Description and Composition of Aceclofen
Aceclofen is a nonsteroidal anti-inflammatory drugs that contains an aceclofenac as its active pharmaceutical ingredient. It is an orally administered phenylacetic acid derivative with effects on a variety of inflammatory mediators. Through its analgesic and anti-inflammatory properties, aceclofenac provides symptomatic relief in a variety of painful conditions.
Pharmacology and Mechanism of Action of Aceclofen
The mode of action of aceclofen is largely based on the inhibition of prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclooxygenase, which is involved in the production of prostaglandins. Aceclofenac has been shown to exert effects on a variety of mediators of inflammation. The drug inhibits synthesis of the inflammatory cytokines interleukin (IL)-1 and tumour necrosis factor and inhibits prostaglandin E (PGE) production. Effects on cell adhesion molecules from neutrophils have also been noted In vitro data indicate inhibition of cyclooxygenase (COX)-1 and 2 by aceclofenac in whole blood assays, with selectivity for COX-2 being evident.
In contrast to some other NSAIDs, aceclofenac has shown stimulatory effects on cartilage matrix synthesis, that may be linked to the ability of the drug to inhibit IL-1 activity. In vitro data indicate stimulation by the drug of synthesis of glycosaminoglycan in osteoarthritic cartilage. There is also evidence that aceclofenac stimulates the synthesis of IL-1 receptor antagonist in human articular chondrocytes subjected to inflammatory stimuli and that 4′-hydroxy aceclofenac has chondroprotective properties attributable to suppression of IL-1 mediated promatrix metalloproteinase production and proteoglycan release.
In patients with osteoarthritis of the knee, aceclofenac decreases pain, reduces disease severity and improves the functional capacity of the knee. It reduces joint inflammation, pain intensity and the duration of morning stiffness in patients with rheumatoid arthritis. The duration of morning stiffness and pain intensity are reduced and spinal mobility improved, by aceclofenac in patients with ankylosing spondylitis.
Pharmacokinetics properties of Aceclofen
Aceclofen is rapidly and completely absorbed after oral administration. Peak plasma concentrations are reached 1 to 3 hours after an oral dose. The drug is highly protein bound (>99%). The presence of food does not alter the extent of absorption of aceclofenac but the absorption rate is reduced The plasma concentration of aceclofenac was approximately twice that in synovial fluid after multiple doses of the drug in patients with knee pain and synovial fluid effusion. Aceclofenac is metabolised to a major metabolite, 4′ hydroxy aceclofenac and to a number of other metabolites including 5-hydroxy aceclofenac, 4′-hydroxydiclofenac, diclofenac and 5-hydroxydiclofenac. These other metabolites account for the fate of approximately 20% of each dose of aceclofenac. Renal excretion is the main route of elimination of aceclofenac with 70 to 80% of an administered dose found in the urine, mainly as the glucuronides of aceclofenac and its metabolites. Of each dose of aceclofenac, 20% is excreted in the faeces. The plasma elimination half life of the drug is approximately 4 hours.
Indications and Uses of Aceclofen
Aceclofen is indicated for the relief of pain and inflammation associated with rheumatoid arthritis, osteoarthritis or ankylosing spondylitis.
Contraindications of Aceclofen
Aceclofen should not be administered to patients hypersensitive to aceclofenac or other NSAIDs, or patients with a history of aspirin or NSAID-related allergic or anaphylactic reactions or with peptic ulcers or GI bleeding, moderate or severe renal impairment.
Close medical surveillance is imperative in patients with symptoms indicative of gastrointestinal disorders, with a history suggestive of gastrointestinal ulceration, with ulcerative colitis or with Crohn’s disease, bleeding diathesis or haematological abnormalities.
Gastrointestinal bleeding or ulcerative perforation, haematemesis and melaena have in general more serious consequences in the elderly. They can occur at any time during treatment, with or without warning symptoms or a previous history. In the rare instances, where gastrointestinal bleeding or ulceration occurs in patients receiving aceclofenac, the drug should be withdrawn.
Close medical surveillance is also imperative in patients suffering from severe impairment of hepatic function.
As with other NSAIDs, allergic reactions, including anaphylactic anaphylactoid reactions, can also occur without earlier exposure to the drug
Patients with mild renal or cardiac impairment and the elderly 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.
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. Hepatitis may occur without prodromal symptoms. Use of aceclofenac in patients with hepatic porphyria may trigger an attack.
Aceclofenac may reversibly inhibit platelet aggregation Caution should also be exercised in patients with history of coagulation defects and history of liver dysfunction.
Renal and hepatic function and blood counts should be monitored during long term treatment.
NSAIDs should be given with care to patients with a history of heart failure or hypertension since oedema has been reported in association with NSAID administration.
Use with caution in patients suffering from or with a history of bronchial asthma since NSAIDs have been known to cause bronchospasm in such patients.
Effects on ability to drive and use machines:
Patients suffering from dizziness, vertigo, or other central nervous system disorders whilst taking NSAIDs should refrain from driving or handling dangerous machinery.
Usage in pregnancy and lactation
The drug is not recommended in pregnant or breast feeding women.
Usage of Aceclofen paediatrics
There are no clinical data on the use of aceclofenac in children and therefore aceclofenac is not recommended for use in children.
