Indications: Etodolac capsule are indicated in:
Long-term symptomatic treatment:
Chronic arthritis, including polyarthritis, ankylosing spondylitis.
Some osteoarthritis diseases cause pain and disability.
Short-term symptomatic treatment of acute osteoarthritis (hip osteoarthritis, knee osteoarthritis).
Short-term symptomatic treatment.
Acute exacerbations of abarticular rheumatism (scapulohumeral periarthritis, tendinitis, bursitis).
Low back pain, severe radiculalgia.
Administration, dosage:
Administration:
Etorlod capsule is taken orally.
The capsules are to be swallowed whole, without chewing them with a glass of water , preferably during meals.
Reserved for adults and children over 15 years old.
Dosage:
The occurrence of side effects can be minimized by using the lowest dose possible during the shortest treatment period necessary to relieve symptoms (see Warnings and precautions).
Average dose: 400 mg/day, 1 capsule 200 mg in the morning and 1 capsule 200 mg in the afternoon, preferably between meals.
The dosage may be adjusted in some patients depending on the acute or chronic nature of the condition and may be increased by, for example, 200 mg or up to 600 mg/day.
Usual dose for treatment of acute attack:
Acute exacerbations of abarticular rheumatism (scapulohumeral periarthritis, tendinitis, bursitis).
Low back pain, severe radiculalgia.
600 mg/day divided into 3 doses, taken in the morning, noon and afternoon, preferably between meals.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling the drug after use.
Contraindications:
Patients with hypersensitivity to etodolac or any of excipients of this medicine.
History of acute allergy or asthma due to use of etodolac or similar drugs such as NSAIDs, acetylsalicylic acid.
History of bleeding or gastrointestinal perforation during previous therapy with NSAIDs.
Active peptic ulcer, peptic ulcer or a history of recurrent hemorrhage.
Severe liver failure.
Severe renal impairment.
Severe heart failure.
Pregnancy, from the beginning of the 6th month (beyond 24 weeks of gestation).
Child under 15 years old.
This medication should generally not be used in combination with:
Oral anticoagulants.
Other NSAIDs (including salicylates from 3 g/day in adults)
Heparin.
Lithium.
Methotrexate from 20 mg / week, pemetrexed.
Warnings and precautions for use:
Special warnings
Concomitant use of etodolac with other NSAIDs, including selective inhibitors of cyclooxygenase 2 (cox-2), should be avoided.
The occurrence of side effects can be minimized by using the lowest dose possible during the shortest treatment period necessary for symptom relief.
Patients with asthma associated with chronic rhinitis, chronic sinusitis and/or nasal polyposis have a higher risk of allergic manifestation when taking acetylsalicylic acid and/or nonsteroidal anti-inflammatory drugs than the rest of the population. Administration of etodolac can lead to an asthma attack, especially in certain subjects allergic to acetylsalicylic acid or to a NSAID (see Contraindications).
Elderly
Elderly people are at increased risk of side effects from NSAIDs, especially gastrointestinal bleeding and potentially fatal perforations.
Gastrointestinal effects
Hemorrhages, ulcers, or sometimes fatal gastrointestinal perforations have been reported with all NSAIDs, at any time during treatment, without necessarily warning signs or history of severe gastrointestinal adverse effects.
The risk of bleeding, ulceration or gastrointestinal perforation increases with the dose used in patients with a history of ulcer, particularly in the event of a complication such as bleeding or perforation (see Contraindications) as well in the elderly. In these patients, treatment should be started at the lowest possible dosage. Protective treatment of the mucous membrane (e.g. misoprostol or proton pump inhibitor) should be considered for these patients, as for patients requiring treatment with low dose acetylsalicylic acid or treated with other medicines which may cause increase the gastrointestinal risk (see below and section Interactions).
Patients with a gastrointestinal history, especially elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), especially at the start of treatment.
Particular attention should be paid to patients receiving associated treatments likely to increase the risk of ulceration or hemorrhage, such as corticosteroids administered orally, oral anticoagulants such as warfarin, selective inhibitors of reuptake of serotonin (SSRI) and antiplatelet agents such as acetylsalicylic acid (see section Interactions).
In the event of a hemorrhage or ulceration occurring in a patient receiving etodolac, treatment should be discontinued.
