Diclofenac Potassium 12.5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Diclofenac potassium 12.5mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Tablet contains and 12.5 mg of Diclofenac potassium..
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film coated Tablet
White round, unscored biconvex film coated tablet, 5mm diameter, with 'I' marked on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Diclofenac potassium tablets are indicated for:
- Rheumatoid arthritis
- Osteoarthrosis
- Low back pain
- Migraine attacks
- Acute musculo-skeletal disorders and trauma such as periarthritis (especially frozen shoulder), tendinitis, tenosynovitis, bursitis, sprains, strains and dislocations; relief of pain in fractures
- Ankylosing spondylitis
- Acute gout
- Control of pain and inflammation in orthopaedic, dental and other minor surgery
- Pyrophosphate arthropathy and associated disorders
4.2 Posology and method of administration
For oral administration.
To be taken preferably with or after food.
The tablets should be swallowed whole with liquid
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4)
Adults
The recommended daily dose is 100-150mg in two or three divided doses. For milder cases, 75-100 mg daily in two or three divided doses is usually sufficient. In migraine an initial dose of 50 mg should be taken at the first signs of an impending attack. In cases where relief 2 hours after the first dose is not sufficient, a further dose of 50 mg may be taken. If needed, further doses of 50 mg may be taken at intervals of 4-6 hours, not exceeding a total dose of 200 mg per day.
Children
For children over 14 years of age, the recommended daily dose is 75-100 mg in two or three divided doses. Diclofenac potassium tablets are not recommended for children under 14 years of age.
The use of Diclofenac potassium in migraine attacks has not been established in children.
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 or 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, or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.
• 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.
This product contains soya. If you are allergic to peanut or soya, do not use this medicinal product.
4.4 Special warnings and precautions for use Warnings
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 Diclofenac 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)
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 NSAlD 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).
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 increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as aspirin (see section 4.5).
When GI bleeding or ulceration occurs in patients receiving diclofenac potassium, the treatment should be withdrawn.
NSAlDs 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).
Hepatic:
Close medical surveillance is imperative in patients suffering from severe impairment of hepatic function.
Hypersensitivity reactions:
As with other non-steroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur without earlier exposure to the drug.
Like other NSAIDs, Diclofenac Potassium may mask the signs and symptoms of infection due to its pharmacodynamic properties.
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 ).
Precautions
Cardiovascular, Renal and Hepatic Impairment:
The administration of an NSAlD 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).
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), Diclofenac Potassium should be discontinued. Hepatitis may occur without prodromal symptoms.
Use of Diclofenac Potassium in patients with hepatic porphyria may trigger an attack.
Haematological:
Diclofenac Potassium may reversibly inhibit platelet aggregation (see “Interactions”). Patients with defects of haemostasis should be carefully monitored.
Long term treatment:
All patients who are receiving long term treatment with non-steroidal, antiinflammatory agents should be monitored as a precautionary measure e.g. renal function, hepatic function (elevation of liver enzymes may occur) and blood counts.
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 (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 uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should 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, hyperlipideamia, diabetes mellitus, smoking)
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 NSAlDs (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 potassium should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Impaired female fertility:
The use of Diclofenac potassium 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 potassium should be considered.
4.5 Interaction with other medicinal products and other forms of interaction
Other analgesics including cyclooxygenase-2 selective inhibitors'. Avoid concomitant use of two or more NSAlDs (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.
Cardiac glycosides: NSAlDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Lithium: Decreased elimination of lithium
Methotrexate: Decreased elimination of methotrexate.
Ciclosporin: lncreased risk of nephrotoxicity.
Mifepristone: NSAlDs should not be used for 8-12 days after mifepristone administration as NSAlDs can reduce the effect of mifepristone.
Corticosteroids: lncreased risk of gastrointestinal ulceration or bleeding (see section 4.4).
Anti-coagulants: NSAlDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4).
Quinolone antibiotics: Animal data indicate that NSAlDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAlDs and quinolones may have an increased risk of developing convulsions.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRls): lncreased risk of gastrointestinal bleeding (see section 4.4).
Tacrolimus: Possible increased risk of nephrotoxicity when NSAlDs are given with tacrolimus.
