Diclofenac Sodium 50mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Diclofenac Sodium 50 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Sodium Diclofenac 50 mg,
Also contains lactose. For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Gastro-resistant Tablet
Orange, circular biconvex tablet with the Chatfield logo on one side and DIC50 on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults and children of 12 years and above:
Rheumatoid arthritis, osteoarthrosis, low back pain and other acute musculo skeletal disorders, acute gout, control of pain and inflammation in orthopaedic, dental and other minor surgery.
Children of 12 years and above:
Juvenile Chronic Arthritis.
The short term treatment of fever related to infection of the ear, nose or throat (ENT), e.g. pharyngotonsillitis, otitis media.
As monotherapy or as adjunct therapy with morphine or other opiates (due to its opiate-sparing effect) for the relief of acute post-operative pain.
This formulation is not recommended for use in children under 12 years of age.
4.2 Posology and method of administration
For oral administration
To be taken preferably with or after food.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).
Adults and children of 12 years and above:
A total of 75 to 150 mg daily given in two or three divided doses.
Children of 12 years and above:
For Juvenile Chronic Arthritis: 1 to 3-mg/kg-body weight per day in divided doses
For the short term treatment of fever related to infection of the ear, nose or throat (ENT) and post-operative pain the following dosage should be given: Children aged 12 years (minimum 35 kg body weight) or over and adolescents should be given up to 2 mg/kg body weight per day in 3 divided doses, depending on the severity of the disorder.
Elderly:
The elderly are at increased risk of 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.
Tablets should be swallowed whole and not chewed.
4.3 Contraindications
NSAIDs are contraindicated in patients who have:
• Hypersensitivity to Diclofenac sodium or to any of the other constituents,
• Active or history of recurrent peptic ulceration / haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
• A history of upper gastrointestinal bleeding or perforation, related to previous NSAID therapy.
• Previously shown hypersensitivity reactions (e.g. asthma, angioedema, urticaria or acute rhinitis) in response to ibuprofen, aspirin or other non-steroidal antiinflammatory agents (NSAIDs).
• Severe heart failure, hepatic failure and renal failure (see section 4.4 - Special warnings and precautions for use)
• Acute porphyria
• During the last trimester of pregnancy (see section 4.6 - Pregnancy and lactation)
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).
Precautions: History of gastro intestinal ulceration, haematemesis, or melaena, ulcerative colitis, Crohn’s disease, bleeding diathesis or haematological abnormalities.
The use of Diclofenac with concomitant NSAIDs including the cyclooxygenase 2 specific inhibitors should be avoided (see section 4.5 - Interactions).
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 -Posology and administration).
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 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, smoking).
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. The lowest effective dose should be used and renal function should be monitored in these patients (see section 4.3 -Contraindications).
If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Diclofenac should be discontinued. Hepatitis may occur with prodromal symptoms.
Use of Diclofenac in patients with hepatic porphyria may trigger an attack.
Diclofenac may reversibly inhibit platelet aggregation. Patients with defects of haemostasis bleeding diathesis or haematological abnormalities should be carefully monitored.
All patients, but particularly the elderly, who are receiving non-steroidal antiinflammatory agents should be monitored as a precautionary measure e.g. renal function, hepatic function and blood counts.
Diclofenac has been reported to depress salicylate levels and vice versa. Gastrointestinal bleeding, ulceration and perforation:
Although enteric-coated NSAIDs cause less gastric irritation, 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 for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).
NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, 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) particularly in the initial stages of the treatment.
Caution should be advised in patients receiving concomitant medications, which could increase the risk of ulceration or bleeding, such as oral corticosteroids, or anticoagulants such as warfarin, selective serotonin-re-uptake inhibitors or antiplatelet agents such as aspirin (see section 4.5 - Interactions)
When GI bleeding or ulceration occurs in patients receiving Diclofenac sodium, the treatment should be withdrawn.
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).
Female fertility:
The use of Diclofenac sodium 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 Diclofenac sodium should be considered.
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 reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment.
Diclofenac should be discontinued at the first appearance of skin rash, mucosal leisions or any other sign of hypersensitivity.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Other Analgesics including cyclooxygenase-2 selective inhibitors: Due to increased risk of adverse effects, avoid concomitant administration of two or more NSAIDs, including aspirin and keterolac (See section 4.4 Special warnings and precautions for use).
Anti-hypertensives: Care should be taken in patients treated with antihypertensive drugs, as there may be a reduced antihypertensive effect in combination with NSAID’s.
Diuretics: Various NSAIDs are liable to inhibit the activity of diuretics. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Concomitant treatment with potassium sparing diuretics may be associated with increased serum potassium levels; hence serum potassium should be monitored.
Cardiac glycosides (e.g. digoxin): NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Lithium: Diclofenac may increase plasma concentration of Lithium.
Methotrexate: Decreased elimination of methotrexate. Cases of serious toxicity have been reported when methotrexate and NSAIDs are given within 24 hours of each other. The interaction is mediated through accumulation of methotrexate resulting from impairment of renal excretion in the presence of the NSAID.
Ciclosporin: Cases of nephrotoxicity have been reported in patients receiving concomitant ciclosporin and NSAIDs. Plasma concentration of diclofenac is increased by ciclosporin (halve dose of diclofenac).
