1. Name Of The Medicinal Product
Rhumalgan SR 75 mg Modified Release Capsules.
2. Qualitative And Quantitative Composition
Each capsule contains 75 mg diclofenac sodium.
For excipients, see 6.1.
3. Pharmaceutical Form
Modified release capsule for oral use.
White opaque hard capsules marked 'DIC75'.
4. Clinical Particulars
4.1 Therapeutic Indications
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: Rhumalgan SR 75mg Modified Release Capsules are not suitable for children.
4.2 Posology And Method Of Administration
For oral administration.
Rhumalgan SR 75 capsules should be swallowed whole and should be taken preferably with or after food.
Where the symptoms are most pronounced during the night or in the morning Rhumalgan SR 75 capsules should preferably be taken in the evening.
Adults:
The recommended initial daily dose is 75-150 mg, administered as Rhumalgan SR 75 mg once or twice daily. In milder cases, as well for long-term therapy, 75 mg daily is usually sufficient.
The maximum daily dosage is 150 mg.
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.
Children:
Rhumalgan SR 75 is not recommended for use in children.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4)
4.3 Contraindications
Hypersensitivity to any of the constituents.
Severe heart failure
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 hepatic, renal and cardiac failure (See section 4.4 - Special warning and precautions for use).
During the last trimester of pregnancy (See section 4.6 - Pregnancy and lactation).
Active or previous peptic ulcer.
History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Use with concomitant NSAIDs including cyclooxygenase 2 specific inhibitors (See section 4.5 - Interactions).
4.4 Special Warnings And Precautions For Use
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, and GI and cardiovascular risks below)
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.
Diclofenac sodium may mask the signs and symptoms of infection due to its pharmacodynamic properties.
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, 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, those recovering from major surgery and the elderly. Renal function should be monitored in these patients (See also section 4.3 – Contraindications).
Effects on renal function are usually reversible on withdrawal of Rhumalgan SR 75.
Occasionally, increases in serum transaminase levels, increases in serum bilirubin or other liver function parameters, as well as increases in serum creatinine and blood urea nitrogen have been reported. Should any of such abnormality prove significant or persistent, the administration of diclofenac sodium should be stopped and the patient should be carefully monitored.
Use of diclofenac sodium in patients with hepatic porphyria may trigger an attack.
If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash, etc.) diclofenac sodium treatment should be discontinued. Hepatitis may occur without prodromal symptoms. Close medical surveillance is imperative in patients suffering from severe impairment of hepatic function.
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.
Caution in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
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.
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 gastrotoxicity or bleeding, such as corticosteroids, or anticoagulants such as warfarin or anti-platelet agents such as aspirin (see section 4.5 - Interactions).
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).
Diclofenac sodium, like other NSAIDs, may reversibly inhibit platelet aggregation.
Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.
When GI bleeding or ulceration occurs in patients receiving Rhumalgan SR 75, the treatment should be withdrawn.
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).
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 Rhumalgan SR 75 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 Rhumalgan SR 75 should be considered.
Patients with rare hereditary problems of galactose or fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Care should be taken in patients treated with any of the following drugs as interactions have been reported in some patients.
Lithium: Decreased elimination of lithium
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Anti-hypertensives: Reduced anti-hypertensive effect.
Diuretics: Reduced diuretic effect (several NSAIDs may inhibit the therapeutic effect 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, which requires a regular analysis of this parameter.
Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See section 4.4 - Special warning and precautions for use). Like other NSAIDs, diclofenac may inhibit platelet aggregation. Monitoring is recommended to ensure the desired response to the anti-coagulant is maintained as there are rare reports of increased risk of haemorrhage with combined diclofenac and anticoagulant therapy.
Anti-diabetics: Clinical studies have shown that diclofenac can be given together with oral anti-diabetic agents without influencing their clinical effect. However, isolated cases have been reported of both hypoglycaemic and hyperglycaemic effects on concomitant use with diclofenac sodium, requiring changes in the dosage of hypoglycaemic agents.
Corticosteroids: Increased risk of GI bleeding (See section 4.4 – Special warning and precautions for use).
Other analgesics: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (See section 4.3 – Contraindications).
Methotrexate: Decreased elimination of 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.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Ciclosporin: Increased risk of nephrotoxicity due to combined decreased synthesis of prostacycline in the kidney. During combined therapy kidney function should be carefully monitored.
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.
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
4.6 Pregnancy And Lactation
Pregnancy:
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 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 warning 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
If serious side effects occur, Rhumalgan SR 75 should be withdrawn. Frequency estimate: very common: >10%, common: >1 -10%, rare: > 0.001 – 1%, isolated cases: <0.001%.
Gastrointestinal tract
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 Special warning and precautions for use) have been reported following administration. Less frequently, gastritis has been observed.
Common: Epigastric pain, other gastro-intestinal disorders (e.g. nausea, vomiting, diarrhoea, abdominal cramps, dyspepsia, flatulence, anorexia).
