Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2015 Publisher: Accord Healthcare Limited, Sage House, 319, Pinner Road, North Harrow, Middlesex HA1 4 HF, United Kingdom
Hypersensitivity to Aceclofenac or to any of the excipients.
Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
History of active bleedings or bleeding disorders
NSAIDS are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. Asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin, or other non-steroidal anti-inflammatory drugs.
Patients with established congestive heart failure (NYHA class II-IV), ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
Severe heart failure, hepatic failure and renal failure (see section 4.4).
History of gastrointestinal bleeding or perforation, related to previous NSAIDS therapy.
Aceclofenac should not be prescribed during pregnancy, especially during the last trimester of pregnancy, unless there are compelling reasons for doing so. The lowest effective dosage should be used (see section 4.6).
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 Aceclofenac with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).
Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also section 4.3).
The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, liver dysfunction, those being treated with diuretics or recovering from major surgery. Effects on renal function are usually reversible on withdrawal of Aceclofenac Tablets.
Patients with mild to moderate renal impairment should be kept under surveillance, since the use of NSAIDs may result in deterioration of renal function. The lowest effective dose should be used and renal function monitored regularly. Effects on renal function are usually reversible on withdrawal of Aceclofenac.
If abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), Aceclofenac Tablets should be discontinued. Close medical surveillance is necessary in patients suffering from mild to moderate impairment of hepatic function. Hepatitis may occur without prodromal symptoms.
Use of NSAIDs in patients with hepatic porphyria may trigger an attack.
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. As the cardiovascular risks of aceclofenac 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.
Aceclofenac should also be administered with caution and under close medical surveillance to patients with congestive heart failure, significant risk factors for cardiovascular events and history of cerebrovascular bleeding.
Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for aceclofenac.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with aceclofenac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).
GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.
Close medical surveillance is imperative in patients with:
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), 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, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).
Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet agents such as aspirin (see section 4.5).
When GI bleeding or ulceration occurs in patients receiving aceclofenac, the treatment should be withdrawn.
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).
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).
The use of Aceclofenac Tablets 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 Aceclofenac Tablets should be considered.
As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Jonson syndrome, and toxic epidermal necrolysis, have been reporting very rarely in association with the use of NSAIDs (see section 4.8). 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. Aceclofenac should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Exceptionally, varicella can trigger serious cutaneous and soft tissues infections complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of Aceclofenac in case of varicella.
Aceclofenac Tablets may reversibly inhibit platelet aggregation (see anticoagulants under ‘Interactions’).
All patients who are receiving NSAIDs should be monitored as a precautionary measure e.g. renal failure, hepatic function (elevation of liver enzymes may occur) and blood counts.
Other analgesics including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.4).
Anti-hypertensives: NSAIDs may reduce the effect of anti-hypertensives. The risk of acute renal insufficient, which is usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients or elderly patients) when ACE-inhibitors or angiotensin II receptor antagonists are combined with NSAIDs. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.
Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Although it was not shown to affect blood pressure control when co-administered with bendrofluazide, interactions with other diuretics cannot be ruled out. When concomitant administration with potassium-sparing diuretics is employed, serum potassium should be monitored.
Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR (glomerular filtration rate) and increase plasma glycoside levels.
Lithium and digoxin: Several NSAID drugs inhibit the renal clearance of lithium, resulting in increased serum concentrations of both. The combination should be avoided unless frequent monitoring of lithium and digoxin levels can be performed.
Methotrexate: Decreased elimination of methotrexate. The possible interaction between NSAIDs and methotrexate should be born in mind also when low doses of methotrexate are used, especially in patients with decreased renal function. When combination therapy has to be used, the renal function should be monitored. Caution should be exercised if NSAIDs and methotrexate are administered within 24 hours of each other, since NSAIDs may increase plasma levels, resulting in increased toxicity.
Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding (see section 4.4).
Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (see section 4.4). Close monitoring of patients on combined anti-coagulants and Aceclofenac Tablets therapy should be undertaken.
Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs): Increased risk of gastrointestinal bleeding (see section 4.4).
Cisclosporin, Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus due to decreased synthesis of prostacyclin in the kidney. During combination therapy it is therefore important to carefully monitor renal function.
Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
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. Thus with Aceclofenac Tablets, consideration should be given to adjustment of the dosage of hypoglycaemic agents.
