氨基水杨酸直肠栓说明书(英文)

氨基水杨酸直肠栓说明书(英文) Page 1 Canasa Package Insert Axcan Proposed Nov. 4 2004 CANASA?? Mesalamine USP Rectal Suppositories 500 mg and 1000 mg NDC 58914-500-56 and NDC 58914-501-56 Rx Only DESCRIPTION The active ingredient in CANASA?? 500 mg and 1000 mg suppositories is mesalamine also known as mesalazine or 5-aminosalicylic acid 5-ASA. Chemically mesalamine is 5-amino-2-hydroxybenzoic acid and is classified as an anti-inflammatory drug. The empirical formula is C7H7NO3 representing a molecular weight of 153.14. The structural formula is: Each CANASA?? rectal suppository contains 500 mg or 1000 mg of mesalamine USP in a base of Hard Fat NF. CLINICAL PHARMACOLOGY Sulfasalazine has been used in the treatment of ulcerative colitis for over 55 years. It is split by bacterial action in the colon into sulfapyridine SP and mesalamine 5-ASA. It is thought that the mesalamine component only is therapeutically active in ulcerative colitis. Mechanism of Action The mechanism of action of mesalamine and sulfasalazine is not fully understood but appears to be topical rather than systemic. Although the pathology of inflammatory bowel disease is uncertain both prostaglandins and leukotrienes have been implicated as mediators of mucosal injury and inflammation. Recently however the role of mesalamine as a free radical scavenger or inhibitor of tumor necrosis factor TNF has also been postulated. Pharmacokinetics Absorption: Mesalamine 5-ASA administered as a rectal suppository is variably absorbed. In patients with ulcerative colitis treated with mesalamine 500 mg rectal suppositories administered once every eight hours for six days the mean mesalamine Page 2 Canasa Package Insert Axcan Proposed Nov. 4 2004 peak plasma concentration Cmax was 353 ng/mL CV55 following the initial dose and 361 ng/mL CV67 at steady state. The mean minimum steady state plasma concentration Cmin was 89 ng/mL CV89 . Absorbed mesalamine does not accumulate in the plasma. Distribution: Mesalamine administered as rectal suppositories distributes in rectal tissue to some extent. In patients with ulcerative proctitis treated with CANASA?? mesalamine USP 500 mg or 1000 mg rectal suppositories rectal tissue concentrations for 5-ASA and N-acetyl 5-ASA have not been rigorously quantified. Metabolism: Mesalamine is extensively metabolized mainly to N-acetyl-5-ASA. The site of metabolism has not been elucidated. In patients with ulcerative colitis treated with one 500 mg mesalamine rectal suppository every eight hours for six days peak concentration Cmax of N-acetyl-5-ASA ranged from 467 ng/mL to 1399 ng/mL following the initial dose and from 193 ng/mL to 1304 ng/mL at steady state. Elimination: Mesalamine is eliminated from plasma mainly by urinary excretion predominantly as N-acetyl-5-ASA. In patients with ulcerative proctitis treated with one mesalamine 500 mg rectal suppository every eight hours for six days lt 12 of the dose was eliminated in urine as unchanged 5-ASA and 8-77 as N-acetyl-5-ASA following the initial dose. At steady state lt 11 of the dose was eliminated as unchanged 5-ASA and 3-35 as N-acetyl-5-ASA. The mean elimination half-life was five hours CV73 for 5-ASA and six hours CV63 for N-acetyl-5-ASA following the initial dose. At steady state the mean elimination half-life was seven hours for both 5-ASA and N-acetyl-5-ASA CV102 for 5-ASA and 82 for N-acetyl-5-ASA. Drug-Drug Interactions: The potential for interactions between mesalamine administered as 500 mg or 1000 mg rectal suppositories and other drugs has not been studied. Special Populations Patients with Renal or Hepatic Impairment: The effect of renal or hepatic impairment on elimination of mesalamine in ulcerative proctitis patients treated with mesalamine 500 mg or 1000 mg suppositories has not been studied. Preclinical Toxicology Preclinical studies of mesalamine were conducted in rats mice rabbits and dogs and kidney was the main target organ of toxicity. In rats adverse renal effects were observed at a single oral dose of 600 mg/kg about 3.2 times the recommended human intra-rectal dose based on body surface area and at IV doses of gt214 mg/kg about 1.2 times the recommended human intra-rectal dose based on body surface area. In a 13-week oral gavage toxicity study in rats papillary necrosis and/or multifocal tubular injury were observed in males receiving 160 mg/kg about 0.86 times the recommended human intra-rectal dose based on body surface area and in both males and females at 640 mg/kg about 3.5 times the recommended human intra-rectal dose based on body surface area. In a combined 52-week toxicity and 127-week carcinogenicity study in rats degeneration of the kidneys and hyalinization of basement membranes and Bowman’s capsule were Page 3 Canasa Package Insert Axcan Proposed Nov. 4 2004 observed at oral doses of 100 mg/kg/day about 0.54 times the recommended human intra-rectal dose based on body surface area and above. In a 14-day rectal toxicity study of mesalamine suppositories in rabbits intra-rectal doses up to 800 mg/kg about 