loss, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

Other adverse reactions reported less commonly include:

Neurological and Special Senses

Visual disturbances, optic neuritis, headache, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, , depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue, drowsiness, tiredness, impaired hearing, anorexia, insomnia, convulsions, irritability, anxiety, psychotic reactions, tremors, memory disturbance, disturbance of vision, nightmares and taste alterations.

Dermatological Reaction

Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity

Renal

Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and renal failure. Occasional effects on the kidney include acute renal insufficiency, urinary abnormalities (e.g., haematuria, proteinuria) and papillary necrosis.

Hepatic

Effects on the liver include occasional reports of elevation of serum aminotransferase enzymes (ALT, ST) and rarely abnormal liver function, hepatitis and jaundice.

Haematological Reactions

Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia and leucopenia.

Other rarely reported reactions include hypotension, hypertension, palpitation, impotence and chest pain.

Reporting of suspected adverse reactions

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

Symptoms

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

Management

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 a potentially life-threatening overdose.

Good urine output should be ensured.

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam.

The correction of severe electrolyte abnormalities may need to be considered.

Other measures may be indicated by the patient's clinical condition.

Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. It is an inhibitor of prostaglandin synthetase.

This extended release diclofenac formulation is designed to release diclofenac over a period of time. Following a pharmacokinetic study with the 100 mg tablet in volunteers, it was found that the average time to reach maximum plasma concentration was 6.05 hours.

The average elimination half-life was found to be 6.75 hours. The average maximum plasma concentrations were found to be 262 ng/ml.

a) General Characteristics of the Active Substance

Diclofenac sodium is almost totally absorbed after oral administration, and it is subject to significant first-pass metabolism with only approximately 60% of an oral dose reaching the systemic circulation.

Diclofenac sodium is highly protein bound (> 99%). It is mainly excreted in the form of metabolites via the urine but also in the bile.

The main metabolite has a minimal anti-inflammatory activity compared to the parent drug.

b) Characteristics in Patients

Plasma concentrations of unchanged diclofenac are not reported to be significantly affected by age, renal or hepatic impairment. The metabolite concentrations may be increased by severe renal impairment.

There is no preclinical data available that is of relevance to the prescriber.

For Uncoated Tablets:

Talc

Ethylcellulose

Magnesium stearate

Povidone

Stearic acid

For Coating:

Hypromellose (E.464)

Ethylcellulose

Diethyl phthalate

Macrogol 4000

Titanium dioxide (E.171)

Red iron oxide (E.172)

Yellow iron oxide (E.172)

Not applicable

36 months

Do not store above 25°C. Store in the original package. Keep container in the outer carton.

The modified-release tablets are enclosed in blisters composed of 250 µm PVC coated with 40 gm^-2 PVdC and 2 µm aluminium coated with 20 gm^-2 PVdC.

The blisters are boxed in cardboard cartons containing 28, 30, 50, 56, 60, 84, 100, 250, 500 and 1000 modified-release tablets and a user leaflet.

Not applicable

Chiesi Limited

333 Styal Road

Manchester

M22 5LG

United Kingdom

PL 08829/0046

8^th January 2002

August 2016