Other NSAIDs: Concomitant therapy with aspirin or other NSAIDs may increase the frequency of adverse reactions, including the risk of GI bleeding.
There is no information on the use of aceclofenac during 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, cardiac malformation or gastroschisis after use of 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 been shown to result in increased pre- and postimplantation 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 the organogenetic period. During the first and second trimester of pregnancy, Aceclofenac should not be given unless clearly necessary. If Aceclofenac is used by a women attempting to conceive, or during the first the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.
Congenital abnormalities have been reported in association with NSAID administration 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 (risk of closure of the ductus arteriosus) and on the possible risk of persistent pulmonary hypertension of the new born, use in the last trimester of pregnancy is contraindicated. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
Consequently, aceclofenac is contraindicated during the third trimester of pregnancy (see section 4.3).
There is no information on the secretion of Aceclofenac to breast milk, there was however no notable transfer of radio labelled (14C) Aceclofenac to the milk of lactating rats.
The use of Aceclofenac Tablets should therefore be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the foetus.
NSAIDs may impair fertility and are not recommended in women trying to conceive. The temporary discontinuation of Aceclofenac should be considered in women having difficulties to conceive or undergoing investigations for infertility.
Undesirable effects such as dizziness, vertigo, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
Exceptionally, occurrence of serious cutaneous and soft tissues infections complications during varicella has been reported in association with NSAID treatment.
Aceclofenac is both structurally related and metabolised to diclofenac for which a greater amount of clinical and epidemiological data consistently point towards an increased risk of general arterial thrombotic events (myocardial infarction or stroke, particularly at high doses and in long treatment). Epidemiological data has also found an increased risk of acute coronary syndrome and myocardial infarction associated with the use of aceclofenac, (see section 4.3 and 4.4 for contraindication and Special warnings and special precautions for use).
Gastrointestinal: The most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (See section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.
Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or © assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angiodema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).
Cardiovascular: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.
Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).
Other adverse reactions reported less commonly include:
Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephritic syndrome and renal failure
Hepatic: Abnormal liver function, hepatitis and jaundice.
Neurological and special senses: Visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (See section 4.4) , depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.
Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.
Dermatological: Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity.
Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Rare: Anaemia
Very rare/isolated reports: Bone Marrow depression, Granulocytopenia, Thrombocytopenia, Neutropenia, Haemolytic anaemia
Rare: Anaphylactic reaction (including shock), Hypersensitivity
Very rare/isolated reports: Hyperkalemia
Very rare/isolated reports: Depression, Abnormal dreams, Insomnia
Common: Dizziness
Very rare/isolated reports: Paraesthesia, Tremor, Somnolence, Headache, Dysgeusia (abnormal taste)
Rare: Visual disturbance
Very rare/isolated reports: Vertigo, Tinnitus
Rare: Cardiac failure
Very rare/isolated reports: Palpitations
Rare: Hypertension
Very rare/isolated reports: Flushing, Hot flush, vasculitis
Rare: Dyspnoea
Very rare/isolated reports: Bronchospasm, Stridor
Common: Dyspepsia, Abdominal pain, Nausea, Diarrhoea
Uncommon: Flatulence, Gastritis, Constipation, Vomiting, Mouth ulceration
Rare: Melaena, Gastrointestinal haemorrhage, Gastrointestinal ulceration
Very rare/isolated reports: Stomatitis, Intestinal perforation, Exacerbation of Crohn’s disease and colitis Ulcerative, Haematemesis, Gastrointestinal haemorrhage, Gastric ulcer, Pancreatitis
Uncommon: Pruritus, Rash, Dermatitis, Urticaria
Rare: Face oedema, Angioedema
Very rare/isolated reports: Purpura, Severe mucocutaneous skin reaction (including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis), Dermatitis bullous
Very rare/isolated reports: Cramps in the leg
Uncommon: Blood urea increased, Blood creatinine increased
Very rare/isolated reports: Renal insufficiency, Nephrotic syndrome, Renal failure
Common: Hepatic enzyme increased
Very rare/isolated reports: Hepatitis, Jaundice, Hepatic injury (including hepatitis), Blood alkaline phosphatase increased
Very rare/isolated reports: Oedema, Fatigue, Cramps in legs
Very rare/isolated reports: Weight increase
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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Not applicable.
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