Etodolac is a non-selective non-steroidal anti-inflammatory (NSAID) drug. It is a reversible COX 1 and COX 2 inhibitor that has analgesic, anti-inflammatory, and anti-pyretic properties.

Indications of Etodolac:

• Acute pain:

  • It is advised for the treatment of severe pain (immediate release only).

• Arthritis:

  • It is helpful in relieving the signs and symptoms of different inflammatory diseases such as osteoarthritis, rheumatoid arthritis, and juvenile arthritis (ER only).

Etodolac treatment dose for adults:

Note:

• In cases of chronic diseases, a response is typically seen within 1 to 2 weeks.

Etodolac treatment dose of Acute pain:

• Immediate-release tablets:

  • 200 to 400 mg orally every 6 to 8 hours.
  • The maximum dose is 1,000 mg once daily

Etodolac treatment dose of Osteoarthritis and rheumatoid arthritis:

• Immediate-release:

  • 400 mg two times a day.
  • 300 mg twice or thrice a day
  • 500 mg twice a day

• Extended-release tablets:

  • 400 to 1,000 mg orally once every 24 hours.

Etodolac treatment dosage in children:

Note:

• Dosage should be given for a short time period and titrated to the lowest effective dose.
• A therapeutic response may take 7-14 days of treatment in chronic disease.

Etodolac treatment dose  of Analgesia (for acute pain):

• Children and Adolescents <18 years (American Pain Society 2016):

  • Immediate release:

    • Patient weight <50 kg:

      • Maximum daily dose: 1,000 mg/day. 5 to 10 mg/kg orally twice daily

    • Patient weight ≥50 kg:

      • Oral maximum daily dose: 300–400 mg every 8–12 hours: 1,000 mg/day

  • Adolescents ≥18 years:

    • Immediate release:

      • 200 to 400 mg every 6 to 8 hours, as required
      • The maximum daily dose is 1,000 mg/day

Etodolac treatment dose of Juvenile idiopathic arthritis:

• Children ≥6 years weighing at least 20 kg and Adolescents:

  • Extended-release tablets:

    • 20 to 30 kg:

      • 400 mg once daily per oral

    • 31 to 45 kg:

      • 600 mg once daily per oral

    • 46 to 60 kg:

      • 800 mg once a day per oral

    • >60 kg:

      • 1,000 mg per oral once daily

Etodolac treatment dose of Rheumatoid arthritis and osteoarthritis:

• Adolescents ≥18 years:

  • Immediate release:

    • 300 to 500 mg per oral every 12 hourly
    • 300 mg thrice a day
    • The maximum daily dose is 1,000 mg/day

  • Extended-release tablets:

    • 400 to 1,000 mg orally, once per day

Etodolac Pregnancy Risk Factor: C

• Some studies have shown birth defects after in-utero NSAID use. However, the data is inconsistent.
• Some of the non-teratogenic effects seen in the fetus/neonate after in utero NSAID exposure include prenatal constriction of the ductus arteriosus/persistent pulmonary hypertension of the newborn, oligohydramnios, necrotizing enterocolitis, renal illness, and intracranial haemorrhage.
• After delivery, resistant patent ductus may still be visible.
• Due to the increased risk of premature closing of the ductus arteriosus, NSAIDs should not be used in the third trimester.
• Although NSAIDs may be useful in mild rheumatoid-arthritis flares during pregnancy, they should be avoided or minimized in the early and later trimesters.
• Women of childbearing years can experience infertility if they continue to use NSAIDs for long periods.
• An increased chance of having an abortion may be caused by the use of NSAIDs near conception.

Etodolac use during breastfeeding:

• It is unknown if etodolac secretes in breast milk.
• NSAIDs are generally safe for women who breastfeed. However, there are other options.
• Breastfeeding women with platelet dysfunction and thrombocytopenia should avoid it.
• The drug can cause fatal side effects in breastfeeding infants. According to the manufacturer, it is best to decide whether to stop breastfeeding or discontinue using the drug.

Etodolac dose adjustment in renal disease:

• Creatinine clearance >88 mL/minute:

  • No dosage adjustment necessary.

• Creatinine clearance 37 to 88 mL/minute:

  • No dosage adjustment necessary; however, use with caution.

• Creatinine clearance <37 mL/minute:

  • There are no specific dosage adjustments provided in the manufacturer’s labeling but it should be used with caution.
  • It is not recommended in patients with advanced renal disease unless benefits are expected to outweigh the risk of worsening renal function.

