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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Enstar XL 100mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100 mg of the active substance Diclofenac sodium.

For excipients, see Section 6.1

3    PHARMACEUTICAL FORM

White to off white, Circular, biconvex tablets with D4 embossed on one side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

In the management of chronic conditions, such as rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.

4.2.    Posology and method of administration

For oral administration.

Adults: One tablet once daily, taken whole with liquid, preferably at meal times.

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: Diclofenac sodium is not recommended for use in children as dosage recommendations and indications for use in this group of patients have not been established.

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 Special Warnings and Precautions for use).

4.3. Contraindications

Hypersensitivity to any of the constituents.

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. Asthma, rhinitis, angiodema 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 warnings and precautions for use).

During the last trimester of pregnancy (see section 4.6 - Pregnancy and lactation).

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

Active, gastric or intestinal ulcer, bleeding or perforation.

History of upper gastrointestinal bleeding or perforation, related to previous NSAID’s therapy.

Use with concomitant NSAIDs including cyclooxygenase 2 specific inhibitors (see section 4.5 - Interactions).

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

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).

Elderly:

Caution is indicated in the elderly on basic medical grounds. In particular, it is recommended that the lowest effective dose be used in frail elderly patients or those with a low body weight (see section 4.2 - Posology and Method of administration).

Haematemesis and melaena have in general more serious consequences in the elderly. They can occur at any time during treatment with or without warning symptoms or a previous history.

The concomitant use of Enstar XL 100mg Tablets with systemic NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided due to the absence of any evidence demonstrating synergistic benefits and the potential for additive undesirable effects (see section 4.5 - Interactions with other medicaments and other forms of interaction).

As with other nonsteroidal anti-inflammatory drugs including diclofenac, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug (see section 4.8 Undesirable effects).

Like other NSAIDs, diclofenac may mask the signs and symptoms of the infection due to its pharmacodynamic properties.

Enstar XL 100mg Tablets contain lactose and therefore are not recommended for patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Pre-existing asthma:

In patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions on NSAIDs like asthma exacerbations (so called intolerance to analgesics / analgesics asthma), Quincke's oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is applicable as well for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

Like other drugs that inhibit prostaglandin synthetase activity, diclofenac sodium and other NSAIDs can precipitate bronchospasm if administered to patients suffering from, or with a previous history of bronchial asthma.

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 dose should be used. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically.

Hepatic effects:

Close medical surveillance is required when prescribing Enstar XL 100mg Tablets to patients with impairment of hepatic function as their condition may be exacerbated.

As with other NSAIDs, including diclofenac, values of one or more liver enzymes may increase. During prolonged treatment with diclofenac, regular monitoring of hepatic function is indicated as a precautionary measure.

If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Enstar XL 100mg Tablets should be discontinued.

Hepatitis may occur with diclofenac without prodromal symptoms.

Caution is called for when using diclofenac in patients with hepatic porphyria, since it may trigger an attack.

Renal effects:

As fluid retention and oedema have been reported in association with NSAIDs therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function, and those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3- Contraindications). Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation therapy is usually followed by recovery to the pretreatment state.

Gastro-intestinal bleeding, ulceration and perforation:

GI bleeding (haematemesis, melaena), ulceration or perforation, which can be fatal, has been reported with all NSAIDs including diclofenac and may occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be withdrawn.

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

As with all NSAIDs, including diclofenac close medical surveillance is imperative and particular caution should be exercised when prescribing diclofenac in patients with symptoms indicative of gastrointestinal disorders, or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation (see section 4.8 - Undesirable effects). The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses including diclofenac, and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation.

The elderly have increased frequency of adverse reactions to NSAIDs especially gastro intestinal bleeding and perforation which may be fatal (see section 4.2- Posology and method of administration).

To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained at the lowest effective dose.

Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low dose acetylsalicylic acid (ASA/aspirin or medicinal products likely to increase gastrointestinal risk. (See section 4.5 - Interactions with other medicaments and other forms of interaction).

Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as acetylsalicylic acid (see section 4.5- Interaction with other medicaments and other forms of interaction).

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).

Skin effects:

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, including diclofenac (see section 4.8 - Undesirable effects). Patients appear to be at the highest risk of 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. Enstar

XL 100mg Tablets should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.

Haematological effects:

During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.

