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4.3 Contra-indications
· Hypersensitivity to the active substance or any of the excipients.
· Patients with aActive, or a history of, gastric or intestinal ointestinal ulcers, bleeding or perforation (two or more distinct episodes of proven ulceration or bleeding).
· History of gastrointestinal bleeding or perforation, relating to previous NSAID therapy
· Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)
· Last trimester of pregnancy (see section 4.6 Pregnancy and lactation)
· Severe hepatic, renal or cardiac failure (see section 4.4 Special warnings and precautions for use).
· Like other non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac is also contraindicated in Ppatients in whom attacks of who have previously shown hyper-sensitivity reactions (e.g. asthma, angioedema, urticaria or acute rhinitis) are precipitated by to ibuprofen, aspirin acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs.
· Severe hepatic, renal and heart failure (see section 4.4 Special warnings and precautions for use).
· During the last trimester of pregnancy (see section 4.6 Pregnancy and lactation).
· History of gastrointestinal bleeding or perforation, relating to previoustherapy.
· Proctitis
4.4 Special warnings and precautions for use
Warnings
In all patients:
General
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 Posology and method of administration and GI and cardiovascular risks below).
The concomitant use of Voltarol with concomitant 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).
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).
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.
Elderly:
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).
Gastrointestinal effects:
Gastrointestinal 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.
Gastrointestinal: 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 with ulcerative colitis, or with Crohn's disease as these conditions may be exacerbated (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).
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding).
Gastrointestinal bleeding or ulceration/perforation: haematemesis melaena ulceration or perforation which can be fatal has been reported with all NSAIDs, including diclofenac. They can occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. In the rare instances when gastrointestinal bleeding or ulceration occurs in patients receiving Voltarol, the drug should be withdrawn.
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 (see section 4.3 Contraindications), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, other drugs likely to increase gastrointestinal risk (see below and section 4.5 Interactions with other medicaments and other forms of interaction).
Caution is recommended should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral systemic corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors (SSRIs) or anti-platelet agents such as aspirin acetylsalicylic acid (see section 4.5 Interaction with other medicaments and other forms of interaction).
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 Undesirable effects).
Hepatic: Close medical surveillance is also imperative in patients suffering from impairment of hepatic function.
Hypersensitivity reactions: 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, Voltarol may mask the signs and symptoms of infection due to its pharmacodynamic properties.
Precautions
Hepatic effects:
Close medical surveillance is required when prescribing Voltarol 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), Voltarol 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 pre-treatment state.
Renal: Patients with renal, cardiac or hepatic impairment and the elderly should be kept under surveillance, since the use of NSAIDs, including diclofenac may result in deterioration of renal function. The lowest effective dose should be used and renal function monitored.
The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, those being treated with diuretics or recovering from major surgery. Effects on renal function are usually reversible on withdrawal of Voltarol.
Hepatic: If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Voltarol should be discontinued. Hepatitis may occur with diclofenac without prodromal symptoms.
Use of Voltarol in patients with hepatic porphyria may trigger an attack.
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 Voltarol (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. Voltarol should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.
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).
Haematological: Voltarol 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.
Longterm 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.
Respiratory disorders:
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, including diclofenac.
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, and smoking).
Haematological effects:
During prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended.
Voltarol 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).
Dermatological: 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 Voltarol (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. Voltarol should be discontinued at the first appearance of skin rash, mucosal lesions or any other signs of hypersensitivity.
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.
Female fertility:
The use of Voltarol 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 Voltarol should be considered (see section 4.6 Pregnancy and Lactation).
4.5 Interaction with other medicaments and other forms of interaction
The following interactions include those observed with diclofenac gastro-resistant tablets and/or other pharmaceutical forms of diclofenac.
Lithium and digoxin: If used concomitantly,Voltarol may increase plasma concentrations of lithium and digoxin. Monitoring of the serum lithium level is recommended.
Digoxin: If used concomitantly, Voltarol may raise plasma concentrations of digoxin. Monitoring of the serum digoxin level is recommended.
Diuretics and antihypertensive agents: Like other NSAIDs, concomitant use of Voltarol 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. Concomitant treatment with potassium-sparing diuretics may be associated with increased serum potassium levels, which should therefore be monitored frequently (see section 4.4 Special warnings and precautions for use).