• Hemodialysis:

  • Not significantly removed.

• KDIGO 2012 guidelines provide the following recommendations for NSAIDs:

  • Estimated Glomerular filtration rate (eGFR) 30 to <60 mL/minute/1.73 m²: 

    • It should not be given in patients with intercurrent disease that increases the risk of acute kidney injury.

  • Estimated glomerular filtration rate <30 mL/minute/1.73 m²: 

    • It is not recommended.

Etodolac dose adjustment in liver disease:

No dosage adjustment is required. However, dose reduction may be needed in case of extensive hepatic metabolism.

Etodolac Side effects:

• Central Nervous System:

  • Dizziness
  • Chills
  • Depression
  • Nervousness

• Dermatologic:

  • Skin Rash
  • Pruritus

• Gastrointestinal:

  • Dyspepsia
  • Abdominal Cramps
  • Diarrhea
  • Flatulence
  • Nausea
  • Vomiting
  • Constipation
  • Melena
  • Gastritis

• Genitourinary:

  • Dysuria

• Neuromuscular & Skeletal:

  • Weakness

• Ophthalmic:

  • Blurred Vision

• Otic:

  • Tinnitus

• Renal:

  • Polyuria

• Miscellaneous:

  • Fever

Contraindication to Etodolac:

• Hypersensitivity to etodolac or any component of its formulation
• Aspirin and other NSAIDs can cause allergic reactions in patients suffering from asthma or urticaria.
• Active peptic ulcer
• Inflammatory bowel disease

Warnings and precautions

• Anaphylactoid reactions

  • Anaphylactoid reactions can occur after or before previous exposure to the drug.
  • Patients with the "aspirin trifecta" (bronchial asthma and aspirin intolerance, rhinitis) are at greater risk.
  • Using NSAID or Aspirin Treatment in cases of bronchospasm or asthma, rhinitis or urticaria is not advised.

• Cardiovascular events: [US Boxed Warn]

  • Use of etodolac can lead to fatal cardiovascular events such as stroke and MI.
  • This risk can be present early in treatment and may increase as long-term therapy is continued.
  • Same risk applies to those with and without established heart disease or other risk factors.
  • Patients with known cardiovascular disease and risk factors are more likely to experience fatal cardiovascular thrombotic events early in treatment.
  • NSAIDs may cause new-onset hypertension, or exacerbation.
  • NSAIDs can cause impaired response to ACE inhibitors and thiazide diuretics.
  • For these reasons, regular blood pressure monitoring and caution in the case of pre-existing hypertension are important.
  • It can cause fluid retention, so be careful with patients suffering from edema.
  • Patients with recent MI or heart failure should not use it unless the benefits outweigh any potential cardiovascular thrombotic events.
  • To avoid cardiovascular events, the lowest effective dose for the shortest time is recommended. This recommendation is consistent with the individual patient's goals.
  • Patients at higher risk should be offered alternative medication.

• CNS effects

  • NSAIDs may cause blurred vision, drowsiness, dizziness, blurred eyesight, or other neurologic effects that can lead to impairment of physical and mental abilities.
  • Patients should be cautious when operating machinery or driving.

• Gastrointestinal events [US Boxed Warning]

  • Long-term NSAID therapy can cause severe side effects such as ulceration, bleeding, and even life-threatening perforation.
  • Patients over 65 years of age and patients with a history peptic ulcer disease or gastrointestinal bleeding are at high risk.
  • These events can occur without warning and at any time during therapy.
  • Patients suffering from active gastrointestinal bleeding shouldn't use NSAIDs.
  • Patients with history of severe lower gastrointestinal bleeding should be advised to avoid non-aspirin-NSAIDs, particularly if they are suffering from angio-ectasia and diverticulosis.
  • You should exercise caution if you have a history of gastrointestinal bleeding, such as anticoagulants, corticosteroids and selective serotonin reuptake inhibits.
  • A warning sign is advanced liver disease, coagulopathy and smoking.
  • To minimize the chance of adverse events, the lowest effective dose should be used for the shortest period.
  • Combining aspirin with other medications can increase the risk of gastrointestinal problems such as ulcers. Therefore, additional gastroprotective therapy like a proton pump inhibitor may be recommended.

• Hematologic effects

  • It reduces platelet adhesion, aggregation, and prolongs bleeding time.
  • Anticoagulant users and patients with coagulation problems need to be closely watched.
  • Those who get long-term NSAID medication may develop anaemia.
  • Rare side effects of NSAIDs include blood dyscrasias include agranulocytosis, thrombocytopenia, and aplastic anaemia.

