CATAFLAM Sugar coated tablet Ref.[28178] Active ingredients: Diclofenac

Warnings

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).

The use of Cataflam with concomitant 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).

Caution is indicated in the elderly on basic grounds especially used in frail elderly patients or those with a low body weight.

General

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac without earlier exposure to the drug. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myoardial infraction. Presenting symptoms of such reactions can include chest pain occurring in association with an allergic reaction to diclofenac.

Gastrointestinal effects

Gastrointestinal bleeding (haematemesis, melaena) ulceration or perforation which can be fatal has been reported with all NSAIDs including diclofenal 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 If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be withdrawn.

As with all NSAIDs, including diclofenac close medical surveillance is imperative and particular caution should be excised 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).The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses including diclofenac, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation.

NSAIDs, including diclofenac, may be associated with increased risk of gastro-intestinal anastomotic leak. Close medical surveillance and caution are recommended when using diclofenac after gastro-intestinal surgery.

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

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).

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

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).

Close medical surveillance and caution should be exercised in patients with ulcerative colitis, or with Crohn’s disease as these conditions may be exacerbated (see section 4.8).

Hepatic effects

Close medical surveillance is required when prescribing Cataflam to patients with impaired hepatic function, as their condition may be exacerbated.

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

If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), Cataflam should be discontinued.

Hepatitis may occur with use of diclofenac without prodromal symptoms.

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

Renal effects

As fluid retention and oedema have been reported in association with NSAID 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 in those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery (see section 4.3). Monitoring of renal function is recommended as a precautionary measure when using Cataflam in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.

Use of Cataflam in patients with hepatic porphyria may trigger an attack.

Haematological: Cataflam may reversibly inhibit platelet aggregation (see anticoagulants in section 4.5). Patients with defects of haemostasis, bleeding diathesis or haematological abnormalities should be carefully monitored.

Long term treatment: All patients who are receiving nonsteroidal 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.

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 edema 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 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, including diclofenac.

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 serious cardiovascular thrombotic events (for example myocardial infarction or stroke). To minimize the potential risk of an adverse cardiovascular event in patients taking a NSAID, especially in those with cardiovascular risk factors, the lowest effective dose should be used for the shortest possible duration.

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration.

As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically.

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).

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 he use of NSAIDs, including Cataflam (see section 4.8). 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. Cataflam should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity. Female fertility: The use of Cataflam 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 Cataflam should be considered.

Masking signs of infections

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

The following interactions include those observed with Cataflam sugar coated tablets and/or other pharmaceutical forms of diclofenac.

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

CYP2C9 inducers: Caution is recommended when co-prescribing diclofenac with CYP2C9 inducers (such as rifampicin), which could result in a significant decrease in plasma concentration and exposure to diclofenac.

Lithium: If used concomitantly, diclofenac may raise plasma concentrations of lithium. Monitoring of the lithium level is recommended.

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

Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of diclofenac with diuretics or antihypertensive agents (e.g. beta-blockers, angiotensin converting enzyme (ACE) inhibitors) may cause a decrease in their antihypertensive effect. 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, and periodically thereafter, particularly for diuretics and ACE inhibitors due to the increased risk of nephrotoxicity. (see section 4.4)

Anticoagulants: Although clinical investigations do not appear to indicate that Cataflam has an influence on the effect of anticoagulants, there are reports of an increased risk of haemorrhage with the combined use of diclofenac and anticoagulant therapy (see section 4.4). Therefore, to be certain that no change in anticoagulant dosage is required, close monitoring of such patients is required. As with other nonsteroidal anti-inflammatory agents, diclofenac in a high dose can reversibly inhibit platelet aggregation.

Antidiabetics: Clinical studies have shown that Cataflam can be given together with oral antidiabetic agents without influencing their clinical effect. However there have been isolated reports of hypoglycaemic and hyperglycaemic effects necessitating changes in the dosage of the antidiabetic agents during treatment with diclofenac. For this reason, monitoring of the blood glucose level is recommended as a precautionary measure during concomitant therapy.

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.

Quinolone antibacterials: There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIs.

Other NSAIDS including cylcooxygenase-2 selective inhibitors and corticosteroids: Co-administration of Cataflam 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).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).

Diuretics: Like other NSAIDS, Cataflam may inhibit the activity of diuretics. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently.

Cardiac glycosides: Concomitant use of cardiac glycosides and NSAIDs in patients may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

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

Antihypertensives: Concomitant use of NSAIDs with antihypertensive drugs (i.e. beta-blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics) may cause a decrease in their antihypertensive effect via inhibition of vasodilatory prostaglandin synthesis.

Ciclosporin: Diclofenac, like other NSAIDs may increase the nephrotoxicity of ciclosporin due to effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin.

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

Pregnancy

Some epidemiological studies suggest an increased risk of miscarriage after use of a prostaglandin synthesis inhibitor (such as NSAIDs) in early pregnancy, however the overall data are inconclusive. Congenital abnormalities have been reported in association with the administration of NSAIDs 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 (e.g. a premature closure of the ductus arteriosus) and in causing uterine inertia, 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). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit outweighs the potential risk to foetus. The lowest effective dose should be used and duration kept as short as possible.

Lactation

Following doses of 50mg enteric coated tablets every 8 hours, traces of active substance have been detected in breast milk, but in quantities so small that no adverse effects on the breast fed infant are to be expected.

NSAIDs should if possible be avoided when breastfeeding.

See section 4.4, regarding female fertility.

Patients who experience dizziness, drowsiness, fatigue or visual disturbances, while taking NSAIDs should refrain from driving or operating machinery.

Adverse drug reactions from clinical trials and/or spontaneous or literature reports (Table 7-1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (>1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

The following undesirable effects include those reported with Cataflam sugar coated tablets and/or other pharmaceutical forms of diclofenac, with either short-term or long-term use.

Table 1. Adverse drug reactions:

^* The frequency reflects data from long-term treatment with a high dose (150 mg/day)

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 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, tel: +357 22 608679, fax: +357 22 608 649.

None.