Unidac

Unidac(sulindac)の使用を決定する前に、Unidac(sulindac)およびその他の治療オプションの潜在的な利点とリスクを慎重に検討してください。. 個々の患者の治療目標と一致する最短の期間、最低有効量を使用します(参照。 警告。).

Unidac(sulindac)は、以下の兆候や症状の緩和における急性または長期の使用に適応されます。

1. 変形性関節症。
2. 関節リウマチ**。
3. 強直性脊椎炎。
4. 急性痛みを伴う肩(急性亜染色体滑液包炎/ ⁇ 上 ⁇ 炎)。
5. 急性痛風性関節炎。

Carefully consider the potential benefits and risks of Unidac (sulindac) and other treatment options before deciding to use Unidac (sulindac). Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with Unidac (sulindac) , the dose and frequency should be adjusted to suit an individual patient's needs.

Unidac (sulindac) should be administered orally twice a day with food. The maximum dosage is 400 mg per day. Dosages above 400 mg per day are not recommended.

In osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, the recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response.

A prompt response (within one week) can be expected in about one-half of patients with osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis. Others may require longer to respond.

In acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis) and acute gouty arthritis, the recommended dosage is 200 mg twice a day. After a satisfactory response has been achieved, the dosage may be reduced according to the response. In acute painful shoulder, therapy for 714 days is usually adequate. In acute gouty arthritis, therapy for 7 days is usually adequate.

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).

以下の副作用が臨床試験で報告されたか、薬剤が販売されてから報告されています。. Unidac(スリンダック)とこれらの副作用の因果関係の確率が存在します。. 臨床試験で観察された副作用は、少なくとも48週間観察された232を含む、1,865人の患者の観察を含みます。.

発生率が1%を超える。

消化器。

Unidac(スリンダック)で発生する最も頻繁なタイプの副作用は胃腸です。これらには、胃腸の痛み(10%)、消化不良***、吐き気*** ⁇ 吐の有無にかかわらず、下 ⁇ ***、便秘***、 ⁇ 腸、食欲不振、消化器けいれんが含まれます。.

皮膚科。

発疹***、そう ⁇ 。.

中央神経系。

めまい***、頭痛***、緊張。.

特別感覚。

耳鳴り。.

その他。

浮腫(参照 警告。).

発生率は100分の1未満です。

消化器。

胃炎、胃腸炎または大腸炎。. 消化性 ⁇ 瘍と消化管出血が報告されています。. GI ⁇ 孔および腸の狭 ⁇ (ダイヤフラム)はめったに報告されていません。.

肝機能異常;黄 ⁇ 、時には発熱;胆 ⁇ うっ滞;肝炎;肝不全。.

胆 ⁇ 摘除術を受けた胆 ⁇ 炎の症状のある患者では、一般的な胆管「スラッジ」と胆道結石にスリンダック代謝産物のまれな報告があります。.

⁇ 炎(参照。 注意。).

老年期;舌炎。.

皮膚科。

口内炎、粘膜の痛みまたは乾燥、脱毛症、光線過敏症。.

多形性紅斑、中毒性表皮壊死症、スティーブンス・ジョンソン症候群、剥離性皮膚炎が報告されています。.

心血管。

うっ血性心不全、特に限界心機能のある患者;動 ⁇ ;高血圧。.

血液学。

血小板減少症;斑状出血;紫斑;白血球減少症;無 ⁇ 粒球症;好中球減少症;再生不良性貧血を含む骨髄抑制;溶血性貧血;経口抗凝固剤を服用している患者のプロトロンビン時間の増加(参照) 注意。).

Genitourinary。

尿変色;排尿障害; ⁇ 出血;血尿;タンパク尿;結晶尿;腎不全を含む腎障害;間質性腎炎;ネフローゼ症候群。.

スリンダック代謝物を含む腎結石はめったに観察されていません。.

代謝。

高カリウム血症。.

筋骨格。

筋力低下。.

精神科。

うつ病;急性精神病を含む精神障害。.

神経系。

めまい;不眠症;傾眠;感覚異常;けいれん;失神;無菌性髄膜炎(特に全身性エリテマトーデス(SLE)と混合結合組織疾患の患者)を参照してください。 注意。).

特別感覚。

かすみ目;視覚障害;聴覚障害;金属または苦い味。.

呼吸器。

鼻血。.

過敏反応。

アナフィラキシー;血管神経性浮腫;じんま疹;気管支けいれん;呼吸困難。.

過敏性血管炎。.

致命的な可能性のある明らかな過敏症症候群が報告されています。. この症候群には、体質症状が含まれる場合があります。 (熱。, 悪寒。, 発汗。, フラッシング。) 皮膚所見。 (発疹または他の皮膚反応-上記を参照。) 結膜炎。, 主要な臓器の関与。 (肝不全を含む肝機能の変化。, 黄 ⁇ 。, ⁇ 炎。, 胸水を伴うまたは伴わない肺炎。, 白血球減少症。, 白血球増加症。, 好酸球増加症。, ⁇ 種性血管内凝固。, 貧血。, 腎障害。, 腎不全を含む。) その他のあまり具体的でない調査結果。 (腺炎。, 関節痛。, 関節炎。, 筋肉痛。, 疲労。, ⁇ 怠感。, 低血圧。, 胸の痛み。, 頻脈。).

因果関係は不明です。

特にグループAのβ-溶血性連鎖球菌に関連する劇症壊死性筋膜炎のまれな発生は、非ステロイド性抗炎症剤で治療された人に記述されており、時には致命的な結果をもたらします(参照)。 また、注意、一般。).

