Name of the Medicinal Product
Etodolac 400 mg Extended Release Tablets
Etodolac 600 mg Extended Release Tablets
Qualitative and Quantitative Composition
Each tablet contains 400 mg etodolac.
Each tablet contains 600 mg etodolac.
Pharmaceutical Form
Extended-Release Tablets
Clinical Particulars
1. Therapeutic Indications
- For the management of signs and symptoms of osteoarthritis and rheumatoid arthritis.
2. Posology and Method of Administration
- 400mg XL - One to two tablets twice daily but no more than three tablets a day
- 600mg XL - One tablet once or twice daily
- The total daily dose should not exceed 1,200mg.
As with other NSAIDs, the lowest dose and longest interval should be sought for each patient. Therefore, after observing the response to initial therapy with Etodolac Extended-Release Tablets, the dose and frequency should be adjusted to suit the individual patient’s needs (tolerance and response). In responsive patients, partial symptomatic relief of symptoms usually occurs within 1 or 2 weeks, although maximum effectiveness may occur only after several weeks of therapy.
During long-term administration, the dose of Etodolac Extended-Release Tablets may be adjusted, up or down, depending on the patient’s clinical response (maximum dose 1200 mg/day).
As with other NSAIDs, Etodolac Extended-Release Tablet is preferably taken after meals or with food or antacids to reduce gastrointestinal irritation, especially during chronic use. However, for faster absorption when a rapid initial effect is required, the first 1 or 2 doses may be taken 30 minutes before meals or at least 2 hours after meals. If an antacid is taken concurrently, an aluminium and magnesium-containing formulation may be preferred. It is recommended to take Etodolac Extended-Release Tablets with a full glass of water and that the patient remains in an upright position for 15-30 minutes after administration. Patients should be advised to avoid alcoholic beverages while under treatment with this medicine.
3. Contraindications
- Hypersensitivity to etodolac or to any of the excipients.
- 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.
- History of gastrointestinal bleeding or perforation, related to previous NSAID's therapy.
- Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
- Severe heart failure, hepatic failure and renal failure.
- During the last trimester of pregnancy.
4. Special Warnings and Precautions for Use
- Undesirable effects may be minimized by using the minimum effective dose for the shortest duration necessary to control symptoms.
- The use of Etodolac Extended-Release Tablets with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
- Although non-steroidal anti-inflammatory drugs do not have the same direct effects on platelets as aspirin, all drugs that inhibit the biosynthesis of prostaglandins may interfere, to some extent, with platelet function. Patients receiving Etodolac Extended-Release Tablets who may be adversely affected by such actions should be carefully observed.
- Patients with rare hereditary problems or galactose intolerance, Lap lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Elderly:
- The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation, which may be fatal.
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 and 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 Extended-Release Tablets should be regularly reviewed as a precautionary measure e.g. for changes in renal function, haematological 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 oedema have been reported in association with NSAID therapy.
- Clinical trial and epidemiological data suggest that the 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 is insufficient data to exclude such a risk for Etodolac.
- Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Etodolac Extended-Release Tablets after careful consideration. Similar consideration should be made before initiating long-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, 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 NSAID's. Patients appear to be at the highest risk of these reactions early in the course of therapy: the onset of the reaction occurs in the majority of cases within the first month of treatment. Etodolac Extended-Release Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.
Respiratory Disorders:
- Caution is required if Etodolac Extended-Release Tablets are 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 erythematosus (SLE) and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis.
Impaired Female Fertility:
- The use of Etodolac Extended-Release Tablets may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing an investigation of infertility, withdrawal of Etodolac Extended-Release Tablets should be considered.
Gastrointestinal 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.
- The risk of bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcers, 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, and 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 their condition may be exacerbated (see section 4.8 – undesirable effects).
5. Interaction with other Medicinal Products and other forms of Interaction
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.
- The concomitant administration of warfarin and Etodolac Extended-Release Tablets should not require a dosage adjustment of either drug, however, it has rarely led to prolonged prothrombin times, therefore caution should be exercised when Etodolac Extended-Release Tablets are administered with warfarin.
- Bilirubin tests can give a false positive result due to the presence of phenolic metabolites of etodolac in the urine.
- Care should also be taken in patients treated with any of the following drugs as interactions have been reported in some patients including an increase in serum levels of these compounds and associated toxicities:
Anti-hypertensives:
- 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 inhibitors:
- 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.
Cyclosporin:
- 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 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.
Pregnancy and Lactation
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 men; 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), 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. 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.
Lactation:
In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.
Effects 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.
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, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease 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
- Nonspecific allergic reactions and anaphylaxis
- Respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or
- Assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema 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.
- Clinical trial and epidemiological data suggest that use of some NSAID's (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: Oedema, pyrexia
- Musculoskeletal connective tissue and bone disorders: Weakness/malaise
- Respiratory, thoracic and mediastinal disorders: Dyspnoea
- 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 the 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 anaemia and haemolyticanaemia.
- Hepatic: Abnormal liver function, hepatitis and jaundice.
- Renal: Bilirubinuria, urinary frequency, dysuria, Nephrotoxicity in various forms including interstitial nephritis, nephrotic syndrome, renal failure.
Overdose
1. Symptoms
- Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, and occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.
2. Therapeutic Measure
- 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.
- 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 thepatient's clinical condition.
Pharmacodynamic Properties
Pharmacotherapeutic group: anti-inflammatory and anti-rheumatic products, non-steroids, acetic acid derivatives and related substances
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 has 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 cyclo-oxygenase 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 of 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 Extended-Release Tablets to steady-state levels over a three-day period, the peak plasma concentration was 11.9 μg/ml at 7.8 hours
Preclinical Safety Data
Preclinical data reveal no special hazard based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
List of Excipients
Microcrystalline cellulose
Hypromellose
Lactose anhydrous
Povidone
Magnesium stearate
Polydextrose
Titanium Dioxide
Triacetin
Macrogol
FD&C Red #40 Aluminum Lake (E129)
FD&C Yellow #6 Aluminum Lake (E110)
FD&C Blue #2 Aluminum Lake (E132)
Black iron oxide (E172)
Yellow iron oxide (E172)
Shelf Life
36 months
Special Precautions for Storage
Store below 25°C.
Nature and contents of the Container
Available in pack sizes of 30, 100 and 1,000 tablets.
Special Precautions for Disposal and other Handling
No special requirements.