A Comprehensive Monograph on Etodolac (DB00749)

Executive Summary

Etodolac is a non-steroidal anti-inflammatory drug (NSAID) belonging to the pyranocarboxylic acid chemical class, utilized for its potent anti-inflammatory, analgesic, and antipyretic properties.[1] Its primary therapeutic application is in the management of pain and inflammation associated with chronic arthritic conditions, such as osteoarthritis and rheumatoid arthritis, as well as for the relief of acute pain.[3] The drug is also approved in an extended-release formulation for the treatment of juvenile rheumatoid arthritis in pediatric patients.[3]

The mechanism of action of Etodolac is centered on the inhibition of prostaglandin synthesis, which it achieves by blocking the activity of cyclooxygenase (COX) enzymes.[6] A defining characteristic of Etodolac is its preferential selectivity for the COX-2 isoform over the COX-1 isoform.[6] This selectivity is clinically significant as it aims to target inflammation at its source while potentially mitigating some of the gastrointestinal adverse effects associated with non-selective NSAIDs that heavily inhibit the protective COX-1 enzyme.[7]

Pharmacokinetically, Etodolac is well-absorbed orally with a bioavailability of at least 80%.[9] It is characterized by extensive binding (>99%) to plasma albumin, undergoes comprehensive hepatic metabolism, and is primarily eliminated via renal excretion of its metabolites.[6] Etodolac is commercially available in both immediate-release (IR) and extended-release (ER) formulations, which possess distinct pharmacokinetic profiles tailored to different clinical needs: rapid onset for acute pain management and sustained levels for chronic disease control, respectively.[1]

The use of Etodolac is governed by critical safety considerations, highlighted by U.S. Food and Drug Administration (FDA) Black Box Warnings. These warnings alert prescribers and patients to an increased risk of serious, and potentially fatal, cardiovascular thrombotic events (e.g., myocardial infarction, stroke) and serious gastrointestinal adverse events, including bleeding, ulceration, and perforation.[12] These class-wide NSAID risks necessitate a careful risk-benefit assessment for each patient, utilizing the lowest effective dose for the shortest possible duration.

Chemical Identity and Physicochemical Properties

The precise identification and characterization of a pharmaceutical agent's chemical and physical properties are fundamental to understanding its behavior in biological systems. Etodolac is a well-defined small molecule with distinct structural and physicochemical attributes that govern its absorption, distribution, and overall pharmacological activity.

Systematic Identification and Nomenclature

Etodolac is systematically classified and identified by a range of international standards. It belongs to the pyranocarboxylic acid group of NSAIDs and is further described chemically as a monocarboxylic acid and an organic heterotricyclic compound.[1] Its primary identifiers are summarized in Table 1. The drug is known by numerous synonyms, with the most common systematic chemical name being (±)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid.[6] Other common synonyms include Etodolic acid, Lodine, Ultradol, AY 24236, and NIH-9918.[6]

Chemical Structure and Stereochemistry

Etodolac possesses the molecular formula C17​H21​NO3​ and has an average molecular weight of approximately 287.36 g/mol.[3] The structural formula reveals a complex tricyclic indole core fused with a pyran ring, to which an acetic acid moiety is attached.

A critical aspect of its structure is its chirality. Etodolac is administered clinically as a racemic mixture, containing equal parts of the [+]S and [-]R-enantiomers.[1] The pharmacological activity, specifically the inhibition of COX enzymes, resides exclusively within the S-(+)-enantiomer.[2] The R-(-)-enantiomer is considered inactive with respect to prostaglandin synthesis inhibition, although some evidence suggests it may inhibit beta-catenin levels in certain cell types, indicating it may not be entirely biologically inert.[18] Both enantiomers are stable, and importantly, there is no evidence of

in vivo chiral inversion from the inactive R-form to the active S-form, a phenomenon observed with some other chiral NSAIDs.[6]