NSAIDs should be administered with caution and under close supervision in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn’s disease), due to the risk of worsening of the disease (see section Undesirable effects).
Cardiovascular and cerebrovascular effects
Adequate monitoring and recommendations are required in patients with a history of hypertension and/or mild to moderate heart failure, as water retention and edema have been reported in association with NSAID therapy.
Cardiovascular thrombosis events
Nonsteroidal anti-inflammatory drugs (NSAIDs), other than aspirin, for systemic use, have shown an increased risk of serious cardiovascular thrombotic event, including myocardial infarction and stroke, which can be fatal. This increased risk of serious cardiovascular thrombotic events began as early as the first weeks of treatment and increased over time. The increase in cardiovascular thrombotic risk has been observed most consistently at higher doses.
Physicians should periodically evaluate the occurrence of cardiovascular events, even if the patient has no prior cardiovascular symptoms. Patients should be warned about the symptoms of serious cardiovascular events and should see a doctor immediately if these symptoms appear.
The occurrence of side effects can be minimized by using the lowest dose possible during the shortest treatment period necessary for symptom relief.
Clinical studies and epidemiological data suggest that the use of certain NSAIDs (especially when used in high doses and over a long period of time) may be associated with a slight increase in the risk of arterial thrombotic events (for example, infarction myocardium or stroke). There is currently insufficient data to rule out this increased risk for etodolac.
Patients with uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease, and/or with a history of stroke (including transient ischemic attack) should not be treated with etodolac only after careful evaluation of the benefit / risk ratio.
Similar attention should be paid before initiating long-term treatment in patients with risk factors for cardiovascular pathologies (such as hypertension, hyperlipidemia, diabetes or smoking).
Skin effects
Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndromes and Lyell syndromes have been very rarely reported during treatment with NSAIDs (see Undesirable effects).
The incidence of these undesirable effects seems to be higher at the start of treatment, the time to onset being, in the majority of cases, during the first month of treatment. Etorlod capsule should be stopped as soon as a skin rash, mucosal lesions or any other sign of hypersensitivity occurs.
Functional renal failure
NSAIDs, by inhibiting the vasodilating action of renal prostaglandins, are capable of causing functional renal failure by reducing glomerular filtration. This side effect is dose dependent.
At the start of treatment or after an increase in the dosage, monitoring of diuresis and renal function is recommended in patients with the following risk factors:
Elderly
Associated medicines such as: IEC, sartans, diuretics (see section Interactions).
Hypovolemia whatever the cause.
Heart failure.
Chronic renal failure.
Nephrotic syndrome.
Lupus nephritis.
Liver decompensated cirrhosis.
Hydro-sodium retention
Hydro-sodium retention with the possibility of edema, hypertension or increased hypertension, worsening of heart failure. Clinical monitoring is necessary from the start of treatment in the event of hypertension or heart failure. A decrease in the effect of antihypertensives is possible (see section Interactions).
Hyperkalemia
Hyperkalaemia favored by diabetes or concomitant treatment with hyperkalaemic drugs (see section Interactions).
Regular monitoring for serum potassium should be done in these circumstances.
Precautions for use
Etodolac, like any drug that inhibits the synthesis of cyclooxygenases and prostaglandins, can affect fertility. Its use is not recommended in women who wish to conceive a child.
This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy and lactation:
Pregnancy:
The inhibition of prostaglandin synthesis by NSAIDs can affect the course of pregnancy and/or the development of fetus.
Risks associated with use during the 1st quarter
Data from epidemiological studies suggest an increased risk of miscarriage, heart defects and gastroschisis after treatment with an inhibitor of prostaglandin synthesis in early pregnancy. The absolute risk of cardiovascular malformation has increased from less than 1% in the general population to approximately 1.5% in people exposed to NSAIDs. The risk seems to increase depending on the dose and the duration of treatment. In animals, administration of an inhibitor of prostaglandin synthesis has been shown to cause increased pre- and post-implantation loss and increased embryo-fetal lethality. In addition, a higher incidence of certain malformations, including cardiovascular defects.
Risks associated with use from the 12th week of amenorrhea and until birth:
From the 12th week of gestation until birth, all NSAIDs, by inhibiting prostaglandin synthesis, may expose the fetus to renal functional impairment.