その他の反応は臨床試験または薬剤の販売以降に報告されていますが、因果関係を確立できない状況で発生しました。. ただし、これらのめったに報告されないイベントでは、その可能性を排除することはできません。. したがって、これらの観察結果は、医師への警告情報として役立つようにリストされています。.

心血管。

不整脈。.

代謝。

高血糖。.

神経系。

神経炎。.

特別感覚。

網膜とその血管の障害。.

その他。

女性化乳房。.

*** 3%から9%の間の発生率。. 患者の1%から3%で発生したこれらの反応には、アスタリスクが付いていません。.

過剰摂取の管理。

過剰摂取の症例が報告されており、まれに死亡が起こっています。. 過剰摂取後に次の兆候と症状が観察される可能性があります: ⁇ 迷、 ⁇ 睡、尿量の減少および低血圧。.

過剰摂取の場合、 ⁇ 吐を誘発するか、胃洗浄によって胃を空にし、患者を注意深く観察し、対症療法と支持療法を行う。.

動物実験では、活性炭の迅速な投与により吸収が低下し、尿のアルカリ化により排 ⁇ が増加することが示されています。.

Unidac(sulindac)は、動物モデルで抗炎症、鎮痛、解熱作用を示す非ステロイド性抗炎症薬(NSAID)です。. 他のNSAIDと同様に、作用機序は完全に理解されていませんが、プロスタグランジン合成酵素阻害に関連している可能性があります。.

Absorption

The extent of sulindac absorption from Unidac Tablets is similar as compared to sulindac solution.

There is no information regarding food effect on sulindac absorption. Antacids containing magnesium hydroxide 200 mg and aluminum hydroxide 225 mg per 5 mL have been shown not to significantly decrease the extent of sulindac absorption.

TABLE 1

Distribution

Sulindac, and its sulfone and sulfide metabolites, are 93.1, 95.4, and 97.9% bound to plasma proteins, predominantly to albumin. Plasma protein binding measured over a concentration range (0.5-2.0 μg/mL) was constant. Following an oral, radiolabeled dose of sulindac in rats, concentrations of radiolabel in red blood cells were about 10% of those in plasma. Sulindac penetrates the blood-brain and placental barriers. Concentrations in brain did not exceed 4% of those in plasma. Plasma concentrations in the placenta and in the fetus were less than 25% and 5% respectively, of systemic plasma concentrations. Sulindac is excreted in rat milk; concentrations in milk were 10 to 20% of those levels in plasma. It is not known if sulindac is excreted in human milk.

Metabolism

Sulindac undergoes two major biotransformations of its sulfoxide moiety: oxidation to the inactive sulfone and reduction to the pharmacologically active sulfide. The latter is readily reversible in animals and in man. These metabolites are present as unchanged compounds in plasma and principally as glucuronide conjugates in human urine and bile. A dihydroxydihydro analog has also been identified as a minor metabolite in human urine.

With the twice-a-day dosage regimen, plasma concentrations of sulindac and its two metabolites accumulate: mean concentration over a dosage interval at steady state relative to the first dose averages 1.5 and 2.5 times higher, respectively, for sulindac and its active sulfide metabolite.

Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation relative to the sulfide metabolite in animals. Studies in man have also demonstrated that recirculation of the parent drug sulindac and its sulfone metabolite is more extensive than that of the active sulfide metabolite. The active sulfide metabolite accounts for less than six percent of the total intestinal exposure to sulindac and its metabolites.

Biochemical as well as pharmacological evidence indicates that the activity of sulindac resides in its sulfide metabolite. An in-vitro assay for inhibition of cyclooxygenase activity exhibited an EC50 of 0.02 μM for sulindac sulfide. In-vivo models of inflammation indicate that activity is more highly correlated with concentrations of the metabolite than with parent drug concentrations.

Elimination

Approximately 50% of the administered dose of sulindac is excreted in the urine with the conjugated sulfone metabolite accounting for the major portion. Less than 1% of the administered dose of sulindac appears in the urine as the sulfide metabolite. Approximately 25% is found in the feces, primarily as the sulfone and sulfide metabolites.

The mean effective half-life (T½) is 7.8 and 16.4 hours, respectively, for sulindac and its active sulfide metabolite.

Because Unidac (sulindac) is excreted in the urine primarily as biologically inactive forms, it may possibly affect renal function to a lesser extent than other non-steroidal anti-inflammatory drugs; however, renal adverse experiences have been reported with Unidac (see ADVERSE REACTIONS).

In a study of patients with chronic glomerular disease treated with therapeutic doses of Unidac (sulindac) , no effect was demonstrated on renal blood flow, glomerular filtration rate, or urinary excretion of prostaglandin E2 and the primary metabolite of prostacyclin, 6-keto-PGF1α. However, in other studies in healthy volunteers and patients with liver disease, Unidac (sulindac) was found to blunt the renal responses to intravenous furosemide, i.e., the diuresis, natriuresis, increments in plasma renin activity and urinary excretion of prostaglandins. These observations may represent a differentiation of the effects of Unidac (sulindac) on renal functions based on differences in pathogenesis of the renal prostaglandin dependence associated with differing dose-response relationships of different NSAIDs to the various renal functions influenced by prostaglandins (see PRECAUTIONS).

In healthy men, the average fecal blood loss, measured over a two-week period during administration of 400 mg per day of Unidac (sulindac) , was similar to that for placebo, and was statistically significantly less than that resulting from 4800 mg per day of aspirin.