Physicochemical Properties

Etodolac is a white crystalline compound.[2] Its solubility profile is characterized by insolubility in water but good solubility in organic solvents such as alcohols, chloroform, dimethyl sulfoxide (DMSO), and ethanol.[2] Specific solubility data indicates concentrations of 100 mM in DMSO and ethanol, and 30 mg/ml in DMF.[8]

The drug's acid-base and lipophilic characteristics are key determinants of its pharmacokinetic behavior. It is a weak acid with a pKa of 4.65.[9] Its high lipophilicity is evidenced by an n-octanol:water partition coefficient of 11.4 at a physiological pH of 7.4.[9] This combination of weak acidity and high lipophilicity is directly responsible for its excellent absorption across the gastrointestinal mucosa, as the molecule is largely non-ionized and lipid-soluble in the acidic environment of the stomach. Once absorbed into the bloodstream (pH ~7.4), it becomes predominantly ionized, a state that drives its extensive binding to plasma proteins and influences its distribution throughout the body.

Table 1: Physicochemical and Identification Properties of Etodolac

Property	Value	Source(s)
Drug Name	Etodolac	3
DrugBank ID	DB00749	3
CAS Number	41340-25-4	15
ATC Code	M01AB08	3
IUPAC Name	(±)-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid	6
Molecular Formula	C17​H21​NO3​	3
Average Molecular Weight	287.35 - 287.37 g/mol	6
Appearance	White crystalline compound	2
Solubility	Insoluble in water; soluble in alcohols, DMSO, chloroform	8
Acidity (pKa)	4.65	9
Partition Coefficient	11.4 (n-octanol:water at pH 7.4)	9

Clinical Pharmacology and Mechanism of Action

The therapeutic utility of Etodolac is derived from its specific interactions with key enzymatic pathways involved in inflammation and pain signaling. Its pharmacodynamic profile is characterized by anti-inflammatory, analgesic, and antipyretic activities, which are the direct result of its molecular mechanism of action.[1]

Primary Mechanism of Action: Prostaglandin Synthesis Inhibition

The foundational mechanism of action for Etodolac, consistent with other NSAIDs, is the inhibition of prostaglandin synthesis.[6] Prostaglandins are lipid compounds that act as critical signaling molecules in the body, mediating the physiological responses of pain, fever, and inflammation.[7] Etodolac interrupts the production of these mediators by inhibiting the cyclooxygenase (COX) enzymes. These enzymes catalyze the conversion of arachidonic acid into prostaglandin precursors.[6] Structural studies indicate that Etodolac binds to the upper portion of the COX enzyme's active site, creating a physical blockade that prevents the substrate, arachidonic acid, from entering and being converted.[6] This reduction in prostaglandin levels at the site of injury or inflammation leads to a decrease in vasodilation, edema, and pain receptor sensitization, thereby producing its therapeutic effects.[7] Its antipyretic effect is thought to arise from a central action on the hypothalamus, leading to peripheral vasodilation and heat loss.[6]

Cyclooxygenase (COX) Enzyme Selectivity

A crucial aspect of Etodolac's pharmacology is its selectivity for the two primary isoforms of the COX enzyme, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and is responsible for producing prostaglandins that mediate homeostatic functions, such as maintaining the protective mucosal lining of the gastrointestinal tract and supporting platelet aggregation.[7] In contrast, COX-2 is typically absent from most tissues but is rapidly induced at sites of inflammation by cytokines and other inflammatory stimuli, making it the primary source of pro-inflammatory prostaglandins.[7]

Etodolac is not a non-selective inhibitor; it demonstrates a clear preferential inhibition of COX-2 over COX-1.[7] This selectivity represents a therapeutic balancing act. The goal is to achieve potent anti-inflammatory effects by inhibiting COX-2 at the site of inflammation while sparing COX-1 activity in the gut and platelets, thereby theoretically reducing the risk of gastrointestinal toxicity and bleeding complications compared to non-selective NSAIDs.[7]