Anticoagulants and anti-platelet agents: 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 Voltarol has an influence on the effect of anticoagulants, there are isolated reports of an increased risk of haemorrhage in patients receiving with the combined use of diclofenac and anticoagulant concomitantly therapy (see section 4.4 Special warnings and precautions for use). 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.
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).
Antidiabetic agents: Clinical studies have shown that Voltarol 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. 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.
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: Diclofenac, like other NSAIDs, 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.
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.
Quinolone antibacterialsmicrobials: Convulsions may occur 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.
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 sulfinpyrazone and voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.
Phenytoin: When using phenytoin concomitantly with diclofenac, monitoring of phenytoin plasma concentrations is recommended due to an expected increase in exposure to phenytoin.
Other NSAIDs including cyclooxygenase-2 selective inhibitors and corticosteroids: Co-administration of Voltarol with aspirin 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).
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Concomitant administration of systemic NSAIDs, including diclofenac may cause increased risk of gastrointestinal bleeding (see section 4.4 Special warnings and precautions for use).
Diuretics: Like other NSAIDs, Voltarol 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.
Potent CYP2C9 inhibitors: Caution is recommended when co-prescribing diclofenac with potent CYP2C9 inhibitors (such as sulfinpyrazone and voriconazole), which could result in a significant increase in peak plasma concentrations and exposure to diclofenac due to inhibition of diclofenac metabolism.
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 and Tacrolimus: Cases of nephrotoxicity have been reported in patients receiving concomitant ciclosporin and NSAIDs, including diclofenac sodium. 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.
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 in believed to increase with dose and duration of therapy. In animals, administration o 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 Voltarol is used by a women 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, Voltarol is contra-indicated during the third trimester of pregnancy.
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, including diclofenac 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 Contraindications). 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
Like other NSAIDs, diclofenac passes into breast milk in small amounts. and tTherefore, NSAIDs Diclefenac should not be administered during breast feeding in order to avoid undesirable effects in the infant. if possible be avoided when breastfeeding.
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 or visual disturbances, while taking NSAIDs should refrain from driving or operating machinery.
4.8 Undesirable effects
If serious side-effects occur, Voltarol should be withdrawn.
Frequency estimate: frequent: >10 %, occasional: >1 - 10 %, rare: >0.001 - 1 %, isolated cases: <0.001 %.
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
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Blood and lymphatic system disorders
|
|
Very rare
|
Thrombocytopenia, leucopoenia, anaemia (including haemolytic and aplastic anaemia), Aagranulocytosis.
|
|
Immune system disorders
|
|
Rare
Very rare
|
Hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock).
Angioneurotic oedema (including face oedema).
|
|
Psychiatric disorders
|
|
Very rare
|
Disorientation, depression, insomnia, nightmare, irritability, psychotic disorder.
|
|
Nervous system disorders
|
|
Common
Rare
Very rare
Unknown
|
Headache, dizziness.
Somnolence, tiredness.
Paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, taste disturbances, cerebrovascular accident.
Confusion, hallucinations, disturbances of sensation, malaise
|
|
Eye disorders
|
|
Very rare
Unknown
|
Visual disturbance, vision blurred, diplopia.
Optic neuritis.
|
|
Ear and labyrinth disorders
|
|
Common
Very rare
|
Vertigo.
Tinnitus, hearing impaired.
|
|
Cardiac disorders
|
|
Very rare
|
Palpitations, chest pain, cardiac failure, myocardial infarction.
|
|
Vascular disorders
|
|
Very rare
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Hypertension, hypotension, vasculitis.
|
|
Respiratory, thoracic and mediastinal disorders
|
|
Rare
Very rare
|
Asthma (including dyspnoea).
Pneumonitis.
|
|
Gastrointestinal disorders
|
|
Common
Rare
Very rare
|
Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, anorexia.
Gastritis, gastrointestinal haemorrhage, haematemesis, diarrhoea haemorrhagic, melaena, gastrointestinal ulcer (with or without bleeding or perforation) (sometimes fatal particularly in the elderly).
Colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn's disease), constipation, Sstomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis.
|
|
Hepatobiliary disorders
|
|
Common
Rare
Very rare
|
Transaminases increased.
