Clinoril Warnings, Precautions, Pregnancy, Nursing, Abuse - Sulindac

Clinoril Warnings, Precautions, Pregnancy, Nursing, Abuse - Sulindac

WARNINGS

Peptic ulceration and gastrointestinal bleeding have been reported in patients receiving CLINORIL. Fatalities have occurred. Gastrointestinal bleeding is associated with higher morbidity and mortality in patients acutely ill with other conditions, the elderly and patients with hemorrhagic disorders. In patients with active gastrointestinal bleeding or an active peptic ulcer, an appropriate ulcer regimen should be instituted, and the physician must weigh the benefits of therapy with CLINORIL against possible hazards, and carefully monitor the patient’s progress. When CLINORIL is given to patients with a history of either upper or lower gastrointestinal tract disease, it should be given under close supervision and only after consulting the ADVERSE REACTIONS section.

Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.

Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.

Rarely, fever and other evidence of hypersensitivity (see ADVERSE REACTIONS) including abnormalities in one or more liver function tests and severe skin reactions have occurred during therapy with CLINORIL. Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with or without fever, may occur usually within the first one to three months of therapy. Determinations of liver function should be considered whenever a patient on therapy with CLINORIL develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with CLINORIL should be discontinued. The elevated temperature and abnormalities in liver function caused by CLINORIL characteristically have reverted to normal after discontinuation of therapy. Administration of CLINORIL should not be reinstituted in such patients.

In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent with those of cholestatic hepatitis. As with other non-steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests without any other signs and symptoms may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. 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 more severe hepatic reaction while on therapy with CLINORIL. Although such reactions as described above are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), CLINORIL should be discontinued.

In clinical trials with CLINORIL, the use of doses of 600 mg/day has been associated with an increased incidence of mild liver test abnormalities (see DOSAGE AND ADMINISTRATION for maximum dosage recommendation).

Non-steroidal anti-inflammatory drugs, including CLINORIL, may mask the usual signs and symptoms of infection. Therefore, the physician must be continually on the alert for this and should use the drug with extra care in the presence of existing infection.

Although CLINORIL has less effect on platelet function and bleeding time than aspirin, it is an inhibitor of platelet function; therefore, patients who may be adversely affected should be carefully observed when CLINORIL is administered.

Pancreatitis has been reported in patients receiving CLINORIL (see ADVERSE REACTIONS). Should pancreatitis be suspected, the drug should be discontinued and not restarted, supportive medical therapy instituted, and the patient monitored closely with appropriate laboratory studies (e.g., serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase, etc.). A search for other causes of pancreatitis as well as those conditions which mimic pancreatitis should be conducted.

Because of reports of adverse eye findings with non-steroidal anti-inflammatory agents, it is recommended that patients who develop eye complaints during treatment with CLINORIL have ophthalmologic studies.

In patients with poor liver function, delayed, elevated and prolonged circulating levels of the sulfide and sulfone metabolites may occur. Such patients should be monitored closely; a reduction of daily dosage may be required.

Edema has been observed in some patients taking CLINORIL. Therefore, as with other non-steroidal anti-inflammatory drugs, CLINORIL should be used with caution in patients with compromised cardiac function, hypertension, or other conditions predisposing to fluid retention.

CLINORIL may allow a reduction in dosage or the elimination of chronic corticosteroid therapy in some patients with rheumatoid arthritis. However, it is generally necessary to reduce corticosteroids gradually over several months in order to avoid an exacerbation of disease or signs and symptoms of adrenal insufficiency. Abrupt withdrawal of chronic corticosteroid treatment is generally not recommended even when patients have had a serious complication of chronic corticosteroid therapy.

As with other non-steroidal anti-inflammatory drugs, long-term administration of sulindac to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal and renal conditions leading to a reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. CLINORIL may affect renal function less than other NSAIDs in patients with chronic glomerular renal disease (see CLINICAL PHARMACOLOGY). Until these observations are better understood and clarified, however, and because renal adverse experiences have been reported with CLINORIL (see ADVERSE REACTIONS), caution should be exercised when administering the drug to patients with conditions associated with increased risk of the effects of non-steroidal anti-inflammatory drugs on renal function, such as those with renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion from any cause, congestive heart failure, septicemia, pyelonephritis, or concomitant use of any nephrotoxic drug. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.

Since CLINORIL is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be anticipated to avoid excessive drug accumulation.

Sulindac metabolites have been reported rarely as the major or a minor component in renal stones in association with other calculus components. CLINORIL should be used with caution in patients with a history of renal lithiasis, and they should be kept well hydrated while receiving CLINORIL.

CLINORIL, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes.

NSAIDs (Non-steroidal Anti-inflammatory Drugs) are often essential agents in the management of arthritis, but they also may be commonly employed for conditions which are less serious.

Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.

Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up (see WARNINGS, Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy).

CLINORIL is not recommended for use in pregnant women, since safety for use has not been established. The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.

In reproduction studies in the rat, a decrease in average fetal weight and an increase in numbers of dead pups were observed on the first day of the postpartum period at dosage levels of 20 and 40 mg/kg/day (2½ and 5 times the usual maximum daily dose in humans), although there was no adverse effect on the survival and growth during the remainder of the postpartum period. CLINORIL prolongs the duration of gestation in rats, as do other compounds of this class which also may cause dystocia and delayed parturition in pregnant animals. Visceral and skeletal malformations observed in low incidence among rabbits in some teratology studies did not occur at the same dosage levels in repeat studies, nor at a higher dosage level in the same species.

Nursing should not be undertaken while a patient is on CLINORIL. It is not known whether sulindac is secreted in human milk; however, it is secreted in the milk of lactating rats.

Safety and effectiveness in pediatric patients have not been established.

As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population (see WARNINGS, Gastrointestinal Effects and Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy).

This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 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 PRECAUTIONS, Renal Effects).