The precise degree of this selectivity varies depending on the assay method used. Some reports indicate that Etodolac is 5 to 50 times more selective for COX-2 than COX-1.[6] Other studies have reported much higher selectivity ratios, such as 179-fold.[18] In vitro IC50 values (the concentration required to inhibit 50% of enzyme activity) from a human whole blood assay were 2.2 µM for COX-2 versus 12 µM for COX-1, while another study reported values of 53 µM for COX-2 and >100 µM for COX-1.[8] Despite these quantitative differences, the consistent finding is that Etodolac has "preferential selectivity" for COX-2.[18] It is important to note that this is not absolute specificity; Etodolac can still fully inhibit COX-1, particularly at higher therapeutic concentrations.[18] This incomplete separation of effects is central to its clinical profile, offering a potential GI safety advantage over traditional NSAIDs but not eliminating the risk of GI adverse events, which is why it still carries the class-wide black box warning for GI toxicity.[8]

Pharmacokinetic Profile: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Etodolac describes its movement into, through, and out of the body. It is characterized by efficient oral absorption, high protein binding, extensive hepatic metabolism, and primary renal excretion. Significant differences exist between the immediate-release (IR) and extended-release (ER) formulations, which are tailored for distinct therapeutic applications. The drug's kinetics are generally well-described by a two-compartment model with first-order absorption.[9]

Absorption

Etodolac is well-absorbed following oral administration and does not undergo significant first-pass metabolism.[1] Its systemic bioavailability is high, consistently reported as being at least 80% and as high as 100% when compared to an oral solution.[2]

The rate of absorption is the key differentiator between the two main oral formulations. The IR formulation is designed for rapid onset, achieving peak plasma concentrations (Tmax​) in approximately 1.4 hours.[1] In contrast, the ER formulation is designed for sustained drug release, with a significantly delayed

Tmax​ of approximately 6.7 hours.[1] This fundamental difference dictates their clinical use: IR for acute pain requiring fast relief, and ER for chronic conditions needing stable, once-daily dosing.

Plasma concentrations are generally dose-proportional up to certain limits (e.g., 400 mg q12h for IR). At higher single doses (e.g., 600 mg IR), peak concentrations can be about 20% higher than predicted by linear kinetics, suggesting a degree of saturation in clearance or distribution mechanisms.[9]

The presence of food does not affect the overall extent of Etodolac absorption but does alter the rate. With the IR formulation, food can delay Tmax​ by 1.4 to 3.8 hours and reduce the peak concentration (Cmax​) by approximately 50%.[11] Conversely, with the ER formulation, food can significantly increase

Cmax​ by 54%.[22] Antacids do not affect the extent of absorption but may slightly decrease

Cmax​ by 15-20%.[9]

Distribution

Once absorbed, Etodolac is extensively bound to plasma proteins, with over 99% bound primarily to albumin.[6] The unbound, pharmacologically active fraction is less than 1% and remains constant across the therapeutic dose range.[9] This high degree of protein binding restricts the drug's distribution into tissues, resulting in a relatively small apparent volume of distribution (

Vd​). The Vd​ is approximately 390 mL/kg for the IR formulation and slightly larger at 566 mL/kg for the ER formulation.[1]

Despite its high plasma binding, Etodolac effectively penetrates into inflamed joints. Studies have shown that it readily enters the synovial fluid. Critically for its therapeutic effect in arthritis, the concentration of the free, active drug in the synovial fluid remains higher than that in the serum during the post-distributive phase, ensuring sustained pharmacological activity at the target site.[24]

Metabolism

Etodolac undergoes extensive biotransformation in the liver.[2] The primary metabolic pathways are oxidation and glucuronidation. Several metabolites have been identified in human plasma and urine, including 6-, 7-, and 8-hydroxylated etodolac, as well as etodolac glucuronide.[9] These hydroxylated metabolites are pharmacologically less active and undergo further conjugation with glucuronic acid before excretion.[2] The specific cytochrome P450 (CYP) enzyme system responsible for the oxidative metabolism of Etodolac has not been identified.[2]