Zidovudine: lncreased risk of haematological toxicity when NSAlDs 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.
Antidiabetic agents: Clinical studies have shown that Diclofenac Potassium 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.
4.6 Fertility, Pregnancy and lactation
Pregnancy:
Congenital abnormalities have been reported in association with NS AID 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 NSAlDs 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). NSAlDs 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 limited studies so far available, NSAlDs can appear in breast milk in very low concentrations. NSAlDs 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 and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
4.8 Undesirable effects
If serious side-effects occur, Diclofenac Potassium should be withdrawn.
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)
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, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative 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.
Hypersensitivity: Hypersensitivity 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, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).
Other adverse reactions reported less commonly include:
Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephritic syndrome and renal failure.
Hepatic: abnormal liver function, hepatitis and jaundice.
Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing autoimmune 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 and drowsiness.
Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.
Dermatological: Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity.
Cardiovascular system: In isolated cases, palpitations, chest pain, hypertension, congestive heart failure.
Other organ systems: Impotence (very rare).
4.9 Overdose
a) Symptoms
Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible
b) Therapeutic measure
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. Other measures may be indicated by the patient's clinical condition.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: NSAID, ATC code: {M01 AB 05}
Diclofenac potassium tablets contain the potassium salt of diclofenac, a nonsteroidal compound with pronounced and clinically demonstrable analgesic, anti-inflammatory and anti-pyretic properties.
Diclofenac is a potent inhibitor of prostaglandin bio-synthesis and modulator of arachidonic acid release and uptake.
Diclofenac potassium tablets have a rapid onset of action and are, therefore, suitable for the treatment of acute episodes of pain and inflammation.
In migraine attacks Diclofenac potassium has been shown to be effective in relieving the headache and in improving the accompanying symptom of nausea.
Diclofenac in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.
5.2 Pharmacokinetic properties
Absorption
Diclofenac is rapidly and completely absorbed from sugar-coated tablets. Food intake does not affect absorption.
Peak plasma concentration after one 12.5 mg tablet was 0.944 pmol/l after 54 minutes. The plasma concentrations show a linear relationship to the size of the dose.
Diclofenac undergoes first-pass metabolism and is extensively metabolised. Distribution
Diclofenac is highly bound to plasma proteins (99.7%), chiefly albumin (99.4%)
Elimination
The total systemic clearance of diclofenac in plasma is 263 ± 56 ml/min (mean ± SD).
The terminal half-life in plasma is 1-2 hours.
Repeated oral administration of Diclofenac Potassium for 8 days in daily doses of 50 mg t i d does not lead to accumulation of diclofenac in the plasma.
Approx. 60% of the dose administered is excreted in the urine in the form of metabolites, and less than 1% as unchanged substance. The remainder of the dose is eliminated as metabolites through the bile in the faeces.
Biotransformation
The biotransformation of diclofenac involves partly glucuronidation of the intact molecule but mainly single and multiple hydroxylation followed by glucuronidation.
Characteristics in patients
The age of the patient has no influence on the absorption, metabolism, or excretion of diclofenac.
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 theoretical steady-state plasma levels of metabolites are about four times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.
In the presence of impaired hepatic function (chronic hepatitis, non-decompensated cirrhosis) the kinetics and metabolism are the same as for patients without liver disease.
5.3 Preclinical safety data
Relevant information on the safety of Diclofenac potassium is included in other sections of the Summary of Product Characteristics.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Silica colloidal anhydrous Sodium starch glycollate Povidone Starch maize
Calcium hydrogen phosphate anhydrous Magnesium stearate
Film coating:
Polyvinyl alcohol partially hydrolysed
Titanium dioxide E171
Talc
Lecithin soya E322 Xanthan gum E415
6.2 Incompatibilities
A Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Do not store above 25 °C
6.5 Nature and contents of container
Blister pack. Pack sizes: 7, 10, 14, 28, 30, 50, 56, 98 and 100 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Aptil Pharma Limited
9th Floor, CP House
97-107 Uxbridge Road, Ealing
London
W5 5TL
MARKETING AUTHORISATION NUMBER(S)
PL 40378/0013
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DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/06/2007
DATE OF REVISION OF THE TEXT
26/05/2012
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