Stadolac 200

Rx

Indications

• For acute and long-term use in the management of signs and symptoms of the following:
  Osteoarthritis.
  Rheumatoid arthritis.
• For the management of acute pain.

Dosage

• Analgesia
  The recommended total daily dose of etodolac for acute pain is up to 1,000 mg, given as 200 to 400 mg every 6 to 8 hours. Doses of etodolac greater than 1,000 mg/day have not been adequately evaluated in well – controlled clinical trials.
• Osteoarthritis and rheumatoid arthritis
  The recommended starting dose of etodolac for the management of the signs and symptoms of osteoarthritis or rheumatoid arthritis is: 300 mg b.i.d., t.i.d., or 400 mg b.i.d., or 500 mg b.i.d. A lower dose of 600 mg/day may suffice for long-term administration.
  Physicians should be aware that doses above 1,000 mg/day have not been adequately evaluated in well-controlled clinical trials.
  In chronic conditions, a therapeutic response to therapy with etodolac is sometimes seen within one week of therapy, but most often is observed by two weeks. After a satisfactory response has been achieved, the patient’s dose should be reviewed and adjusted as required.
  Special populations
• Renal insuffiency
  Dosage adjustment of etodolac is generally not required in patients with mild to moderate renal impairment. Etodolac should be used with caution in such patients, because, as with other NSAIDs, it may further decrease renal function in some patients with impaired renal function.
• Geriatric use:
  As with any NSAID, caution should be exercised in treating the elderly (65 years and older) and when increasing the dose.
  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.
  Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients. 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.
• Pediatric use:
  Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Usage

• Stadolac 200 is administered via the oral route.

• Patients with known hypersensitivity to etodolac or other ingredients in Stadolac 200 capsules.
• Patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
• In the setting of coronary artery bypass graft (CABG) surgery.

Risk of cardiovascular thrombotic events

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 postmarketing 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 to 500 mg of etodolac b.i.d. (i.e., 600 to 1,000 mg/day).

Incidence greater than or equal to 1% – probably causally related

• Chills and fever.
• Dyspepsia (10%), abdominal pain*, diarrhea*, flatulence*, nausea*, abdominal distension, epigastric pain, abnormal stools, constipation, gastritis, melena, vomiting.
• Asthenia/malaise*, dizziness*, depression, nervousness, fatigue.
• Pruritus, rash.
• Blurred vision, tinnitus.
• Dysuria, urinary frequency.
• Arthralgia
  * 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 postmarketing experience, not seen in clinical trials, are considered rarer and are italicized.)

• Allergic reaction, anaphylactic/anaphylactoid reactions (including shock).
• Hypertension, congestive heart failure, flushing, palpitations, syncope, vasculitis (including necrotizing and allergic).
• Thirst, dry mouth, ulcerative stomatitis, anorexia, eructation, elevated liver enzymes, cholestatic hepatitis, hepatitis, cholestatic jaundice, duodenitis, jaundice, hepatic failure, liver necrosis, fatal fulminant hepatitis, peptic ulcer with or without bleeding and/or perforation, intestinal ulceration, pancreatitis.
• Ecchymosis, anemia, thrombocytopenia, bleeding time increased, agranulocytosis, hemolytic anemia, aplastic anemia, leukopenia, neutropenia, pancytopenia.
• Edema, serum creatinine increase, hyperglycemia in previously controlled diabetic patients.
• Insomnia, somnolence.
• Asthma, pulmonary infiltration with eosinophilia.
• Angioedema, sweating, urticaria, exfoliative dermatitis, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson syndrome, toxic epidermal necrolysis, leukocytoclastic vasculitis, hyperpigmentation, erythema multiforme.
• Photophobia, transient visual disturbances.
• 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.)

• Infection, headache.
• Arrhythmias, myocardial infarction, cerebrovascular accident.
• Esophagitis with or without stricture or cardiospasm, colitis, GI discomfort, burning sensation, blood in stools, gastralgia, upper abdominal discomfort.
• Change in weight.
• Paresthesia, confusion, irritability.
• Bronchitis, bronchospasm, dyspnea, pharyngitis, rhinitis, sinusitis.
• Alopecia, maculopapular rash, photosensitivity, skin peeling.
• Conjunctivitis, deafness, taste perversion, loss of taste.
• Cystitis, hematuria, leukorrhea, renal calculus, interstitial nephritis, uterine bleeding irregularities, renal impairment.
• Muscle pain.