Usage of Aceclofenac geriatrics
The pharmacokinetics of aceclofenac are not altered in elderly patients, therefore it is not considered necessary to modify the dose or dose frequency
As with other non-steroidal anti-inflammatory drugs (NSAIDs). caution should be exercised in the treatment of elderly patients, who are generally more prone to adverse reactions, and who are more likely to be suffering from impaired renal, cardiovascular or hepatic function and receiving concomitant medication. The elderly should be monitored for GI bleeding for 4 weeks following initiation of NSAID therapy.
Drug interactions with Aceclofen
Drug interactions associated with aceclofenac are similar to those observed with other NSAIDs.
Aceclofenac, like many NSAIDs, may increase plasma concentration of lithium.
Through their renal effects, NSAIDs may increase plasma glycoside (including digoxin) levels, exacerbate cardiac failure and reduce the glomerular filtration rate in patients receiving glycosides.
Aceclofenac, like other NSAIDs may inhibit the activity of diuretics. 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. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
Like other NSAIDs, aceclofenac may enhance the activity of anticoagulants. Close monitoring of patients on combined anticoagulant and aceclofenac therapy should be undertaken.
There have been isolated reports of hypoglycaemic and hyperglycaemic effects. Thus with aceclofenac, consideration should be given to adjustment of the dosage of hypoglycaemic agents.
Caution should be exercised if NSAIDs and methotrexate are administered within 24 hours of each other, since NSAIDs may increase methotrexate plasma levels, resulting in increased toxicity.
NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of Other mifepristone.
Other NSAIDs and Steroids
Concomitant therapy with aspirin, other NSAIDs and steroids may increase the frequency of adverse reactions, including the risk of GI bleeding.
Cyclosporin nephrotoxicity may be increased by the effect of NSAIDs on renal prostaglandins.
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 a NSAID.
Side Effects of Aceclofen
Aceclofen is well tolerated, with most adverse events being minor and reversible.
The most frequent are gastrointestinal disorders, in particular dyspepsia, abdominal pain, nausea and diarrhea, and occasional occurrence of dizziness. Dermatological complaints Including pruritus and rash and abnormal hepatic enzyme and serum creatinine levels have also been reported. If serious reactions occur, aceclofenac should be withdrawn.
Although the incidence of GI adverse events with aceclofenac was similar to those of comparator NSAIDs in individual clinical trials, withdrawal rates due to these events were significantly lower with aceclofenac than with ketoprofen and tenoxicam Costs incurred as a result of adverse event management are lower with aceclofenac than with a range of comparator NSAIDS. Although statistical analyses were not consistently available, faecal bleeding and endoscopy studies in humans have indicated overall less Gi bleeding and GI mucosal damage with aceclofenac than with naproxen or diclofenac.
The following adverse events (described as common (<10% -> 1%), uncommon (<1%->0.1%), rare (<0.1% ->0.01%) and very rare/isolated reports (<0,01%) were reported in clinical studies and postmarketing surveillance.
Blood and lymphatic system disorders:
Rare: Anaemia. Very rare: Granulocytopenia, thrombocytopenia, neutropenia, haemolytic anaemia.
Immune system disorders
Rare: Anaphylactic reaction (including shock), hypersensitivity.
Metabolism and nutrition disorders:
Very rare: Hyperkalemia
Very rare: Depression, abnormal dreams, insomnia.
Nervous system disorders:
Common: Dizziness. Very rare: Paraesthesia, tremor, somnolence, headache, dysgeusia (abnormal taste)
Rare: Visual disturbance
Ear and labyrinth disorders:
Very rare: Vertigo
Very rare: Palpitations
Very rare: Flushing, hot flush
Respiratory, thoracic and mediastinal disorders:
Rare: dyspnoea. Very rare: Bronchospasm, stridor.
Common: Dyspepsia, abdominal pain, nausea and diarrhea. Uncommon: Flatulence, gastritis, constipation, vomiting, mouth ulceration. Rare: Melaena. Very rare: Stomatitis, haematemesis, gastrointestinal haemorrhage, gastric ulcer, pancreatitis
Very rare: Hepatitis, jaundice
Skin and subcutaneous tissue disorders:
Uncommon: Pruritus, rash, dermatitis, urticaria. Rare: Face oedema. Very rare: Purpura, bullous dermatitis
Renal and urinary disorders:
Very rare: Renal insufficiency, nephrotic syndrome
General disorders and administration site conditions:
Very rare: Oedema, fatigue, cramps in legs
Common: Increased hepatic enzyme. Uncommon: Increased blood urea, increased blood creatinine. Very rare: Increased blood alkaline phosphatase, weight increase.
Dosage and Administration of Aceclofen
Aceclofen tablets should be swallowed whole with a sufficient quantity of liquid. When aceclofenac was administered to fasting and fed healthy volunteers only the rate and not the extent of aceclofenac absorption was affected and as such aceclofenac should be taken preferably with or after food.
The usual dose of aceclofenac is 100 mg given twice daily by mouth. One tablet in the morning and one in the evening.
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.
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 100 mg be used.
Overdosage of Aceclofen
Management of acute poisoning with NSAIDs consists of supportive and symptomatic measures. essentially There are no human data available on the consequences of aceclofenac overdosage. The therapeutic measures to be taken are: absorption should be prevented, as soon as possible after overdosage by means of gastric lavage and treatment with activated charcoal; supportive and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal irritation, and respiratory depression, specific therapies such as forced diuresis, dialysis or hemoperfusion are probability of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism.
Storage of Aceclofen
How to store aceclofenac: Store below 30°C, in a dry place. KEEP OUT OF REACH OF CHILDREN.