Volsaid Retard 100
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Volsaid Retard 100
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each modified-release tablet contains 100 mg diclofenac sodium.
For excipients see section 6.1.
3 PHARMACEUTICAL FORM
Modified-release tablets.
Pale red, round, biconvex tablet. One side is marked “DIC 100” and the reverse side is plain.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) recommended for the treatment of:
- rheumatoid arthritis; osteoarthritis; ankylosing spondylitis
- acute gout
- low back pain
- 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
4.2 Posology and method of administration
Route of Administration For oral administration
Dosage Recommendations
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
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.
4.3 Contraindications
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 (see section 4.4).
During the last trimester of pregnancy (see section 4.6).
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.
4.4 Special warnings and precautions for use
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).
The use of Volsaid with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).
Elderly
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).
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. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also section 4.3). 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 risks 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 reevaluated 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 (see section 4.3), 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 patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).
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 (see section 4.5).
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 (see section 4.8).
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).
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 (see section 4.8). 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.
4.5 Interaction with other medicinal products and other forms of interaction
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 (see section 4.4).
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 (see section 4.4).
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. (See section 4.4).
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.
4.6 Fertility, pregnancy and lactation
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 (see section 4.3). 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.
See section 4.4 Special warnings and precautions for use, regarding female fertility.
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
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 (see section 4.4). 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 (See section 4.4) 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.
Clinical trial and epidemiological data consistently point towards an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) associated with the use of diclofenac, particularly at high dose (150 mg daily) and in long term treatment (see section 4.3 and 4.4 for Contraindications and Special warnings and precautions for use).
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, (see section 4.4), 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.
4.9 Overdose
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. It is an inhibitor of prostaglandin synthetase.
5.2 Pharmacokinetic properties
This extended release diclofenac formulation is designed to release diclofenac over a period of time. Following a pharmacokinetic study with the 100mg 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 262ng/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.
5.3 Preclinical safety data
There is no preclinical data that is of relevance to the prescriber.
6.1 List of excipients
For Uncoated Tablets:
Talc
Ethylcellulose Magnesium stearate Povidone Stearic acid For Coating:
Hypromellose (E464)
Ethylcellulose Diethyl phthalate Macrogol 4000 Titanium dioxide (E171)
Red Iron Oxide (E172)
Yellow Iron Oxide (E172)
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 Keep container in the outer carton
6.5 Nature and contents of container
The modified-release tablets are enclosed in blisters composed of 250pm PVC coated with 40gm' PVdC and 25pm aluminium coated with 20gm' 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.
6.6 Special precautions for disposal
Not applicable
7. MARKETING AUTHORISATION HOLDER
Chiesi Limited 333 Styal Road Manchester M22 5LG United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 08829/0046
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22/01/1996
10 DATE OF REVISION OF THE TEXT
20/10/2016