Mifepristone: NSAIDs should be avoided for at least 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Corticosteroids: Increased risk of gastro-intestinal ulceration or bleeding (See section 4.4 - Special warnings and precautions for use).
Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as, warfarin, phenindione, and heparins. Avoid concomitant use (See section 4.4 -Special warnings and precautions for use).
Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. 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.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Antidiabetic agents: Clinical studies have shown that Diclofenac can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects therefore caution and adequate monitoring are advised.
Sulphonylureas: NSAIDs possibly enhance effects of sulphonylureas.
Antiepileptics: Effect of phenytoin is possibly enhanced by NSAIDs, like diclofenac.
Zidovudine: There is 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
Pregnancy:
Diclofenac Sodium should not be administered during pregnancy unless considered essential, in which case the lowest effective dosage should be used. 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 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 to the patient outweighs the potential risk to the foetus.
Lactation
In the 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
Dizziness, drowsiness, fatigue, visual disturbances or headaches are possible undesirable effects after taking NSAIDs. If affected, patients should not drive or operate machinery.
4.8 Undesirable effects
Diclofenac should be withdrawn if serious side effects occur.
Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, nmay occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain or cramps, epigastric distress, anorexia, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (See section 4.4 - Special warnings and precautions for use) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.
Hypersensitivity: Hypersensitivty reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritis, urticaria, purpura, angio-oedema, eczema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).
Cardiovascular and cerebrovascular: Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (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) (see section 4.4). Palpitations and chest pain have been reported.
Other adverse events reported less commonly include:
Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, haematuria, proteinuria, renal papillary necrosis and renal failure.
Hepatic: Abnormal liver function, hepatitis, jaundice and elevation of serum aminotransferase enzymes (ALT, AST).
Neurological and special senses: Visual disturbances, optic neuritis, diplopia, memory disturbances, paraesthesia, headaches, hearing impairment, 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, anxiety, nightmares, tremor, psychotic reactions, taste alteration disorders, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue, drowsiness, insomnia, nervousness, irritability and convulsions.
Haematological: Thrombocytopenia, leucopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.
Dermatological: Bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported very rarely. Photosensitivity, disturbances of sensation and loss of hair.
4.9 Overdose
Symptoms
Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, or occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage is also possible.
Therapeutic measures
Patients should be treated symptomatically as required. Within one hour of ingestion of potentially toxic amount, activated charcoal may be given. 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. Correction of severe electrolyte abnormalities may need to be considered. 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. Other measures may be indicated by the patients’s clinical condition.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Diclofenac Sodium is a non-steroidal agent with marked analgesic/anti-inflammatory and antipyretic properties. Like most other drugs in this class, it is an inhibitor of prostaglandin synthetase.
There is limited clinical trial experience of the use of diclofenac in JRA/JIA paediatric patients. In a randomised, double-blind, 2-week, parallel group study in children aged 3-15 years with JRA/JIA, the efficacy and safety of daily 2-3 mg/kg BW diclofenac was compared with acetylsalicylic acid (ASS, 50-100 mg/kg BW/d) and placebo - 15 patients in each group. In the global evaluation, 11 of 15 diclofenac patients, 6 of 12 aspirin and 4 of 15 placebo patients showed improvement with the difference being statistically significant (p < 0.05). The number of tender joints decreased with diclofenac and ASS but increased with placebo. In a second randomised, double-blind, 6-week, parallel group study in children aged 4-15 years with JRA/JIA, the efficacy of diclofenac (daily dose 2-3 mg/kg BW, n=22) was comparable with that of indomethacin (daily dose 2-3 mg/kg BW, n=23).
5.2 Pharmacokinetic properties
Diclofenac is absorbed from the gastro-intestinal tract. Peak plasma concentrations occur about 2 hours after ingestion of enteric-coated tablets. At therapeutic concentrations it is more than 99% bound to plasma proteins. It is metabolised and excreted mainly in the urine. Small amounts are excreted in the bile.
5.3 Preclinical safety data
Diclofenac Sodium was considered to be unsafe in patients with acute porphyria because it has been shown to be porphyrinogenic in animals or in-vitro systems.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Anhydrous Lactose Microcrystalline Cellulose Maize Starch Magnesium Stearate Colloidal Anhydrous Silica
Coating:
Cellulose Acetate Phthalate Macrogol 6000 Castor Oil
Hydroxypropylcellulose Titanium Dioxide E171 Sunset Yellow E110
6.2 Incompatibilities
Not Applicable
6.3 Shelf life
Polypropylene containers: 36 months Blister packs: 24 months
6.4 Special precautions for storage
Polypropylene containers: Do not store above 25°C. Keep the container tightly closed.
Blister packs: Do not store above 25°C. Store in the original package.
6.5 Nature and contents of container
Polypropylene tamper evident containers.
Pack sizes: 14, 15, 21, 28, 42, 56, 70, 84, &100 tablets.
PVC/Aluminium foil blister packs.
Pack sizes: 14, 15, 21, 28, 42, 56, 70, 84 & 100 tablets.
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
Chelonia Healthcare Limited 11 Boumpoulinas Street,
3rd Floor, 1060 Nicosia Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 33414/0143
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20/03/2009
10 DATE OF REVISION OF THE TEXT
05/12/2014