• Hepatic effects

  • Transaminitis can occur, so it is important to monitor any abnormal liver functions.
  • Rarely, life-threatening hepatic reactions, such as fulminant liver disease, hepatic necrosis or hepatic failure, can occur. 
  • If you have any clinical signs or symptoms of liver disease, stop taking the drug immediately.

• Hyperkalemia:

  • Hyperkalemia may be more common with NSAIDs. Risk factors include old age, DM, renal disease, and combination therapy that can induce hyperkalemia (eg ACE-inhibitors).

• Effects on the renal system:

  • The effects of NSAIDs on prostaglandin synthesis and renal blood flow can cause renal decompensation.
  • Dehydration, hypokalemia and CCF are all risk factors for renal toxicities. Hepatic impairment, diuretics, old age, and hepatic impairment are also possible.
  • It is important to hydrate before you start therapy.
  • Long-term NSAID treatment can cause renal papillary necrosis or other injuries.

• Reactions to skin:

  • There have been reports of toxic epidermal necrolysis, exfoliative dermatitis, Stevens Johnson syndrome (SJS), and other skin-related side effects.
  • Skin rash should be treated immediately if it is present.

• Aseptic meningitis

  • Aseptic meningitis can be very serious in those with systemic lupus, mixed connective tissue disorders and systemic lupus.

• Asthma

  • Patients with asthma who are sensitive to aspirin should not take NSAIDs as they can lead to fatal bronchospasm.

Etodolac: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

Different parameters including:

• full blood count
• chemistry profile
• weight gain
• edema
• liver function tests (baseline and monthly during chronic therapy)
• renal function (serum BUN, serum creatinine, urinealysis)
• occult blood loss
• blood pressure
• bleeding
• bruising
• gastrointestinal effects (bleeding, dyspepsia) should be strictly monitored.

How to administer Etodolac?

To avoid gastric distress, it is advised to take with food or milk.

Etodolac mechanism of action:

• It results in a reversible inhibition (COX-1 or 2) of cyclooxygenase-1, 2 (COX-2), enzymes.
• This causes decreased production of prostaglandin precursors.
• This drug is an anti-inflammatory, analgesic and anti-pyretic agent.
• Other possible mechanisms that contribute to anti-inflammatory effects to varying degrees have also been suggested, such as chemotaxis inhibition and altering lymphocyte activity.
• Neutrophil aggregation/activation inhibition has also been suggested.

The Onset of action:

• Analgesia: Immediate release: ~0.5 hour
• Arthritis (chronic management): Typically within 14 days
• Maximum effect: Analgesia: 1 to 2 hours

Duration of action:

• Mean range: 4 to 6 hours

Absorption

• rapid and is ≥80%

Protein binding:

• >99% is bound to albumin

Metabolism:

• Hepatic to several hydroxylated metabolites and etodolac glucuronide.
• Hydroxylated metabolites undergo further glucuronidation

Bioavailability:

• ≥80%

The terminal half-life elimination:

• Immediate release:
  • Children: 6.5 hours
  • Adults: 6.4 hours
• Extended-release:
  • Children: 12 hours;
  • Adults: 8.4 hours

The time to reach peak serum concentration:

• Immediate release:
  • Children (6 to 16 years, n=11): 1.4 hours (Boni 1999);
  • Adults: ~1 to 2 hours, increased 1.4 to 3.8 hours with food
• Extended-release: 5 to 7 hours

Excretion:

• Urine 73% (1% unchanged); feces 16% (clearance similar in pediatric patients and adults ~0.05 L/hour/kg).

Etodolac Brand Names (International):

• Lodine
• NU-Etodolac
• TARO-Etodolac
• Achera
• Acudor
• Dolchis
• Eccoxolac
• Ensidol
• ETL
• Etodin Fort
• Etodine
• Etoflam
• Etol
• Etonox
• Etopan
• Etopan XL
• Etova
• Etova-400
• Etova-500
• Flancox
• Hypen
• Jenac
• Lacoxa
• Lodine
• Lodine Retard
• Lodine SR
• Lodine XL
• Lonene
• Lonine
• Napilac
• Nimodol
• Nimodol SR
• Orpan
• Osteluc
• Pandolac
• Pandolac XR
• Punita
• Sodolac
• Todo
• Todolac
• Toselac

Etodolac Brand Names in Pakistan:

No Brands Available in Pakistan.