Unidac

Considere cuidadosamente los posibles beneficios y riesgos de Unidac (sulindac) y otras opciones de tratamiento antes de decidir usar Unidac (sulindac). Use la dosis efectiva más baja para la menor duración consistente con los objetivos individuales de tratamiento del paciente (ver ADVERTENCIAS).

Unidac (sulindac) está indicado para uso agudo o a largo plazo en el alivio de signos y síntomas de lo siguiente:

1. Osteoartritis
2. Artritis reumatoide **
3. Espondilitis anquilosante
4. Hombro agudo y doloroso (bursitis subacromial aguda / tendinitis supraspinatus)
5. Artritis gotosa aguda

Considere cuidadosamente los posibles beneficios y riesgos de Unidac (sulindac) y otras opciones de tratamiento antes de decidir usar Unidac (sulindac). Use la dosis efectiva más baja para la menor duración consistente con los objetivos individuales de tratamiento del paciente (ver ADVERTENCIAS).

Después de observar la respuesta a la terapia inicial con Unidac (sulindac), la dosis y la frecuencia deben ajustarse para satisfacer las necesidades de un paciente individual.

Unidac (sulindac) debe administrarse por vía oral dos veces al día con alimentos. La dosis máxima es de 400 mg por día. No se recomiendan dosis superiores a 400 mg por día.

En la osteoartritis, la artritis reumatoide y la espondilitis anquilosante, la dosis inicial recomendada es de 150 mg dos veces al día. La dosis puede reducirse o aumentarse según la respuesta.

Se puede esperar una respuesta rápida (dentro de una semana) en aproximadamente la mitad de los pacientes con osteoartritis, espondilitis anquilosante y artritis reumatoide. Otros pueden requerir más tiempo para responder.

En el hombro doloroso agudo (bursitis subacromial aguda / tendinitis supraspinatus) y artritis gotosa aguda, la dosis recomendada es de 200 mg dos veces al día. Después de lograr una respuesta satisfactoria, la dosis puede reducirse de acuerdo con la respuesta. En el hombro doloroso agudo, la terapia durante 714 días suele ser adecuada. En la artritis gotosa aguda, la terapia durante 7 días suele ser adecuada.

Unidac (sulindac) is contraindicated in patients with known hypersensitivity to sulindac or the excipients (see DESCRIPTION).

Unidac (sulindac) should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactic/Anaphylactoid Reactions, and PRECAUTIONS – Preexisting Asthma).

Unidac (sulindac) is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

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 does increase the risk of serious GI events (see GI WARNINGS).

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 1014 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including Unidac (sulindac) , 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 Unidac (sulindac) , 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.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Unidac (sulindac) should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including Unidac (sulindac) , 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 3-6 months, and in about 2-4% 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.

NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding 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.

Hepatic Effects

In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent with those of cholestatic hepatitis (see WARNINGS, Hypersensitivity). As with other non-steroidal antiinflammatory drugs, borderline elevations of one or more liver tests without any other signs and symptoms may occur in up to 15% of patients taking NSAIDs including Unidac (sulindac). These laboratory 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. 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 Unidac (sulindac). 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.), Unidac (sulindac) should be discontinued.

In clinical trials with Unidac (sulindac) , 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).

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 non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume-depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

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

Anaphylactic/Anaphylactoid Reactions

As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to Unidac (sulindac). Unidac (sulindac) 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 (see CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma). Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including Unidac (sulindac) , 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.

Hypersensitivity

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 Unidac (sulindac). 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 Unidac (sulindac) develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with Unidac (sulindac) should be discontinued. The elevated temperature and abnormalities in liver function caused by Unidac (sulindac) characteristically have reverted to normal after discontinuation of therapy. Administration of Unidac (sulindac) should not be reinstituted in such patients.

Pregnancy

In late pregnancy, as with other NSAIDs, Unidac (sulindac) should be avoided because it may cause premature closure of the ductus arteriosus.

PRECAUTIONS

General

Unidac (sulindac) 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 slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of Unidac (sulindac) in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Unidac (sulindac). 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 Unidac (sulindac) , 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 Unidac (sulindac) who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Unidac (sulindac) should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Renal Calculi

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

Pancreatitis

Pancreatitis has been reported in patients receiving Unidac (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.

Ocular Effects

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 Unidac (sulindac) have ophthalmologic studies.

Hepatic Insufficiency

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.

SLE and Mixed Connective Tissue Disease

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, there may be an increased risk of aseptic meningitis (see ADVERSE REACTIONS).

