(Aceclofenac Tablets 100 mg)
For the use of a Registered Medical Practitioner only
Each film-coated tablet contains:
Aceclofenac Ph. Eur 100mg
Excipients: microcrystalline cellulose, croscarmellose sodium, povidone (K 30), glyceryl dipalmitostearate type 1, opadry OY-S-58910, purified water.
ACENAC contains aceclofenac. Aceclofenac is a non-steroidal agent with marked anti-inflammatory and analgesic properties. Chemically it is [[[2-[(2,6- Dichlorophenyl) aminolphenyl]acetyl]oxy]acetic acid. It is a phenylacetic acid derivative related to diclofenac. Molecular weight of aceclofenac is 354.2. It’s molecular formula is C16H13CI2NO4
ACENAC tablet is indicated for the relief of pain and inflammation in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
DOSAGE AND ADMINISTRATION
ACENAC tablets are supplied for oral administration and should be swallowed whole with a sufficient quantity of liquid.
To be taken preferably with or after food.
When aceclofenac was administered to fasting and fed healthy volunteers only the rate and not the extent of aceclofenac absorption was reported to be affected.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see WARNINGS AND PRECAUTIONS).
The recommended dose is 200 mg daily, taken as two separate 100mg doses, one tablet in the morning and one in the evening.
The elderly, who are more likely to be suffering from impaired renal, cardiovascular or hepatic function and receiving concomitant medication, are at increased risk of the serious consequences of adverse reactions. If a non-steroidal anti- inflammatory drug (NSAID) is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for gastrointestinal (GI) bleeding during NSAID therapy.
The pharmacokinetics of aceclofenac is not altered in elderly patients, therefore it is not considered necessary to modify the dose or dose frequency.
There is no evidence that the dosage of aceclofenac needs to be modified in patients with mild renal impairment, but as with other NSAIDs caution should be exercised (see WARNINGS AND PRECAUTIONS).
There is some evidence that the dose of aceclofenac should be reduced in patients with hepatic impairment and it is suggested that an initial daily dose of 100mg be used.
USE IN SPECIAL POPULATIONS1
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.
The regular use of NSAIDs during the last trimester of pregnancy may decrease uterine tone and contraction. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see CONTRAINDICATIONS). 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.
There was no evidence of teratogenesis in rats although the systemic exposure was low and in rabbits, treatment with aceclofenac (10 mg/kg/day) resulted in a series of morphological changes in some foetuses.
NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.
The use of aceclofenac should therefore be avoided in pregnancy and lactation unless the potential benefits to the other outweigh the possible risks to the foetus.
See WARNINGS AND PRECAUTIONS, regarding female fertility.
There are no clinical data on the use of aceclofenac in children and therefore it is not recommended for use in children.
Aceclofenac tablets are contraindicated in patients with hypersensitivity to aceclofenac or to any of the excipients.
Patients with active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
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 severe heart failure, hepatic failure and renal failure (see WARNINGS AND PRECAUTIONS).
Patients with history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.
Aceclofenac tablets 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 USE IN SPECIAL POPULATIONS).
WARNINGS AND PRECAUTIONS1
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see DOSAGE AND ADMINISTRATION, and GI and cardiovascular risks below).
The use of aceclofenac with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see DRUG INTERACTIONS).
The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see DOSAGE AND ADMINISTRATION).
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.
Cardiovascular, Renal and Hepatic Impairment
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 CONTRAINDICATIONS).
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 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 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 aceclofenac in patients with hepatic porphyria may trigger an attack.
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.
The use of some NSAIDs (particularly at high doses and in long term treatment) has been reported to be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Such a risk cannot be excluded 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).
Gastrointestinal (GI) Bleeding, Ulceration and Perforation
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 symptoms indicative of gastro-intestinal disorders, with a history suggestive of gastro-intestinal ulceration, with ulcerative colitis or with Crohn’s disease, bleeding diathesis or haematological abnormalities.
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 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, or other drugs likely to increase gastrointestinal risk (see below and DRUG INTERACTIONS).
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 DRUG INTERACTIONS).
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 ADVERSE REACTIONS).
Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease
In patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see ADVERSE REACTIONS).
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 ADVERSE REACTIONS). 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. Aceclofenac should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Impaired Female Fertility
The use of aceclofenac 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 should be considered.
As with other NSAIDs, allergic reactions, including anaphylactic/ anaphylactoid reactions, can also occur without earlier exposure to the drug.
Aceclofenac may reversibly inhibit platelet aggregation (see DRUG 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.
Effect on Ability to Drive and Use Machines
Undesirable effects such as dizziness, drowsiness, fatigue and visual disturbances are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.
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 WARNINGS AND PRECAUTIONS).
Anti-hypertensives: Reduced anti-hypertensive effect.
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: Decreased elimination of lithium.
Methotrexate: Decreased elimination of methotrexate. 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.
Ciclosporin: Increased risk of nephrotoxicity.
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 WARNINGS AND PRECAUTIONS).
Anti-coagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin (see WARNINGS AND PRECAUTIONS). Close monitoring of patients on combined anticoagulants and aceclofenac therapy should be undertaken.
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 WARNINGS AND PRECAUTIONS).
Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
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: With aceclofenac, 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.
