Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see 4.2, and GI and cardiovascular risks below).
The concomitant use of diclofenac 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.
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.
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur in rare cases with diclofenac without earlier exposure to the drug.
Like other NSAIDs, diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Gastrointestinal bleeding, 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 gastrointestinal events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the patient should be instructed to consult their doctor and the medicinal product should be withdrawn.
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 (GI) 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 is higher with increasing NSAID doses and in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation. The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.
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. proton pump inhibitors or misoprostol) should be considered for these patients, and also for patients requiring concomitant use of medicinal products containing low-dose acetylsalicylic acid [(ASA)/aspirin] or other medicinal products likely to increase gastrointestinal risk.
Patients with a history of GI toxicity, particularly the 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, anti-platelet agents or selective serotonin-reuptake inhibitors (see section 4.5 Interaction with other medicinal products and other forms of interaction).
Close medical surveillance and caution should also be exercised in patients with ulcerative colitis or Crohn's disease, as their condition may be exacerbated (see 4.8, Undesirable effects).
Close medical surveillance is required when prescribing diclofenac to patients with impaired 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, if clinical signs or symptoms consistent with liver disease develop, or if other manifestations occur (e.g. eosinophilia, rash), diclofenac should be discontinued. Hepatitis may occur with use of diclofenac without prodromal symptoms.
Caution is called for when using diclofenac in patients with hepatic porphyria, since it may trigger an attack.
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 4.3 Contraindications). Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases and in patients receiving long term treatment with diclofenac. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.
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, Undesirable effects). 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. Difene should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Cardiovascular and cerebrovascular effects
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.
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 doses, 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.
Use of diclofenac is recommended only for short term treatment. During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.
Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with defects of haemostasis should be carefully monitored.
Treatment with diclofenac is associated with several haematopoietic disorders, including thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), pancytopaenia, and agranulocytosis. Patients with unexplained haematopoietic disorders may be at increased risk of worsening of their condition and should be monitored.
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.
Patients with rare hereditary problems of fructose intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Diclofenac should only be given after careful evaluation of the risk/benefit ratio:
In congenital impairment of porphyrin metabolism (e.g. acute intermittent porphyria);
Taking NSAIDs at the same time as alcohol can potentiate the undesirable effects caused by the active substance, especially those affecting the gastrointestinal tract.