In utero which can be observed from 12 weeks of amenorrhea (initiation of fetal diuresis): Oligoamnios (most often reversible at the end of treatment), even anamnios in particular during prolonged exposure.
At birth, renal failure (reversible or not) may persist in particular in the event of late and prolonged exposure (with a risk of delayed severe hyperkalemia).
Risks associated with use beyond the 24th week of amenorrhea and until birth:
Beyond the 24th week of amenorrhea, NSAIDs may expose the fetus to cardiopulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension). Constriction of the arterial duct can occur from the beginning of the 6th month (beyond the 24th week of amenorrhea) and can lead to right fetal or neonatal heart failure or even fetal death in utero.
At the end of pregnancy, the mother and the newborn can present:
An extension of the bleeding time due to an anti-aggregating action which can occur even after administration of very low doses of drug;
Inhibition of uterine contractions leading to a delay in term or a prolonged delivery.
Consequently:
Unless absolutely necessary, this medication should not be prescribed for a woman who is planning to become pregnant or during the first 5 months of pregnancy. If this medicine is given to a woman who wants to be pregnant or who is less than 6 months pregnant, the dose should be as low as possible and the duration of treatment as short as possible. Long-term use is strongly discouraged.
From the beginning of the 6th month (beyond 24 weeks of amenorrhea): Any taking of this medication, even on an ad hoc basis, is contraindicated. An inadvertent intake from this date justifies cardiac and renal, fetal and /or neonatal monitoring depending on the exposure term. The duration of this monitoring will be adapted to the elimination half-life of the molecule.
Lactation:
Since NSAIDs pass into breast milk, this medicine is not recommended for women who are breast-feeding.
Fertility:
Like all other NSAIDs, the use of this medication can temporarily affect female fertility by affecting ovulation; it is therefore not recommended for women wishing to conceive. In women who have difficulty designing or performing fertility tests, discontinuation of treatment should be considered.
Effects on ability to drive, use machines:
Etodolac has minor or moderate influence on the ability to drive and use machines. When driving vehicles or using machines, account should be taken of the possible occurrence of headache, slight dizziness and tiredness.
Interactions, incompatibilities of medicine:
Interaction of the drug with other drugs and other types of interactions:
Risk related to hyperkalemia
Certain drugs or therapeutic classes are likely to promote the onset of hyperkalaemia: Potassium salts, hyperkalaemic diuretics, ACE inhibitors, angiotensin II antagonists, nonsteroidal anti-inflammatory drugs, heparins (low molecular weight or unfractionated), immunosuppressants such as ciclosporin or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalemia. This risk is particularly important with potassium-sparing diuretics, especially when combined with each other or with potassium salts, while the combination of an ACE inhibitor and an NSAID, for example, is at lower risk as soon as the moment that the recommended precautions are implemented.
To know the risks and the levels of constraints specific to hyperkalaemic drugs, it is necessary to refer to the interactions specific to each substance.
However, certain substances, such as trimethoprim, are not subject to specific interactions with regard to this risk. Nevertheless, they can act as favoring factors when they are combined with other drugs like those mentioned above.
Simultaneous administration of etodolac with the following products requires careful monitoring of the patient’s clinical and biological status.
Associations not recommended:
Oral anticoagulants
Increased risk of bleeding from the oral anticoagulant (aggression of the gastroduodenal mucosa by NSAIDs). NSAIDs are likely to increase the effects of blood thinners, such as warfarin (see section Special warning).
If the combination cannot be avoided, close clinical and biological monitoring.
Other NSAIDs
Increased risk of ulcerogenic and digestive haemorrhage.
Acetylsalicylic acid (aspirin) in anti-inflammatory doses (≥ 1 g per dose and / or ≥ 3 g per day), and in analgesic or antipyretic doses (≥ 500 mg per dose and/or <3 g per day).
Unfractionated heparins, low molecular weight and related heparins (in curative doses and/or in the elderly)
Increased risk of haemorrhage (inhibition of platelet function and aggression of the peptic mucosa by NSAIDs).
If the combination cannot be avoided, close clinical (and biological monitoring for unfractionated heparins).
Lithium
Etodolac may increase in lithium which can reach toxic values (decrease in renal excretion of lithium).
If the combination cannot be avoided, monitor lithium closely and adjust the lithium dosage during the combination and after stopping the non-steroidal anti-inflammatory drug.