8.6 times the recommended human intra-rectal dose based on body surface area was not associated with any adverse effects. In a six-month oral toxicity study in dogs doses of 80 mg/kg about 1.4 times the recommended human intra-rectal dose based on body surface area and higher caused renal pathology similar to that described for the rat. In a rectal toxicity study of mesalamine suppositories in dogs a dose of 166.6 mg/kg about 3.0 times the recommended human intra-rectal dose based on body surface area produced chronic nephritis and pyelitis. In the 12-month eye toxicity study in dogs Keratoconjunctivitis sicca KCS occurred at oral doses of 40 mg/kg about 0.72 times the recommended human intra-rectal dose based on body surface area and above. CLINICAL STUDIES Two double-blind placebo-controlled multicenter studies were conducted in North America in patients with mild to moderate active ulcerative proctitis. The primary measures of efficacy were the same in all trials clinical disease activity index sigmoidoscopic and histologic evaluations. The main difference between the studies was dosage regimen: 500 mg three times daily 1.5 g/d in Study 1 and 500 mg twice daily 1.0 g/d in Study 2. A total of 173 patients were studied Study 1 N79 Study 2 N94. Eighty-nine 89 patients received mesalamine suppositories and eighty-four 84 patients received placebo suppositories. Patients were evaluated clinically and sigmoidoscopically after three and six weeks of suppository treatment. In Study No. 1 patients were 17 to 73 years of age mean 39 yrs 57 were female and 97 were white. Patients had an average extent of proctitis upper disease boundary of 10.8 cm. Eighty-four percent 84 of the study patients had multiple prior episodes of proctitis. In Study No. 2 patients were 21 to 72 years of age mean 39 yrs 62 were female and 96 were white. Patients had an average extent of proctitis upper disease boundary of 10.3 cm. Seventy-eight percent 78 of the study patients had multiple prior episodes of proctitis. Compared to placebo mesalamine suppository treatment was statistically plt0.01 superior to placebo in all trials with respect to improvement in stool frequency rectal bleeding mucosal appearance disease severity and overall disease activity after three and six weeks of treatment. Daily diary records indicated significant improvement in rectal bleeding in the first week of therapy while tenesmus and diarrhea improved significantly within two weeks. Investigators rated patients receiving mesalamine much improved compared to patients receiving placebo plt0.001. The effectiveness of mesalamine suppositories was statistically significant irrespective of sex extent of proctitis duration of current episode or duration of disease. A multicenter open-label randomized parallel group study in ninety-nine 99 patients diagnosed with mild to moderate ulcerative proctitis compared the clinical efficacy of the CANASA?? 1000 mg suppository to that of the CANASA?? 500 mg suppository. The primary measures of efficacy included clinical disease activity index sigmoidoscopic and Page 4 Canasa Package Insert Axcan Proposed Nov. 4 2004 histologic evaluations. Patients were randomized to one of two treatment groups with a dosage regimen of one 500 mg mesalamine suppository BID morning and HS or one 1000 mg mesalamine suppository HS for 6 weeks. Patients were evaluated clinically and sigmoidoscopically after three and six weeks of suppository treatment. Of the 81 patients in the Per Protocol population forty-six 46 patients received mesalamine 500 mg suppositories BID and thirty-five 35 patients received mesalamine 1000 mg suppositories HS. The efficacy of the 1000 mg HS treatment was not statistically or clinically different after 6 weeks from the 500 mg BID treatment and both were effective in the treatment of ulcerative proctitis. Both treatments resulted in a significant decrease between Baseline and 6 weeks in the Disease Activity Index DAI a composite index reflecting rectal bleeding stool frequency mucosal appearance at endoscopy and a global assessment of disease. In the 500 mg BID group the mean DAI value decreased from 6.6 to 1.6 and in the 1000 mg HS group the mean DAI value decreased from 6.2 to 1.3 over 6 weeks of treatment representing a decrease of greater than 75 in both groups. Seventy-eight percent 78 36/46 of patients in the 500 mg BID group and 86 30/35 of the patients in the 1000 mg HS group achieved a substantial improvement in symptoms defined as a DAI score of less than 3 after 6 weeks of treatment. These patients regained normal daily stools lost their rectal bleeding and lost signs of inflammation at endoscopic visualization. The time to onset of response to the study drug was within 3 weeks of initiation of therapy in each treatment group but further improvement was observed between 3 and 6 weeks of treatment. INDICATIONS AND USAGE CANASA?? 500 mg and 1000 mg Suppositories are indicated for the treatment of active ulcerative proctitis. CONTRAINDICATIONS CANASA?? 