Excretion

The elimination of Etodolac and its metabolites occurs primarily through the kidneys. Approximately 72% of an administered dose is recovered in the urine, with fecal excretion accounting for another 16%.[6] Very little of the parent drug is excreted unchanged (~1% in urine). The majority of the renally excreted dose consists of metabolites: etodolac glucuronide (~13%), hydroxylated metabolites (~5%), hydroxylated metabolite glucuronides (~20%), and other unidentified metabolites (~33%).[6]

The oral clearance of Etodolac is approximately 47-49 mL/h/kg.[1] The terminal elimination half-life (

t1/2​) is formulation-dependent, averaging 6.4 to 7.3 hours for the IR formulation and extended to 8.4 hours for the ER formulation.[9] In pediatric patients with JRA, the half-life is notably longer, at approximately 12.1 hours.[10]

Table 2: Comparative Pharmacokinetic Parameters of Etodolac Formulations

Parameter	Immediate-Release (IR)	Extended-Release (ER)	Source(s)
Bioavailability (F)	≥80%	≥80%	10
Time to Peak (Tmax​)	1.4 hours	6.7 hours	1
Oral Clearance (CL/F)	49.1 mL/h/kg	46.8 mL/h/kg	1
Apparent Volume of Distribution (Vd​/F)	393 mL/kg	566 mL/kg	1
Terminal Half-Life (t1/2​)	6.4 - 7.3 hours	8.4 hours	9

Clinical Efficacy and Therapeutic Indications

Etodolac is approved for the symptomatic treatment of several inflammatory and pain-related conditions. Its clinical utility stems directly from its anti-inflammatory and analgesic properties. It is crucial to recognize that Etodolac provides symptomatic relief by targeting the inflammatory mediators but does not alter the underlying pathophysiology or progression of chronic diseases like arthritis.[27] Its role is to manage symptoms, improve function, and enhance quality of life.

Management of Osteoarthritis (OA)

Etodolac is widely indicated for the acute and long-term management of the signs and symptoms of osteoarthritis.[3] In patients with OA, it effectively alleviates key symptoms including joint pain, stiffness, swelling, and inflammation, thereby improving mobility and function.[4] Clinical trials have demonstrated that the efficacy of Etodolac in treating OA is comparable to that of other commonly prescribed NSAIDs, such as naproxen and nabumetone.[29]

Management of Rheumatoid Arthritis (RA)

The drug is also approved for the acute and long-term symptomatic treatment of rheumatoid arthritis.[3] RA is a systemic autoimmune disease characterized by chronic inflammation of the joints. Etodolac helps to control the pain, tenderness, swelling, and stiffness associated with the condition.[30] In the management of RA, Etodolac serves as an important adjunctive therapy for symptom control, often used alongside disease-modifying antirheumatic drugs (DMARDs) that target the underlying autoimmune process.

Treatment of Juvenile Rheumatoid Arthritis (JRA)

The extended-release formulation of Etodolac is specifically approved for the symptomatic treatment of juvenile rheumatoid arthritis in children and adolescents aged 6 to 16 years.[3] Clinical trials have confirmed its efficacy in controlling the signs and symptoms of JRA in this population, with a safety profile similar to that observed in adults.[22] The safety and effectiveness of Etodolac have not been established in children younger than 6 years of age.[13]

Analgesia for Acute Pain

The immediate-release formulations of Etodolac are indicated for the management of mild to moderate acute pain.[3] Its rapid onset of action makes it suitable for various acute pain states, including postoperative pain and pain following traumatic injury.[6] In some regions, Etodolac is available in combination products with other agents, such as the muscle relaxant thiocolchicoside or the H2-receptor antagonist famotidine, to manage specific types of pain or to mitigate gastrointestinal side effects.[6]