Methotrexate used at doses greater than or equal to 20 mg/week
Increase in hematological toxicity of methotrexate (decrease in renal clearance of methotrexate by anti-inflammatory drugs).
Pemetrexed (patients with low to moderate renal function, creatinine clearance between 45 ml/min and 80 ml/min)
Risk of increased toxicity of pemetrexed (decrease in renal clearance by NSAIDs).
Associations subject to precautions for use:
Ciclosporin, tacrolimus
Risk of addition of nephrotoxic effects, especially in the elderly.
Monitor renal function at the start of NSAID treatment.
Diuretics, ACE inhibitors, angiotensin II receptor antagonists
Acute renal failure in the patient at risk (elderly and/or dehydrated subject) by reduction of glomerular filtration (inhibition of vasodilating prostaglandins by NSAIDs).
Moreover, reduction of the antihypertensive effect.
Hydrate the patient; Look at the kidney function at the start of the treatment.
Methotrexats used at doses less than or equal to 20 mg/week
Increase in hematological toxicity of methotrexate (decrease in renal clearance of methotrexate by anti-inflammatory drugs).
Weekly control of the hemogram during the first weeks of the association.
Increased monitoring in case of impairment (even slight) of renal function, as well as in the elderly.
Pemetrexed (patients with normal kidney function)
Risk of increased toxicity of pemetrexed (decrease in renal clearance by NSAIDs).
Biological monitoring of the renal function.
Associations to take into account:
Acetylsalicylic acid in anti-aggregating doses (from 50 mg to 375 mg per day in 1 or more doses)
Increased risk of ulcerogenic and digestive haemorrhage.
Glucocorticoids (except hydrocortisone in replacement therapy)
Increased risk of gastrointestinal ulceration and hemorrhage (see section Special warning).
Antiplatelet agents and serotonin reuptake inhibitors (SSRIs)
Increased risk of gastrointestinal hemorrhage (see section Special warning).
Unfractionated heparins, low molecular weight heparins (preventive doses)
Increased risk of bleeding.
Beta blockers (except esmolol)
Reduction of the antihypertensive effect (inhibition of vasodilatory prostaglandins by NSAIDs and water-sodium retention with pyrazole NSAIDs).
Deferasirox
Increased risk of ulcerogenic and digestive haemorrhage.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Adverse reactions are ranked according to frequency: Very common (ADR > 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000), cannot be estimated from the available data “Unknown”.
Gastrointestinal effects
The most common side effects are gastrointestinal in nature. Peptic ulcers, perforations or gastrointestinal bleeding, sometimes fatal, may occur, especially in the elderly, (see section Special warning).
Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, ulcerative stomatitis, abdominal pain, melena, hematemesis, exacerbation of ulcerative colitis or Crohn’s disease (see section Special warning) have been reported following administration of NSAIDs.
Less frequently, gastritis has been observed.
Cardiovascular effects
Edema, hypertension and heart failure have been reported in association with NSAID therapy.
Cardiovascular and cerebrovascular effects (see section Warning and precautions for use).
Rarely have been reported: Elevated blood pressure, tachycardia, chest pain, arrhythmia, palpitations, hypotension, congestive heart failure.
Hypersensitivity reactions
Respiratory: Possibility of an asthma attack, especially in subjects allergic to aspirin and other non-steroidal anti-inflammatory drugs.
Skin reactions
Very rarely bullous reactions (including Stevens-Johnson syndrome and Lyell syndrome) have been observed.
Also reported: Rash, hives and worsening of chronic hives, pruritus, purpura.
Especially, photosensitization cases have been reported.
Biological changes
Hepatic: Transient and minimal elevation of serum transaminases.
Effects on the central nervous system
Headache, slight dizziness and tiredness have been reported.
Kidney effects
Water retention, hyperkalemia (see sections Special warning and Interaction of medicine).
Acute renal failure (ARF) function in patients with risk factors (see section Special warning).
Renal organ damage which may result in ARI: Isolated cases of interstitial nephritis, acute tubular necrosis, nephrotic syndrome, papillary necrosis has been reported.
Guidance on handling ADR:
Stop taking the drug if the patient shows signs of serious side effects: Black stools; unusual, persistent stomach pain; arm, jaw, chest pain; vomiting blood; Rapid breathing; unusual sweating; weak; unusual vision changes.
