Source: Υπουργείο Υγείας (CY) Revision Year: 2014 Publisher: HEXAL AG, Industriestraße 25, D-83607 Holzkirchen, Telephone: +49 (0) 80 24 / 908-0, Telefax: +49 (0) 80 24 / 908-1290, e-mail: service@hexal.de <u>Distributor in Cyprus:</u> P.T.Hadjigeorgiou Co Ltd, ...
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, have 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 If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the medicinal product should be withdrawn.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 and in the elderly.
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) 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 section 4.8 Undesirable effects).
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.
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 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. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
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 section 4.3 Contraindications). Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation of therapy is usually followed by recovery to the pre-treatment state.
Treatment with NSAIDs including diclofenac, particularly at high dose and in long term, may be associated with a small increased risk of serious cardiovascular thrombotic events (including myocardial infarction and 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.
Use of Diclac 50 HEXAL 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.
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.
The concomitant use of diclofenac with systemic NSAIDs including cyclooxygenase-2 selective inhibitors, should be avoided due to undesirable effects (see section 4.5 Interaction with other medicinal products and other forms of interaction).
Like other NSAIDs, diclofenac may mask the signs and symptoms of infection due to its pharmacodynamic properties.
The following interactions include those observed with diclofenac gastro-resistant tablets [oral form] [suppositories] and/or other pharmaceutical forms of diclofenac.
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.
If used concomitantly, diclofenac may raise plasma concentrations of lithium. Monitoring of the serum lithium level is recommended.
If used concomitantly, diclofenac may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.
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 Special warnings and precautions for use).
Diclofenac, like otherNSAIDs, may increase the nephrotoxicity of ciclosporin due to the effect on renal prostaglandins. Therefore, it should be given at doses lower than those that would be used in patients not receiving ciclosporin.
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).
There have been isolated reports of convulsions which may have been due to concomitant use of quinolones and NSAIDs.
Concomitant administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal undesirable effects (see section 4.4 Special warnings and precautions for use).
Caution is recommended since concomitant administration could increase the risk of bleeding (see section 4.4 Special warnings and precautions for use). Although clinical investigations do not appear to indicate that diclofenac affects the action of anticoagulants, there are isolated reports of an increased risk of haemorrhage in patients receiving diclofenac and anticoagulants concomitantly. Close monitoring of such patients is therefore recommended.
Concomitant administration of systemic NSAIDs, including diclofenac, and SSRIs may increase the risk of gastrointestinal bleeding (see section 4.4 Special warnings and precautions for use).
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 both 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.
When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
Caution is recommended when NSAIDs, including diclofenac, are administered less than 24 hours before or after treatment with methotrexate, since blood concentrations of methotrexate may rise and the toxicity of this substance be increased.
There are insufficient data on the use of diclofenac in pregnant women . Therefore, diclofenac should not be used during the first two trimesters of pregnancy unless the expected benefits to the mother outweigh the risk to the foetus. As with other NSAIDs, use of diclofenac during the third trimester of pregnancy is contraindicated owing to the possibility of uterine inertia and/or premature closure of the ductus arteriosus (see section 4.3 Contraindications and section 5.3 Preclinical safety data).
Like other NSAIDs diclofenac passes into the breast milk in small amounts. Therefore, diclofenac should not be administered during breast feeding in order to avoid undesirable effects in the infant.
As with other NSAIDs, 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 infertility, withdrawal of diclofenac should be considered.
Not applicable.
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 for Contraindications and Special warnings and special precautions for use).
Adverse drug reactions from clinical trials and/or spontaneous or literature cases (Table 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 reactionsfirst. 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 onthe following convention (CIOMS III): very common (>1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000).
Table 1. Adverse drug reactions:
| Blood and lymphatic system disorders | |
| Very rare: | Thrombocytopenia, leukopenia, 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 |
| Very rare: | Paraesthesia, memory impairment, convulsion, anxiety, tremor, meningitis aseptic, dysfagia, cerebrovascular accident |
| Eye disorders | |
| Very rare: | Visual impairment, vision blurred, diplopia |
| 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, vasculitis |
| Respiratory, thoracic and mediastinal disorders | |
| Rare: | Asthma (including dyspnoea) |
| Very rare: | Pneumonitis |
| Gastrointestinal disorders | |
| Common: | Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, decreased appetite |
| Rare: | Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer (with or without bleeding or perforation) [Diclofenac containing medicinal products for rectal use additionally:] proctitis |
| Very rare: | Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, oesophageal disorder, intestinal diaphragm disease, pancreatitis [Diclofenac containing medicinal products for rectal use additionally:] haemorrhoids aggravated |
| Hepatobiliary disorders | |
| Common: | Transaminases increased |
| Rare: | Hepatitis, jaundice, liver disorder |
| Very rare: | Hepatitis fulminant, hepatic necrosis, hepatic failure |
| Skin and subcutaneous tissue disorders | |
| Common: | Rash |
| Rare: | Urticaria |
| Very rare: | Dermatitis bullous, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), dermatitis exfoliative, alopecia, photosensitivity reaction, purpura, Henoch-Schonlein purpura, pruritus |
| Renal and urinary disorders | |
| Very rare: | Renal failure acute, haematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis |
| General disorders and administration site conditions | |
| Common: | Injection site reaction, injection site pain, injection site induration (Applicable only for Diclofenac solution for injection) Application site irritation. (Applicable only for Diclofenac suppositories) |
| Rare: | Oedema Injection site necrosis. (Applicable only for Diclofenac solution for injection) |
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 4.4).
None known to date.
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