Information for Patients

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1. Unidac (sulindac) , like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
2. Unidac (sulindac) , like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
3. Unidac (sulindac) , like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, Unidac (sulindac) should be avoided because it may cause premature closure of the ductus arteriosus.

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. 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, Unidac (sulindac) should be discontinued.

Pregnancy

Teratogenic Effects. Pregnancy Category C.

Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Unidac (sulindac) should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

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. Unidac (sulindac) prolongs the duration of gestation in rats, as do other compounds of this class. 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.

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 Unidac (sulindac) on labor and delivery in pregnant women are unknown.

Nursing Mothers

It is not known whether this drug is excreted in human milk; however, it is secreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Unidac (sulindac) , 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 have not been established.

Geriatric Use

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 -Risk of Ulceration, Bleeding, and Perforation).

Unidac (sulindac) 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 WARNINGS, Renal Effects).

The following adverse reactions were reported in clinical trials or have been reported since the drug was marketed. The probability exists of a causal relationship between Unidac (sulindac) and these adverse reactions. The adverse reactions which have been observed in clinical trials encompass observations in 1,865 patients, including 232 observed for at least 48 weeks.

Incidence Greater Than 1%

Gastrointestinal

The most frequent types of adverse reactions occurring with Unidac (sulindac) are gastrointestinal; these include gastrointestinal pain (10%), dyspepsia***, nausea*** with or without vomiting, diarrhea***, constipation***, flatulence, anorexia and gastrointestinal cramps.

Dermatologic

Rash***, pruritus.

Central Nervous System

Dizziness***, headache***, nervousness.

Special Senses

Tinnitus.

Miscellaneous

Edema (see WARNINGS).

Incidence Less Than 1 in 100

Gastrointestinal

Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI perforation and intestinal strictures (diaphragms) have been reported rarely.

Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure.

There have been rare reports of sulindac metabolites in common bile duct “sludge” and in biliary calculi in patients with symptoms of cholecystitis who underwent a cholecystectomy.

Pancreatitis (see PRECAUTIONS).

Ageusia; glossitis.

Dermatologic

Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.

Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis have been reported.

Cardiovascular

Congestive heart failure, especially in patients with marginal cardiac function; palpitation; hypertension.

Hematologic

Thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia; bone marrow depression, including aplastic anemia; hemolytic anemia; increased prothrombin time in patients on oral anticoagulants (see PRECAUTIONS).

Genitourinary

Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome.

Renal calculi containing sulindac metabolites have been observed rarely.

Metabolic

Hyperkalemia.

Musculoskeletal

Muscle weakness.

Psychiatric

Depression; psychic disturbances including acute psychosis.

Nervous System

Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis (especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, see PRECAUTIONS).

Special Senses

Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste.

Respiratory

Epistaxis.

Hypersensitivity Reactions

Anaphylaxis; angioneurotic edema; urticaria; bronchial spasm; dyspnea.

Hypersensitivity vasculitis.

A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic reactions - see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain, tachycardia).

Causal Relationship Unknown

A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, sometimes with fatal outcome (see also PRECAUTIONS, General).

Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians.

Cardiovascular

Arrhythmia.

Metabolic

Hyperglycemia.

Nervous System

Neuritis.

Special Senses

Disturbances of the retina and its vasculature.

Miscellaneous

Gynecomastia.

*** Incidence between 3% and 9%. Those reactions occurring in 1% to 3% of patients are not marked with an asterisk.

Gestión de sobredosis

Se han reportado casos de sobredosis y rara vez, se han producido muertes. Se pueden observar los siguientes signos y síntomas después de una sobredosis: estupor, coma, disminución de la producción de orina e hipotensión.

En caso de sobredosis, el estómago debe vaciarse induciendo vómitos o lavado gástrico, y el paciente debe observar cuidadosamente y recibir tratamiento sintomático y de apoyo.

Los estudios en animales muestran que la absorción disminuye por la pronta administración de carbón activado y la excreción se ve reforzada por la alcalinización de la orina.

Unidac (sulindac) es un medicamento antiinflamatorio no esteroideo (AINE) que exhibe actividades antiinflamatorias, analgésicas y antipiréticas en modelos animales. El mecanismo de acción, como el de otros AINE, no se comprende completamente, pero puede estar relacionado con la inhibición de la prostaglandina sintetasa.

Absorción

El grado de absorción de sulindaco de las tabletas Unidac es similar en comparación con la solución de sulindac.

No hay información sobre el efecto alimentario sobre la absorción de sulindaco. Se ha demostrado que los antiácidos que contienen hidróxido de magnesio 200 mg e hidróxido de aluminio 225 mg por 5 ml no disminuyen significativamente el grado de absorción de sulindaco.

