Therapeutic Indications

Posology

• Adults: One tablet daily, taken with a glass of water. ETOMAX must be swallowed whole the safety of doses in excess of 600 mg per day has not been established. No occurrence of tolerance or tachyphylaxis has been reported.
• Elderly: No change in initial dosage is generally required in the elderly. The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.
• Pediatrics population: Use in children is not recommended.
• Method of Administration: For oral administration. To be taken preferably with or after food. Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

• Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation, which may be fatal.
• Platelets: Although non-steroidal anti-inflammatory drugs do not have the same direct effects on platelets as aspirin dose, all drugs which inhibit the biosynthesis of prostaglandins may interfere, to some extent, with platelet function. Patients receiving etodolac who may be adversely affected by such actions should be carefully observed.
• Cardiovascular, Renal and Hepatic Impairment: In patients with renal, cardiac or hepatic impairment especially those taking diuretics and the elderly, renal function should be monitored in these patients. Caution is required since the use of NSAIDs may result in a dose dependent reduction in prostaglandin formation and precipitate renal failure. The dose should be kept as low as possible. However, impairment of renal or hepatic functions due to other causes may alter drug metabolism; patients receiving concomitant long-term therapy, especially the elderly, should be observed for potential side effects and their drug doses adjusted as needed, or the drug discontinued. Patients on long-term treatment with etodolac should be regularly reviewed as a precautionary measure e.g. for changes in renal function, hematological parameters, or hepatic function.
• 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 edema have been reported in association with NSAID therapy. 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 etodolac.
• Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with etodolac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidemia, diabetes mellitus, and smoking).
• 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. 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. Etodolac should be discontinued at the first appearance of the skin rash, mucosal lesions, or any other sign of hypersensitivity.
• Respiratory Disorders: Caution is required if etodolac is administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients. SLE and mixed connective tissue disease In patients with systemic lupus erythematous (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8)
• Impaired Female Fertility: The use of etodolac may impair female fertility and is not recommended in woman attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of etodolac should be considered.
• Gastrointestinal Bleeding, Ulceration And Perforation: Serious gastrointestinal adverse effects such as bleeding, ulceration and 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. If any sign of gastrointestinal bleeding occurs, etodolac should be stopped immediately .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, 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.
• 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 anti-platelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving etodolac, 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. Patients with rare hereditary problems or galactose intolerance, the Lap lactase deficiency or glucose-galactose mal absorption should not take this medicine.

• Corticosteroids: increased risk of gastrointestinal ulceration or bleeding.
• Anti-Coagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin. (Since etodolac is extensively protein-bound, it may be necessary to modify the dosage of other highly protein-bound drugs.
• Bilirubin Tests Can Give a False Positive Result due to the presence of phenolic metabolites of etodolac in the urine.
• Anti-Hypertensive: Reduced anti-hypertensive effect.
• Mifepristone: NSAIDs should not be used for 8 – 12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.
• Other Analgesics Including cyclooxygenase-2 selective inhibitor: Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects.
• 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.
• Diuretics: Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
• Cardiac Glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
• Lithium: Decreased elimination of lithium.
• Methotrexate: Decreased elimination of methotrexate.
• Ciclosporin: Increased risk of nephrotoxicity.
• Anti-Platelet Agents and Selective Serotonin Reuptake Inhibitors (Ssris): Increased risk of gastrointestinal bleeding.
• Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.
• Zidovudine: Increased risk of hematological toxicity when NSAIDs are given with zidovudine. There is an evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

• Pregnancy: Drugs which inhibit prostaglandin biosynthesis may cause dystocia and delayed parturition as evidenced by studies in pregnant animals. 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 fetal cardiovascular system, some inhibitors of prostaglandin biosynthesis have been shown to interfere with the risk of closure of the ductus arteriosus, use in the last trimester of pregnancy is contraindicated. The onset of labor may be delayed and the duration increased with an increased bleeding tendency in both mother and child.NSAIDs should not be used during the first two trimesters of pregnancy or labor unless the potential benefit to the patient outweighs the potential risk to the fetus.
• Breast-feeding: In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

Undesirable Effects

• 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. Nausea, vomiting, diarrhoea, epigastric pain, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease, indigestion, heartburn, rectal bleeding have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely. Reported side effects include vasculitis, palpitations, anaphylactoid reaction, have been reported following administration.
• 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 dyspnea, or
  (c) Assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiform).
• Cardiovascular and Cerebrovascular: Edema, 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 of stroke).
• Other Adverse Reactions Reported Less Commonly Include: Endocrine disorders, Edema, pyrexia musculoskeletal connective tissue and bone disorders Weakness/malaise Respiratory, thoracic and mediastinal disorders Dyspnea
• 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 erythematous, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue, tremor, insomnia, and drowsiness.
• Dermatological: Bullous reactions including Stevens-Johnson syndrome, and Toxic Epidermal Necrolysis (very rare). Photosensitivity.
• Haematological: Thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia and hemolytic anemia.
• Hepatic: Abnormal liver function, hepatitis and jaundice.
• Renal: Bilirubinuria, urinary frequency, dysuria, Nephrotoxicity in various forms including interstitial nephritis, nephrotic syndrome and renal failure.

a) Symptoms

b) Therapeutic measure

• 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.
• Frequent or prolonged convulsions should be treated with intravenous diazepam.
• Other measures may be indicated by the patient's clinical condition.

Pharmacodynamics Properties

• Pharmacotherapeutic group: anti-inflammatory and anti-rheumatic products, non-steroids, acetic acid derivatives and related substances
• Mechanism of Action: Inhibition of prostaglandin synthesis and COX-2 selectivity all non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the formation of prostaglandins. It is this action which is responsible both for their therapeutic effects and some of their side-effects. The inhibition of prostaglandin synthesis observed with etodolac differs from that of other NSAIDs. In an animal model at an established anti-inflammatory dose, cytoprotective PGE concentration in the gastric mucosa have been shown to be reduced to a lesser degree and for a shorter period than other NSAIDs. This finding is consistent with subsequent in-vitro studies which have found etodolac to be selective for induced cyclooxygenase 2 (COX-2, associated with inflammation) over COX-1 (cytoprotective).
• Furthermore, studies in human cell models have confirmed that etodolac is selective for the inhibition of COX-2. The clinical benefit of preferential COX-2 inhibition over COX-1 has yet to be proven.
• Anti-Inflammatory Effects: Experiments have shown etodolac to have marked anti-inflammatory activity, being more potent than several clinically established NSAIDs.

Pharmacokinetic Properties

• In man, etodolac is well absorbed following oral administration.
• Etodolac is highly bound to serum proteins.
• The elimination half-life averages seven hours in man.
• The primary route of excretion is in the urine, mostly in the form of metabolites.
• In subjects receiving daily doses of etodolac 400 mg or 600 mg to steady state levels over a three day period, the peak plasma concentrations were 7.5 μg/ml at 7.9 hours and 11.9 μg/ml at 7.8 hours.

Special Precautions for Storage