Additional adverse reactions reported with NSAIDS

• Sepsis, death.
• Tachycardia.
• Gastric ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis.
• Lymphadenopathy.
• Anxiety, dream abnormalities, convulsions, coma, hallucinations, meningitis, tremors, vertigo.
• Respiratory depression, pneumonia.
• Oliguria/polyuria, proteinuria.

Risk of cardiovascular thrombotic events

• Systemic non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, either of which can be fatal. This risk may occur as early as the first weeks of treatment and may increase with duration of use. The cardiovascular thrombotic risk has been observed most consistently at higher doses.
• Physicians should assess periodically appearance of cardiovascular adverse events, even in the absence of previous cardiovascular symptoms. Patients should be warned about the symptoms of serious cardiovascular events and seek physicians immediately if these symptoms occur.
• To minimize the risk for an adverse cardiovascular event in patients treated with etodolac, prescribe the lowest effective daily dose for the shortest duration possible.

Warnings
Cardiovascular effects

• Cardiovascular thrombotic events
  Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
  There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as etodolac, increases the risk of serious gastrointestinal (GI) events.
• Status post coronary artery bypass graft (CABG) surgery
  Two-large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.
• Post-MI patients
  Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first-year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
  Avoid the use of etodolac in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If etodolac is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
• Hypertension
  NSAIDs, including etodolac, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including etodolac, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
• Heart failure and edema
  The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
  Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of etodolac may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)].
  Avoid the use of etodolac in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If etodolac is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Gastrointestinal (GI) effects-risk of gi ulceration, bleeding, and perforation

• NSAIDs, including etodolac, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.
• NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease, and/or gastrointestinal bleeding, and who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore, special care should be taken in treating this population.
• To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal effects

• Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which mayprecipitate overt renal decompensation. Patients at greater risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
• Renal pelvic transitional epithelial hyperplasia, a spontaneous change occurring with variable frequency, was observed with increased frequency in treated male rats in a 2-year chronic study.
  Caution is recommended in patients with pre-existing kidney disease.

Advanced renal disease

• No information is available from controlled clinical studies regarding the use of etodolac in patients with advanced renal disease. Therefore, treatment with etodolac is not recommended in these patients with advanced renal disease. If etodolac therapy must be initiated, close monitoring of the patient’s renal function is advisable.

Anaphylactoid reactions

• As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to etodolac. Etodolac should not be given to patients with the aspirin triad.
  This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Fatal reactions have been reported in such patients.
• Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin reactions

• NSAIDs, including etodolac, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Drug reaction with eosinophilia and systemic symptoms (DRESS)

• DRESS has been reported in patients taking NSAIDs such as etodolac. Some of these events have been fatal or lifethreatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved.
  It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue etodolac and evaluate the patient immediately.

Fetal toxicity

• Premature closure of fetal ductus arteriosus: Avoid use of NSAIDs, including etodolac, in pregnant women at about 30 weeks gestation and later. NSAIDs including etodolac, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
• Oligohydramnios/neonatal renal impairment
  Use of NSAIDs, including etodolac, at about 20 weeks gestation or later in pregnancy may cause 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. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
  If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit etodolac use to the lowest effective dose and shortest duration possible.
  Consider ultrasound monitoring of amniotic fluid if etodolac treatment extends beyond 48 hours. Discontinue etodolac if oligohydramnios occurs and follow up according to clinical practice.

Precautions

• General
  Etodolac cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation.
  Patients on prolonged corticosteroid therapy should have their therapy tapered solely if a decision is made to discontinue corticosteroids.
  The pharmacological activity of etodolac in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
• Hepatic effects
  Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including etodolac. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported.
  A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with etodolac. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), etodolac should be discontinued.
• Hematological effects
  Anemia is sometimes seen in patients receiving NSAIDs including etodolac. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including etodolac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
  NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving etodolac who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
• Pre-existing asthma
  Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthmas has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, etodolac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma.
• Laboratory tests
  Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically for signs or symptoms of anemia. Appropriate measures should be taken in case such signs of anemia occur. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, etodolac should be discontinued.
• Excipients
  Stadolac 200 contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
  Stadolac 200 contains less than 1 mmol sodium (23 mg) per hard gelatin capsule, that is to say essentially ‘sodium-free’.
• Use of NSAIDs, including etodolac, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of etodolac use between about 20 and 30 weeks of gestation and avoid etodolac use at about 30 weeks of gestation and later in pregnancy.
• 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.
• There is no evidence that etodolac affects the ability to drive or to operate machinery.