500 mg and 1000 mg Suppositories are contraindicated in patients who have demonstrated hypersensitivity to mesalamine 5-aminosalicylic acid or to the suppository vehicle saturated vegetable fatty acid esters Hard Fat NF or to salicylates including aspirin. PRECAUTIONS Mesalamine has been implicated in the production of an acute intolerance syndrome characterized by cramping acute abdominal pain and bloody diarrhea sometimes fever headache and a rash in such cases prompt withdrawal is required. The patient’s history of sulfasalazine intolerance if any should be re-evaluated. If a rechallenge is performed later in order to validate the hypersensitivity it should be carried out under close supervision and only if clearly needed giving consideration to reduced dosage. In the literature one patient previously sensitive to sulfasalazine was rechallenged with 400 mg oral mesalamine within eight hours she experienced headache fever intensive abdominal colic profuse diarrhea and was readmitted as an emergency. She responded poorly to steroid therapy and two weeks later a pancolectomy was required. The possibility of increased absorption of mesalamine and concomitant renal tubular damage Page 5 Canasa Package Insert Axcan Proposed Nov. 4 2004 as noted in the preclinical studies must be kept in mind. Patients on CANASA?? 500 mg or 1000 mg especially those on concurrent oral products which contain or release mesalamine and those with pre-existing renal disease should be carefully monitored with urinalysis BUN and creatinine testing. In a clinical trial most patients who were hypersensitive to sulfasalazine were able to take mesalamine enemas without evidence of any allergic reaction. Nevertheless caution should be exercised when mesalamine is initially used in patients known to be allergic to sulfasalazine. These patients should be instructed to discontinue therapy if signs of rash or fever become apparent. A small proportion of patients have developed pancolitis while using mesalamine. However extension of upper disease boundary and/or flare-ups occurred less often in the mesalamine-treated group than in the placebo-treated group. Rare instances of pericarditis have been reported with mesalamine containing products including sulfasalazine. Cases of pericarditis have also been reported as manifestations of inflammatory bowel disease. In the cases reported there have been positive rechallenges with mesalamine or mesalamine containing products. In one of these cases however a second rechallenge with sulfasalazine was negative throughout a 2 month follow-up. Chest pain or dyspnea in patients treated with mesalamine should be investigated with this information in mind. Discontinuation of CANASA?? suppositories may be warranted in some cases but rechallenge with mesalamine can be performed under careful clinical observation should the continued therapeutic need for mesalamine be present. There have been two reports in the literature of additional serious adverse events: one patient who developed leukopenia and thrombocytopenia after seven months of treatment with one 500 mg suppository nightly and one patient with rash and fever which was a similar reaction to sulfasalazine. Information for Patients: See patient information printed at the end of this insert. Carcinogenesis Mutagenesis Impairment of Fertility Mesalamine caused no increase in the incidence of neoplastic lesions over controls in a two-year study of Wistar rats fed up to 320 mg/kg/day of mesalamine admixed with diet about 1.7 times the recommended human intra-rectal dose based on body surface area. Mesalamine was not mutagenic in the Ames test the mouse lymphoma cell TK/- forward mutation test or the mouse micronucleus test. No effects on fertility or reproductive performance of the male and female rats were observed at oral mesalamine doses up to 320 mg/kg/day about 1.7 times the recommended human intra-rectal dose based on body surface area. The oligospermia and infertility in men associated with sulfasalazine have not been reported with mesalamine. Page 6 Canasa Package Insert Axcan Proposed Nov. 4 2004 Pregnancy Teratogenic Effects Pregnancy Category B Teratology studies have been performed in rats at oral doses up to 320 mg/kg/day about 1.7 times the recommended human intra-rectal dose based on body surface area and in rabbits at oral doses up to 495 mg/kg/day about 5.4 times the recommended human intra-rectal dose based on body surface area and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are however no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response this drug should be used in pregnancy only if clearly needed. Nursing Mothers It is not known whether mesalamine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when CANASA?? 500 mg or 1000 mg suppositories are administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of CANASA?? did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic renal or cardiac function and of concomitant disease or other drug therapy. Mesalamine 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 .