Enstar XL 100mg Tablets may reversibly inhibit platelet aggregation (see anticoagulants in section 4.5 - Interaction with other medicaments and other forms of interactions). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

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 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 fertility, withdrawal of diclofenac should be considered.

Hypersensitivity reactions:

As with other nonsteroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.

Long-term treatment:

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.

4.5 Interaction with other medicinal products and other forms of interaction

Other NSAIDs including cyclooxygenase-2 selective inhibitors and corticosteroids: Co-administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the risk of gastrointestinal bleeding or ulceration. Avoid concomitant use of two or more NSAIDs (see section 4.4 Special warnings and precautions for use).

Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of Diclofenac with diuretics and antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.

Therefore, the combination should be administered with caution and patients, especially the elderly, should have their blood pressure periodically monitored. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity.

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

Lithium: If used concomitantly, Diclofenac may increase plasma concentrations of lithium Monitoring of the serum lithium level is recommended.

Digoxin: If used concomitantly, Diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.

Methotrexate: Diclofenac can inhibit the tubular renal clearance of methotrexate hereby increasing methotrexate levels. Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increase. Cases of serious toxicity have been reported when methotrexate and NSAIDs including diclofenac 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

Ciclosporin: Increased risk of nephrotoxicity. Cases of nephrotoxicity have been reported in patients receiving concomitant ciclosporin and NSAIDS, including diclofenac. This might be mediated through combined renal antiprostaglandin effects of both the NSAIDS and ciclosporin.

Mifepristone: NSAIDs should not be used 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteroids: Increased risk of GI bleeding (See section 4.4 - Special warnings and precautions for use).

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See section 4.4 - -Special warnings and precautions for use). Although clinical investigations do not appear to indicate that diclofenac has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage with the combined use of diclofenac and anticoagulant therapy. Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other non-steroidal anti-inflammatory agents, diclofenac in high doses can reversibly inhibit platelet aggregation.

Quinolone antibiotics: Animal studies indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics, 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.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. This might be mediated through renal antiprostagladin effects of both NSAID and calcineurin inhibitor.

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 which have required adjustment to the dosage of hypoglycaemic agents. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

Drugs known to cause hyperkalemia: Concomitant treatment with potassium-sparing diuretics, ciclosporin, tacrolimus or trimethoprim may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4 Special warnings and precautions for use).

Selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of SSRI's may increase the risk of gastrointestinal bleeding (see section 4.4 Special warnings and precautions for use).

Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.

Colestipol and cholestyramine: These agents can induce a delay or decrease in absorption of diclofenac. Therefore, it is recommended to administer diclofenac at least one hour before or 4 to 6 hours after administration of colestipol/ cholestyramine.

Potent CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.

4.6 Pregnancy and lactation

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and or cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1% up to approximately 1.5%.

The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has shown to result in increased pre-and post-implantation loss and embryo-foetal lethality.

In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during organogenetic period. If Diclofenac is used by a woman attempting to conceive, or during the 1st trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

-    cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)

-    renal dysfunction, which may progress to renal failure with oligo-hydroamniosis

The mother and the neonate, at the end of the pregnancy, to:

-    possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses

-    inhibition of uterine contractions resulting in delayed or prolonged labour

Consequently, Diclofenac is contraindicated during the third trimester of pregnancy.

Lactation

Like other NSAIDs, diclofenac passes into breast milk in small amounts. Therefore Diclofenac should not be administered during breast feeding in

order to avoid undesirable effects in the infant (see section 5.2 Pharmacokinetic properties).

Female fertility

As with other NSAIDs, the use of diclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who may have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of diclofenac should be considered. See also section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects on ability to drive and use machines

Patients who experience visual disturbances, dizziness, vertigo, somnolence, central nervous system disturbances, drowsiness or fatigue while taking NSAIDs should refrain from driving or operating machinery 4.8. Undesirable effects

Adverse reactions are ranked under the heading of frequency, the most frequent first, using the following convention: very common: (>1/10); common (> 1/100, <1/10); uncommon (> 1/1,000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000); not known: cannot be estimated from available data.

The following undesirable effects include those reported with other short-term or

long-term use.
Table 1
Blood and lymphatic system disorders
Very rare	Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.
Immune system disorders
Rare	Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).
Very rare	Angioneurotic oedema (including face oedema).
Psychiatric disorders
Very rare	Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
Nervous system disorders
Common	Headache, dizziness.