Overdose and management:
Overdose: There have been no reports of etodolac overdose. Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and lethargy may occur but are rare.
Management:
Treatment is usually symptomatic and supportive. If you have taken an overdose, you need to apply the following measures to increase excretion and inactivation of the drug: Gastric lavage, induce vomiting and diuresis, give activated charcoal or salt detergent. It is difficult to remove by dialysis because it is up to 99% bound to plasma proteins.
Pharmacodynamics:
Pharmacological group: Anti-inflammatory and antirheumatic drugs, non-steroids – Acetic acid derivatives and related substances.
ATC code: M01AB08
Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition.
Etodolac is a racemic mixture of [-] R- and [+] S-etodolac. As with other NSAIDs, it has been demonstrated in animals that the [+] S-form is biologically active. Both enantiomers are stable and there is no [-R to [+] S conversion in vivo.
Pharmacokinetics:
Absorption:
The systemic bioavailability of etodolac is 100% as compared to solution and at least 80% as determined from mass balance studies. Etodolac is well absorbed and had a relative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (±1 SD) peak plasma concentrations (Cmax) range from approximately 14 ± 4 to 37 ± 9 mcg/mL after 200 to 600 mg single doses and are reached in 80 ± 30 minutes. The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear following doses up to 600 mg every 12 hours. Peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg every 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis of lower doses. The extent of absorption of etodolac is not affected when etodolac is administered after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration by 1.4 to 3.8 hours.
Distribution:
The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin. The free fraction is less than 1% and is independent of etodolac total concentration over the dose range studied. It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Data from in vitro studies, using peak serum concentrations at reported therapeutic does in humans, show that the etodolac free fraction is not significantly altered by acetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid.
Metabolism:
Etodolac is extensively metabolized in the liver. The role, if any, of a specific cytochrome P450 system in the metabolism of etodolac is unknown. Several etodolac metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8-hydroxylated-etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolite does not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.
Elimination:
The mean oral clearance of etodolac following oral dosing is 49 (±16) mL/h/kg. Approximately 1% of an etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite:
| – etodolac, unchanged | 1% |
| – etodolac glucuronide | 13% |
| – hydroxylate metabolites (6-, 7- and 8-OH) | 5% |
| – hydroxylated metabolite glucuronides | 20% |
| – unidentified metabolites | 33% |
Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild to moderate renal dysfunction is generally necessary. The terminal half-life (t1/2) of etodolac is 6.4 hours (22% CV). In patients with severe renal dysfunction or undergoing hemodialysis, dosing adjustment is not generally necessary.
Fecal excretion accounted for 16% of the dose.
Special populations
Elderly
In etodolac clinical studies, no overall differences in safety or effectiveness were observed between these patients and younger patients. In pharmacokinetic studies, age was shown not to have any effect on etodolac half-life or protein binding, and there was no change in expected drug accumulation. Therefore, no dosage adjustments generally necessary in the elderly on the basis of pharmacokinetics.
Etodolac is eliminated primarily by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Pediatric
Safety and effectiveness in pediatric patients below the age of 18 years have not been established.
Race
Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion.
Hepatic insufficiency
Etodolac is predominantly metabolized by the liver. In patients with compensated hepatic cirrhosis, the disposition of total and free etodolac is not altered. Patients with acute and chronic hepatic diseases do not generally require reduced doses of etodolac compared to patients with normal hepatic function. However, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure. Etodolac plasma protein binding did not change in patients with compensated hepatic cirrhosis given etodolac.
Renal insufficiency
Etodolac pharmacokinetics have been investigated in subjects with renal insufficiency. Etodolac renal clearance was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance 37 to 88 mL/min). Furthermore, there were no significant differences in the disposition of total and free etodolac in these patients. However, etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. In patients undergoing hemodialysis, there was a 50% greater apparent clearance of total etodolac, due to a 50% greater unbound fraction. Free etodolac clearance was not altered, indicating the importance of protein binding in etodolac’s disposition. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis.
Storage conditions, shelf life, quality specification of the medicine:
Storage conditions: Protect from humidity and light, below 300C.
Shelf life: 36 months from the manufacture date.
Quality specification: In house.
