Etodolac (Page 6 of 8)

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including etodolac, can cause premature closure of the fetal ductus arteriosus (see WARNINGS, Fetal Toxicity).

Oligohydramnios/Neonatal Renal Impairment

If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If etodolac treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue etodolac and follow up according to clinical practice (see WARNINGS, Fetal Toxicity).

Data

Human Data

Premature Closure of Fetal Ductus Arteriosus

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number ofcase reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of etodolac on labor and delivery in pregnant women are unknown.

Nursing Mothers

Trace amounts of some NSAIDs have been reported in human milk. It is not known whether etodolac is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from etodolac, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric Use

As with any NSAID, caution should be exercised in treating the elderly (65 years and older) and when increasing the dose (see WARNINGS).

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 adjustment is generally necessary in the elderly on the basis of pharmacokinetics (see CLINICAL PHARMACOLOGY , Special Populations).

Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients (see WARNINGS). In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population.

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 (see WARNINGS , Renal Effects).

ADVERSE REACTIONS

In patients taking etodolac or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 10% of patients are:

Gastrointestinal experiences including

Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting.

Other events including

Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritis, rashes, tinnitus.

Adverse reaction information for etodolac was derived from 2,629 arthritic patients treated with etodolac in double-blind and open-label clinical trials of 4 to 320 weeks in duration and worldwide post-marketing surveillance studies. In clinical trials, most adverse reactions were mild and transient. The discontinuation rate in controlled clinical trials, because of adverse events, was up to 10% for patients treated with etodolac.

New patient complaints (with an incidence greater than or equal to 1%) are listed below by body system. The incidences were determined from clinical trials involving 465 patients with osteoarthritis treated with 300 mg to 500 mg of etodolac b.i.d. (i.e., 600 mg/day to 1000 mg/day).

Incidence Greater Than Or Equal To 1% — Probably Causally Related

Body as a Whole

Chills and fever.

Digestive System

Dyspepsia (10%), abdominal pain1 , diarrhea2 , flatulence3 , nausea4 , abdominal distension, epigastric pain, abnormal stools, constipation, gastritis, melena, vomiting.

Nervous System

Asthenia/malaise5 , dizziness6 , depression, nervousness, fatigue.

Skin and Appendages

Pruritus, rash.

Special Senses

Blurred vision, tinnitus.

Urogenital System

Dysuria, urinary frequency.

Musculoskeletal

Arthralgia

1 Drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac.

2 Drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac.

3 Drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac.

4 Drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac.

5 Drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac.

6 Drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac.

Drug-related patient complaints occurring in fewer than 3%, but more than 1%, are unmarked.

Incidence Less Than 1% — Probably Causally Related

(Adverse reactions reported only in worldwide post-marketing experience, not seen in clinical trials, are considered rarer and are italicized.)

Body as a Whole

Allergic reaction, anaphylactic/anaphylactoid reactions (including shock).

Cardiovascular System

Hypertension, congestive heart failure, flushing, palpitations, syncope, vasculitis (including necrotizing and allergic).

Digestive System

Thirst, dry mouth, ulcerative stomatitis, anorexia, eructation, elevated liver enzymes, cholestatic hepatitis, hepatitis, cholestatic jaundice, duodenitis, jaundice, hepatic failure, liver necrosis, peptic ulcer with or without bleeding and/or perforation, intestinal ulceration, pancreatitis.

Hemic and Lymphatic System

Ecchymosis, anemia, thrombocytopenia, bleeding time increased, agranulocytosis, hemolytic anemia, aplastic anemia, leukopenia, neutropenia, pancytopenia.

Metabolic and Nutritional

Edema, serum creatinine increase, hyperglycemia in previously controlled diabetic patients.

Nervous System

Insomnia, somnolence.

Respiratory System

Asthma, pulmonary infiltration with eosinophilia.

Skin and Appendages

Angioedema, sweating, urticaria, exfoliative dermatitis, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson Syndrome, toxic epidermal necrolysis , leukocytoclastic vasculitis , hyperpigmentation, erythema multiforme.

Special Senses

Photophobia, transient visual disturbances.

Urogenital System

Elevated BUN, renal failure, renal insufficiency, renal papillary necrosis.

Incidence Less Than 1% — Causal Relationship Unknown

(Medical events occurring under circumstances where causal relationship to etodolac is uncertain. These reactions are listed as alerting information for physicians.)

Body as a Whole

Infection, headache.

Cardiovascular System

Arrhythmias, myocardial infarction, cerebrovascular accident.

Digestive System

Esophagitis with or without stricture or cardiospasm, colitis, GI discomfort, burning sensation, blood in stools, gastralgia, upper abdominal discomfort.

Metabolic and Nutritional

Change in weight.

Nervous System

Paresthesia, confusion, irritability.

Respiratory System

Bronchitis, bronchospasm, dyspnea, pharyngitis, rhinitis, sinusitis.

Skin and Appendages

Alopecia, maculopapular rash, photosensitivity, skin peeling.

Special Senses

Conjunctivitis, deafness, taste perversion, loss of taste.

Urogenital System

Cystitis, hematuria, leukorrhea, renal calculus, interstitial nephritis, uterine bleeding irregularities, renal impairment.

Musculoskeletal

Muscle pain.

Additional Adverse Reactions Reported with NSAIDs

Body as a Whole

Sepsis, death

Cardiovascular System

Tachycardia

Digestive System

Gastric ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis

Hemic and Lymphatic System

Lymphadenopathy

Nervous System

Anxiety, dream abnormalities, convulsions, coma, hallucinations, meningitis, tremors, vertigo

Respiratory System

Respiratory depression, pneumonia

Urogenital System

Oliguria/polyuria, proteinuria

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