Dosage, Formulations, and Administration

The administration of Etodolac requires careful consideration of the specific indication, patient characteristics, and chosen formulation. The overarching principle of NSAID therapy is to use the lowest effective dose for the shortest duration necessary to achieve therapeutic goals, thereby minimizing the risk of adverse events.[26]

Available Formulations and Strengths

Etodolac is available in multiple oral dosage forms to accommodate different clinical needs [31]:

• Immediate-Release Capsules: 200 mg and 300 mg.
• Immediate-Release Tablets: 400 mg and 500 mg.
• Extended-Release (ER) Tablets: 400 mg, 500 mg, and 600 mg.

Administration Guidelines

To minimize the potential for gastrointestinal irritation, Etodolac may be administered with food, milk, or a full glass (8-12 oz) of water.[31] Extended-release tablets are designed for slow, continuous drug release and must be swallowed whole. They should never be crushed, broken, or chewed, as this would disrupt the release mechanism and could lead to a rapid release of the entire dose, increasing the risk of adverse effects.[27] In patients with chronic arthritic conditions, a therapeutic response is generally observed within one to two weeks of initiating therapy.[5]

Recommended Dosing Regimens

Dosage must be individualized based on the patient's response and tolerance. The recommended dosing regimens for approved indications are summarized in Table 3.

Table 3: Recommended Dosing Regimens for Approved Indications

Indication	Patient Population	Formulation	Recommended Dosage	Maximum Daily Dose	Source(s)
Acute Pain	Adults	Immediate-Release	200 - 400 mg every 6-8 hours	1000 mg	5
Osteoarthritis & Rheumatoid Arthritis	Adults	Immediate-Release	300 mg 2-3 times daily, OR 400-500 mg twice daily (Total 600-1000 mg/day)	1000 mg	5
Osteoarthritis & Rheumatoid Arthritis	Adults	Extended-Release	400 - 1000 mg once daily	1200 mg	27
Juvenile Rheumatoid Arthritis	Children (6-16 yrs)	Extended-Release	Weight-based, once daily:		5
	20-30 kg		400 mg	1000 mg
	31-45 kg		600 mg
	46-60 kg		800 mg
	>60 kg		1000 mg

Dose Adjustments in Special Populations

• Geriatric Patients: While specific pharmacokinetic-based dose adjustments are not generally required, elderly patients are at a higher risk for NSAID-related adverse effects, particularly renal and gastrointestinal toxicity. Therefore, therapy should be initiated at the lower end of the dosing range and patients should be monitored closely.[5]
• Renal Impairment: No dose adjustment is typically necessary for patients with mild-to-moderate renal dysfunction; however, caution is advised as NSAIDs can precipitate renal decompensation. Etodolac is not recommended for use in patients with severe renal impairment.[5]
• Hepatic Impairment: Dose adjustments are generally not needed for patients with compensated liver disease. However, clearance may be reduced in severe hepatic failure, warranting caution.[2]

Safety Profile, Adverse Reactions, and Risk Management

The safety profile of Etodolac is largely defined by the risks common to the entire NSAID class. While its preferential COX-2 selectivity may modulate the risk of certain adverse events, it does not eliminate them. A thorough understanding of its potential toxicities, contraindications, and warnings is essential for safe and effective use.