Hepatitis, jaundice, liver disorder.
Fulminant hepatitis, hepatic necrosis, hepatic failure.
|
|
Skin and subcutaneous tissue disorders
|
|
Common
Rare
Very rare
|
Rash.
Urticaria.
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.
|
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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
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Application site irritation, oedema
|
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Reproductive system and breast disorders
|
|
Very rare
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Impotence
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Gastrointestinal tract
Occasional: Epigastric pain, other gastrointestinal disorders (e.g. nausea, vomiting, diarrhoea, abdominal cramps, dyspepsia, flatulence, anorexia).
Rare: Gastritis, gastrointestinal bleeding (haematemesis, melaena, and bloody diarrhoea), gastrointestinal ulcers with or without bleeding or perforation (sometimes fatal, particularly in the elderly) may occur (see section 4.4 Special warnings and precautions for use).
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, colonic damage and stricture formation), pancreatitis, constipation.
Suppositories only:
Occasional: Local reactions (e.g. itching, burning and increased bowel movement). In isolated cases: Exacerbation of haemorrhoids.
Central Nervous System disorders:
Occasional: Headache, dizziness, or vertigo.
Rare: Drowsiness, tiredness hypotension.
In isolated cases: Disturbances of sensation, paraesthesia, memory disturbance, disorientation, insomnia, irritability, convulsions, depression, confusion, hallucinations, malaise, anxiety, nightmares, tremor, psychotic reactions, aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus and mixed tissue disease), with symptoms such as fever, stiff neck, headache, nausea and vomiting.
Special senses:
Isolated cases: Disturbances of vision (blurred vision, optic neuritis, diplopia), impaired hearing, tinnitus, taste disturbances.
Skin:
Occasional: 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.
Kidney:
Rare: Oedema.
In isolated cases: Acute renal insufficiency, urinary abnormalities (e.g. haematuria, proteinuria), interstitial nephritis, nephrotic syndrome, papillary necrosis.
Liver:
Occasional: Elevation of serum aminotransferase enzymes (ALT, AST).
Rare: Liver function disorders including hepatitis (in isolated cases fulminant) with or without jaundice.
Blood:
In isolated cases: Thrombocytopenia, leucopenia, agranulocytosis, haemolytic anaemia, aplastic anaemia.
Vascular:
Isolated cases: Vasculitus.
Respiratory:
Isolated cases: Pneumonitis.
Cardiovascular system:
Isolated cases: Palpitations, chest pain, hypertension, congestive heart failure.
Other organ systems:
Isolated cases: Impotence.
Hypersensitivity:
Hypersensitivity reactions have been reported following treatment with NSAIDs. These consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising of 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 necroylsis and etheryma multiforme).
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) (see section 4.4 Special warnings and special precautions for use).
4.9 Overdose
Symptoms
There is no typical clinical picture resulting from diclofenac over dosage. Over dosage can cause Ssymptoms such as include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, dizziness, disorientation, excitation, coma, drowsiness, tinnitus, fainting, occasionally or convulsions. In rare cases the case of significant poisoning acute renal failure and liver damage are possible.
Therapeutic measures
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 potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patients clinical condition.
Section 5.1
The following has been added for 12.5mg and 25mg only:
12.5mg/25mg Suppositories only
There is a limited clinical trial experience of the use of diclofenac in JRA/JIA paediatric patients. In a randomised, double-blind, 2-week, parallel group study in children aged 3-15 years with JRA/JIA, the efficacy and safety of daily 2-3 mg/kg BW diclofenac was compared with acetylsalicylic acid (ASS, 50-100 mg/kg BW/d) and placebo – 15 minutes in each group. In the global evaluation, 11 of 15 diclofenac patients, 6 of 12 aspirin and 4 of 15 placebo patients showed improvement with the difference being statistically significant (p <0.05). The number of tender joints decreased with diclofenac and ASS but increased with placebo. In a second randomised, double-blind, 6 week, parallel group study in children aged 4-15 years with JRA/JIA, the efficacy of diclofenac (daily dose 2-3 mg/kg BW, n=22) was comparable with that of indomethacin (daily dose 2-3 mg/kg BW, (n=23).
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