Gastrointestinal: The most commonly-reported adverse events are gastrointestinal in nature. Peptic ulcers, perforation or Gl bleeding, sometimes fatal, particularly in the elderly, may occur (see WARNINGS AND PRECAUTIONS). Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see WARNINGS AND PRECAUTIONS) have been reported following administration. Less frequently, gastritis has been reported. Pancreatitis has been reported very rarely.
Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (i) nonspecific allergic reactions and anaphylaxis (ii) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (iii) 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 and cerebrovascular: Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.
The use of some NSAIDs (particularly at high doses and in long term treatment) has been reported to be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see WARNINGS AND PRECAUTIONS).
The majority of adverse reactions reported have been reversible and of a minor nature. The most frequent are gastro-intestinal disorders, in particular dyspepsia, abdominal pain, nausea and diarrhoea, and occasional occurrence of dizziness. Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment. Dermatological complaints including pruritus and rash have been reported.
Investigations: Abnormal hepatic enzyme and serum creatinine levels have also been reported.
Other adverse reactions reported less commonly include:
Renal: Nephrotoxicity in various forms, including interstitial nephritis, nephrotic 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 WARNINGS AND PRECAUTIONS), 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.
If serious adverse reactions occur, aceclofenac should be withdrawn.
The following is a table of adverse reactions reported with aceclofenac, grouped by System-Organ Class and estimated frequencies.
|System-Organ Class||Common <10% to >1%||Uncommon <1% to >0.1%||Rare <0.1% to >0.01%||Very Rare/isolated Reports <0.01%|
|Blood and lymphatic system disorders||Anaemia||Granulocytopenia, Thrombocytopenia, Neutropenia, Haemolytic anaemia|
|Immune system disorders||Anaphylactic reaction (including shock), Hypersensitivity|
|Metabolism and nutrition disorders||Hyperkalemia|
|Psychiatric disorders||Depression, Abnormal dreams, Insomnia|
|Nervous system disorders||Dizziness||Paraesthesia,
Dysgeusia (abnormal tatste)
|Eye disorders||Visual disturbance|
|Ear and labyrinth disorders||Vertigo|
|Vascular disorders||Flushing, Hot flush|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea||Bronchospasm, Stridor|
Vomiting, Mouth ulceration
|Hepatobiliary disorders||Hepatitis, Jaundice|
|Skin and subcutaneous tissue disorders||Pruritus, Rash, Dermatitis, Urticaria||Face oedema||Purpsra, Dermatitis bullous|
|Renal and urinary disorders||Renal insufficiency, Nephrotic syndrome|
|General disorders and administration site conditions||Oedema, Fatigue, Cramps in legs|
|Investigations||Hepatic enzyme increased||Blood urea increased, Blood creatinine||Blood alkanine phosphatase, Increased Weight|
Symptoms of aceclofenac overdosage include headache, nausea, vomiting, epigastric pain, gastrointestinal irritation, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, hypotension, respiratory depression, fainting and occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.
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 a potentially life-threatening overdose. Specific therapies such as dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism.
Good urine output should be ensured. Renal and liver function should be closely monitored.
Patients should be observed for at least four hours after ingestion of potentially toxic amounts. In case of frequent or prolonged convulsions, patients should be treated with intravenous diazepam. Other measures may be indicated by the patient’s clinical condition.
Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures.
PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES1
Aceclofenac is a non-steroidal agent with marked anti- inflammatory and analgesic properties.
The mode of action of aceclofenac is largely based on the inhibition to prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclo-oxygenase, which is involved in the production of prostaglandins.
After oral administration, aceclofenac is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately 1.25 to 3.00 hours following ingestion. Aceclofenac penetrates into the synovial fluid, where the concentrations reach approximately 57% of those in plasma. The volume of distribution is approximately 25 L.
The mean plasma elimination half-life is around 4 hours. Aceclofenac is highly protein bound (>99%). Aceclofenac circulates mainly as unchanged drug. 4-‘ Hydroxyaceclofenac is the main metabolite detected in plasma. Approximately two thirds of the administered dose is excreted via the urine, mainly as hydroxymetabolites.
No changes in the pharmacokinetics of aceclofenac have been reported in the elderly.
PRECLINICAL SAFETY DATA1
The results from preclinical studies reported with aceclofenac are consistent with those expected for NSAIDs. The principal target organ was the gastro-intestinal tract. No unexpected findings were recorded.
Aceclofenac was not considered to have any mutagenic activity in three in vitro studies and an in vivo study in the mouse.
Aceclofenac was not found to be carcinogenic in either the mouse or rat.
Store below 25°C, protected from moisture.
KEEP ALL MEDICINES OUT OF THE REACH OF CHILDREN.
Pack of 10 Tablets
1 UK Summary of Product Characteristics of PRESERVEX® film-coated tablets 100 mg, Almirall S.A, Spain, text revision in January 2011.
2 Sweetman, S. ed (2007). Aceclofenac. In: Martindale: The complete drug reference. London, Pharmaceutical Press.
Information compiled in April 2014.
Preservex is trademark of Almirall Limited and is not trademark of Ranbaxy. The maker of this brand is not affiliated with and does not endorse Ranbaxy or its products.
Manufactured in India by
Sun Pharmaceutical Ind. Ltd.
Industrial Area – 3,
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