FDA Black Box Warnings

Etodolac carries the most serious warnings issued by the FDA, which are prominently displayed on its labeling to emphasize potentially fatal risks.[12]

• Cardiovascular Thrombotic Events: All non-aspirin NSAIDs, including Etodolac, are associated with an increased risk of serious cardiovascular thrombotic events, such as myocardial infarction (MI) and stroke, which can be fatal.[12] This risk can manifest early in the course of treatment and may increase with longer duration of use. Patients with pre-existing cardiovascular disease or those with risk factors for cardiovascular disease are at a greater baseline risk.[12] Consequently, Etodolac is contraindicated for the management of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery, as clinical trials in this setting have shown an increased incidence of MI and stroke.[12]
• Gastrointestinal Risk: NSAIDs are associated with an increased risk of serious gastrointestinal (GI) adverse events, including inflammation, bleeding, ulceration, and perforation of the stomach or intestines.[12] These events can occur at any time during therapy, may present without preceding warning symptoms, and can be fatal.[12] The risk for serious GI events is significantly higher in elderly patients.[12]

Contraindications

In addition to its use in the CABG setting, Etodolac is contraindicated in the following patient populations [12]:

• Patients with a known hypersensitivity to Etodolac or any of the product's components.
• Patients who have experienced asthma, urticaria (hives), or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, and sometimes fatal, anaphylactic reactions have been reported in these individuals.[18]

Warnings and Precautions

• Hepatotoxicity: Elevation of liver enzymes may occur. Although rare, severe hepatic reactions such as jaundice, fatal fulminant hepatitis, and liver necrosis have been reported with NSAID use. Therapy should be discontinued if signs or symptoms of liver disease develop.[1]
• Hypertension: NSAIDs can lead to the new onset or worsening of pre-existing hypertension, which may contribute to the increased risk of cardiovascular events. Blood pressure should be monitored closely during treatment.[14]
• Heart Failure and Edema: Fluid retention and edema have been observed in patients taking NSAIDs. Etodolac should be used with caution in patients with heart failure or pre-existing fluid retention.[1]
• Renal Toxicity: Long-term NSAID use can result in renal papillary necrosis and other forms of renal injury. Patients at highest risk include the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics or ACE inhibitors.[12]
• Serious Skin Reactions: NSAIDs can cause rare but severe and potentially life-threatening skin reactions, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN). Etodolac should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity.[1]
• Fetal Toxicity: Use of NSAIDs during the third trimester of pregnancy should be avoided as it may cause premature closure of the fetal ductus arteriosus.[1] Use at or after 20 weeks gestation can cause fetal renal dysfunction leading to oligohydramnios.[1] Etodolac has also been associated with developmental and female reproductive toxicity.[15]

Adverse Drug Reactions

The most frequently reported adverse reactions involve the gastrointestinal system. A summary of common and serious adverse effects includes:

• Common (1-10% incidence): Dyspepsia, abdominal pain, diarrhea, flatulence, nausea, constipation, headache, dizziness, rash, tinnitus, and fatigue.[12]
• Serious (less common): GI ulceration with or without bleeding/perforation, congestive heart failure, hypertension, anemia, thrombocytopenia, elevated liver enzymes, renal failure, pancreatitis, and severe skin reactions (SJS/TEN).[12]

Significant Interactions

Etodolac is subject to a large number of clinically significant interactions that can alter its efficacy and safety profile or that of concomitant medications. One database identifies 388 drug-drug interactions, with 100 classified as major and 280 as moderate.[34] Careful review of a patient's medication regimen is imperative before initiating therapy.

Drug-Drug Interactions

The most critical drug-drug interactions are summarized in Table 4. These interactions often arise from overlapping pharmacodynamic effects (e.g., bleeding risk, nephrotoxicity) or pharmacokinetic alterations (e.g., changes in renal clearance).