Rare: Gastro-intestinal bleeding, (haematemis, melaena, bloody diarrhoea), gastro-intestinal ulcers with or without bleeding or perforation.
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), pancreatitis, constipation.
Central Nervous System (Neurological and special senses)
Visual disturbances, optic neuritis, headaches, 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 and drowsiness.
Common: Headache, dizziness, or vertigo.
Rare: drowsiness, tiredness.
In isolated cases: Disturbances of sensation, paraesthesia, memory disturbance, disorientation, insomnia, irritability, convulsions, depression, anxiety, nightmares, tremor, psychotic reactions, aseptic meningitis.
Special Senses
Isolated cases: disturbances of vision (blurred vision, diplopia), impaired hearing, tinnitus, taste disturbances.
Dermatological
Photosensitivity
Common: 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.
Renal
Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.
Rare: Oedema
In isolated cases: Acute renal insufficiency, urinary abnormalities (e.g. haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, papillary necrosis.
Hepatic
Abnormal liver function, hepatitis and jaundice.
Common: Elevation of serum aminotransferase enzymes (ALT, AST).
Rare: Liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice.
Haematological
Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.
In isolated cases: Thrombocytopenia, leucopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.
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).
Rare: Hypersensitivity reactions (e.g. bronchospasm, anaphylactic/anaphylactoid systemic reactions including hypotension).
Isolated cases: Vasculitis, pneumonitis.
Cardiovascular system
Oedema has been reported in association with NSAID treatment.
Isolated cases: palpitations, chest pain, hypertension, congestive heart failure
Other Organ Systems:
Isolated Cases: Impotence
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).
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. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC: M01AB05
Rhumalgan SR 75 contains the prostaglandin synthetase inhibitor diclofenac sodium.
This is a phenylacetic acid derivative with anti-inflammatory, analgesic and antipyretic properties.
Inhibition of prostaglandin biosynthesis (demonstrated in experiments), is considered fundamental to its mechanism of action. Prostaglandins play a major role in causing inflammation, pain and fever.
In rheumatic diseases the anti-inflammatory and analgesic properties of diclofenac sodium elicit a clinical response, characterised by marked relief from signs and symptoms such as pain at rest, pain on movement, morning stiffness and swelling of the joints, as well as by an improvement in function.
5.2 Pharmacokinetic Properties
The summary pharmacokinetic parameters of Rhumalgan SR 75 modified release capsules in healthy volunteers are:
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Absorption:
Diclofenac sodium is rapidly absorbed from the gut and undergoes first-pass metabolism.
Rhumalgan SR 75 capsules give peak plasma concentrations after approximately 2.5 hours on an empty stomach and after approximately 6 hours after administration after a high fat meal (data obtained with 100mg capsules).
Food has no relevant clinical influence on the re-absorption and systemic availability of Rhumalgan capsules.
Distribution:
Diclofenac is bound to serum proteins at a rate of 99.7%, mainly to albumin (99.4%).
The apparent volume of distribution calculated is 0.12-0.17 l/kg.
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 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.
Diclofenac and its metabolites cross the placenta and traces of diclofenac have been found in the milk of lactating women.
Biotransformation
The 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 (3'-hydroxy-, 4'-hydroxy, 5'-hydroxy, 4',5'-dihydroxy-, 3'-hydroxy-4'-methoxy-diclofenac), most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, but to a 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. One metabolite, 3'-hydroxy-4'-methoxy-diclofenac has a much longer plasma half-life. However, this metabolite is virtually inactive.
About 60% of the administered dose is eliminated in the urine in the form of metabolites. Less than 1% is excreted as unchanged substance. The remainder of the dose is eliminated as metabolites through the bile in the faeces.
Bioavailability and repeat dose administration
Since about half the active substance is metabolised during its first passage through the liver ('first pass' effect), the bioavailability after oral ingestion is about 50 % of that observed after parenteral administration of an equal dosage.
Pharmacokinetic behaviour does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.
Characteristics in patients:
No relevant age-dependent differences in the drug absorption, metabolism or excretion have been observed.
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 hydroxy-metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.
In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.
5.3 Preclinical Safety Data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Capsule contents
Sugar spheres (sucrose, maize starch)
Macrogol 6000
Ammonia methacrylate copolymer Type A
Talc
Lactose monohydrate
Polysorbate 80
Capsule shell
Gelatin
Titanium dioxide (E171)
Printing ink
Shellac
Propylene glycol
Black iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
36 months, as packaged for sale.
6.4 Special Precautions For Storage
Store in the original package.
6.5 Nature And Contents Of Container
Blister strips made of Poliamide/Aluminium/PVC 25µm/45µm/60µm coupled with an aluminium lid 25µm in packs of 56 capsules.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
Sandoz Limited
37 Woolmer Way
Bordon
Hampshire
GU35 9QE
8. Marketing Authorisation Number(S)
PL 04416/0737
9. Date Of First Authorisation/Renewal Of The Authorisation
8 October 2004
10. Date Of Revision Of The Text
December 2008
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