CUADRO 1

Distribución

Sulindac, y sus metabolitos de sulfona y sulfuro, se unen 93.1, 95.4 y 97.9% a proteínas plasmáticas, predominantemente a albúmina. La unión a proteínas plasmáticas medida en un rango de concentración (0.5-2.0 μg / ml) fue constante. Después de una dosis oral de sulfindac radiomarcada en ratas, las concentraciones de radiomarcabel en los glóbulos rojos fueron aproximadamente el 10% de las del plasma. Sulindac penetra las barreras del cerebro y la placenta. Las concentraciones en el cerebro no superaron el 4% de las del plasma. Las concentraciones plasmáticas en la placenta y en el feto fueron inferiores al 25% y al 5% respectivamente, de las concentraciones plasmáticas sistémicas. Sulindac se excreta en la leche de rata; las concentraciones en la leche fueron del 10 al 20% de esos niveles en plasma. No se sabe si el sulindac se excreta en la leche humana.

Metabolismo

Sulindac se somete a dos biotransformaciones principales de su resto sulfóxido: oxidación a la sulfona inactiva y reducción al sulfuro farmacológicamente activo. Este último es fácilmente reversible en animales y en el hombre. Estos metabolitos están presentes como compuestos sin cambios en el plasma y principalmente como conjugados de glucurónido en orina y bilis humanas. Un análogo dihidroxidihidroeléctrico también se ha identificado como un metabolito menor en la orina humana.

Con el régimen de dosificación dos veces al día, se acumulan concentraciones plasmáticas de sulindac y sus dos metabolitos: concentración media durante un intervalo de dosificación en estado estacionario en relación con los promedios de la primera dosis 1.5 y 2.5 veces más altos, respectivamente, para sulindac y su metabolito de sulfuro activo .

Sulindac y su metabolito sulfona sufren una extensa circulación enterohepática en relación con el metabolito sulfuro en animales. Los estudios en el hombre también han demostrado que la recirculación del fármaco original sulindac y su metabolito de sulfona es más extensa que la del metabolito de sulfuro activo. El metabolito de sulfuro activo representa menos del seis por ciento de la exposición intestinal total al sulindaco y sus metabolitos.

La evidencia bioquímica y farmacológica indica que la actividad de sulindac reside en su metabolito sulfuro. Un ensayo in vitro para la inhibición de la actividad ciclooxigenasa exhibió una CE50 de 0.02 μM para sulfuro de sulindaco. Los modelos de inflamación in vivo indican que la actividad está más altamente correlacionada con las concentraciones del metabolito que con las concentraciones de fármaco original.

Eliminación

Aproximadamente el 50% de la dosis administrada de sulindac se excreta en la orina con el metabolito de sulfona conjugado que representa la porción principal. Menos del 1% de la dosis administrada de sulindac aparece en la orina como el metabolito sulfuro. Aproximadamente el 25% se encuentra en las heces, principalmente como metabolitos de sulfona y sulfuro.

La vida media efectiva (T½) es de 7,8 y 16,4 horas, respectivamente, para el sulindaco y su metabolito de sulfuro activo.

Debido a que Unidac (sulindac) se excreta en la orina principalmente como formas biológicamente inactivas, posiblemente puede afectar la función renal en menor medida que otros medicamentos antiinflamatorios no esteroideos; sin embargo, se han informado experiencias adversas renales con Unidac (ver REACCIONES ADVERSAS).

En un estudio de pacientes con enfermedad glomerular crónica tratados con dosis terapéuticas de Unidac (sulindac), no se demostró ningún efecto sobre el flujo sanguíneo renal, la tasa de filtración glomerular o la excreción urinaria de prostaglandina E2 y el metabolito primario de la prostaciclina, 6-ceto-PGF1α . Sin embargo, en otros estudios en voluntarios sanos y pacientes con enfermedad hepática, se encontró que Unidac (sulindac) embota las respuestas renales a la furosemida intravenosa, es decir., la diuresis, la natriuresis, los incrementos en la actividad de la renina plasmática y la excreción urinaria de prostaglandinas. Estas observaciones pueden representar una diferenciación de los efectos de Unidac (sulindac) en las funciones renales en función de las diferencias en la patogénesis de la dependencia de prostaglandinas renales asociada con diferentes relaciones dosis-respuesta de diferentes AINE a las diversas funciones renales influenciadas por las prostaglandinas (ver PRECAUCIONES).

En hombres sanos, la pérdida promedio de sangre fecal, medida durante un período de dos semanas durante la administración de 400 mg por día de Unidac (sulindac), fue similar a la del placebo y fue estadísticamente significativamente menor que la resultante de 4800 mg por día de aspirina.