Table 4: Clinically Significant Drug-Drug Interactions of Etodolac

Interacting Drug/Class	Potential Effect	Clinical Recommendation/Management	Source(s)
Anticoagulants (e.g., Warfarin)	Increased risk of serious bleeding due to inhibited platelet function and potential for GI erosion.	Avoid combination if possible. Monitor coagulation parameters (e.g., INR) and for signs of bleeding closely.	18
Aspirin & other NSAIDs	Increased risk of serious GI adverse events (ulcers, bleeding) without additional therapeutic benefit.	Concurrent use is not recommended.	14
ACE Inhibitors & ARBs (e.g., Lisinopril, Losartan)	Diminished antihypertensive effect. Increased risk of renal impairment, especially in elderly or volume-depleted patients.	Monitor blood pressure and renal function.	26
Diuretics (Loop & Thiazide)	Reduced natriuretic effect of diuretics. Increased risk of nephrotoxicity.	Monitor for signs of worsening renal function and diuretic efficacy.	14
Lithium	Increased serum lithium levels and risk of lithium toxicity due to reduced renal clearance.	Avoid combination if possible. If used together, monitor lithium levels frequently.	18
Methotrexate	Increased plasma concentrations and hematological toxicity of methotrexate due to decreased renal clearance.	Use with caution, especially with high-dose methotrexate therapy. Monitor for methotrexate toxicity.	32
Ciclosporin	Increased risk of nephrotoxicity from both agents.	Monitor renal function closely if co-administered.	18
SSRIs (e.g., Fluoxetine, Sertraline)	Increased risk of bleeding, particularly GI bleeding.	Use with caution and monitor for signs of bleeding.	18
Oral Corticosteroids (e.g., Prednisone)	Increased risk of GI ulceration and bleeding.	Use with caution. Consider gastroprotective therapy in high-risk patients.	30

Drug-Lifestyle and Drug-Food Interactions

• Alcohol: Concomitant use of alcohol with Etodolac is considered a major interaction. Alcohol is a direct mucosal irritant and can significantly increase the risk of NSAID-induced stomach bleeding. Patients should be strongly advised to avoid consuming alcohol while taking Etodolac.[23]
• Tobacco: Smoking is also a major interaction that enhances the risk of gastrointestinal side effects, including peptic ulcer disease and GI bleeding. Patients should be counseled to avoid tobacco use during therapy.[23]
• Food: As noted in the Pharmacokinetics section, food does not alter the total amount of Etodolac absorbed but can affect the rate. Taking Etodolac with food is often recommended to reduce direct gastric irritation.[23]
• Supplements: Certain herbal supplements known to have anticoagulant or antiplatelet effects (e.g., white willow, agrimony, American ginseng) may increase the risk of bleeding when taken with Etodolac.[32] Patients taking Etodolac should not supplement with potassium without medical consultation due to the risk of hyperkalemia.[36]

Global Market and Brand Information

Etodolac was first patented in 1971 and received approval for medical use in the United States in 1991.[18] It has since become a widely prescribed NSAID globally for its efficacy in treating arthritis and pain.

Brand Names in the United States

In the U.S. market, Etodolac is most commonly known by its brand names, which correspond to its release formulation [3]:

• Lodine®: Immediate-release capsules and tablets.
• Lodine® XL: Extended-release tablets.

In addition to the brand-name products, generic versions of Etodolac are widely available, which has increased its accessibility.[26] In 2023, it was the 296th most commonly prescribed medication in the United States.[18]

International Brand Names

Etodolac is marketed worldwide under a multitude of brand names, reflecting its extensive global use. A selection of these international brands includes [18]:

• Canada: Lodine, and generic Etodolac from manufacturers such as Apotex Inc..[38]
• United Kingdom: Lodine SR, Eccoxolac, Ebretin, Etopan.[18]
• Europe (selected):
• France: Lodine.[18]
• Italy: Lodine.[26]
• Portugal: Dualgan, Sodolac, Articulan.[18]
• Turkey: Dolarit, Edolar, Etol, Barca.[18]
• Bulgaria: Etodin Fort.[18]
• India: Etogesic, Etova, Proxym, Etura, Penalgon-ER, Cutodo.[18]
• Japan: Haipen, Akomicol, Niconas, Osteluc.[18]
• Brazil: Flancox.[18]
• South Korea: Etodin.[18]
• Egypt: Etodine.[18]

This widespread availability underscores Etodolac's established role in the global management of inflammatory and painful conditions.

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