Rare	Somnolence, tiredness.
Very rare	Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident.
Unknown	Confusion, hallucinations, disturbances of sensation, malaise.
Eye disorders
Very rare	Visual disturbance, vision blurred, diplopia.
Unknown	Optic neuritis.
Ear and labyrinth disorders
Common	Vertigo.
Very rare	Tinnitus, hearing impaired.
Cardiac disorders
Very rare	Palpitations, chest pain, cardiac failure, myocardial infarction.
Vascular disorders
Very rare	Hypertension, hypotension, vasculitis.
Respiratory, thoracic and mediastinal disorders
Rare	Asthma (including dyspnoea).
Very rare	Pneumonitis.
Gastrointestinal disorders
Common	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.
Rare	Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer with or without bleeding or perforation (sometimes fatal particularly in the elderly).
Very rare	Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures,

	pancreatitis.
Hepatobiliary disorders
Common	Transaminases increased.
Rare	Hepatitis, jaundice, liver disorder.
Very rare	Fulminant hepatitis, hepatic necrosis, hepatic failure.
Skin and subcutaneous tissue disorders
Common	Rash.
Rare	Urticaria.
Very rare	Bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), dermatitis exfoliative, loss of hair, photosensitivity reaction, purpura, allergic purpura, pruritus.
Renal and urinary disorders
Very rare	Acute renal failure, haematuria, proteinuria, nephrotic syndrome, interstitial nephritis, renal papillary necrosis.
General disorders and administration site conditions
Rare	Oedema
Reproductive system and breast disorders
Very rare	Impotence.

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 (150mg daily) and in long term treatment. (see section 4.3 for Contraindications and 4.4 Special warnings and special precautions for use).

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 fro 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

Diclofenac is a non-steroidal agent with marked analgesic/anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase). Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

5.2 Pharmacokinetics properties

Absorption

The same amount of active substance is released and absorbed from SR 75mg and XL 100mg tablets as from enteric-coated tablets. Mean peak plasma concentrations of diclofenac are reached at 4 hours, 0.508 ± 0.185pg/ml (0.5pg/mL =1.6pmol/L) or 0.4 ± 0.184pg/ml (0.4pg/mL =1.25pmol/L) after XL 100mg or 75mg SR, respectively. 75mg SR and XL 100mg are modified release preparations and plasma concentrations of diclofenac of 13ng/mL (40nmol/L) can be recorded at 24 hours (XL 100mg) and 16 hours (75mg SR) after administration. Absorption is unaffected by food.

Bioavailability:

The systemic availability of diclofenac from the SR formulations is on average 82% of that achieved with the same dose of enteric-coated tablets (possibly due to release rate dependent first-pass metabolism). As a result of the slower release of active substance, peak plasma concentrations are lower than for the equivalent enteric-coated tablets.

Pharmacokinetic behaviour does not change on repeated administration. Accumulation does not occur, provided the recommended dosage intervals are observed. Trough levels of diclofenac in the plasma after XL 100mg daily or 75mg SR twice daily are around 22ng/ml or 25ng/ml (70nmol/l or 80nmol/l), respectively.

Distribution

The active substance is 99.7% protein bound, mainly to albumin (99.4%).

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 the 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 was detected in a low concentration (100 ng/mL) in breast milk in one nursing mother. The estimated amount ingested by an infant consuming breast milk is equivalent to a 0.03 mg/kg/day dose (see section 4.6 Pregnancy and lactation).

Metabolism

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, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much 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.

About 60% of the administered dose is excreted in the urine in the form of the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.

Characteristics in patients

Elderly: No relevant age-dependent differences in the drug's absorption, metabolism, or excretion have been observed, other than the finding that in five elderly patients, a 15 minute iv infusion resulted in 50% higher plasma concentrations than expected with young healthy subjects.

Patients with renal impairment: 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 less than 10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.

Patients with hepatic disease: 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

Multiple dose studies were performed in rats, dogs and monkeys. At toxic doses there were gastro-intestinal ulcers and disorders in the blood picture in all species. Genetic toxicology studies with diclofenac sodium show that diclofenac is not a mutagen. Carcinogenicity studies have been conducted in mice and rats. No carcinogenic effect has been seen.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose

Magnesium stearate

Hydrogenated vegetable oil Type I (Sterotex)

Povidone K30

Talc

6.2 Incompatibilities

None known.

6.3 Shelf life

2 years.

10 DATE OF REVISION OF THE TEXT

18/06/2014