美沙拉秦灌肠剂药品说明书（英文）

Kyorin Pharmaceutical Co., Ltd. 1 Revised: February 2011 (9th version) Standard Commodity Classification No. of Japan 872399 - ULCERATIVE COLITIS REMEDY- PENTASA® Enema 1 g < Mesalazine Enema 1%> Prescription drugNote) Storage Approval No. 21400AMY00240000 Date of listing in the NHI reimbursement price April 2003 Date of initial marketing in Japan June 2003 This product should be stored in a light-proof sealed container at room temperature. Date of latest reexamination December 2009 Expiration date International birth date September 1986 This product should be used before the expiration date (within three years after production) indicated on the outer cases. Caution This product should be used immediately after opening an aluminum-foil bag. Note) Caution: Use only as directed by a physician. CONTRAINDICATIONS (This product is contraindicated in the following patients.) (1) Patients with serious renal dysfunction [Renal dysfunction may be further aggravated.] (2) Patients with serious hepatic dysfunction [Hepatic dys- function may be further aggravated.] (3) Patients with a history of hypersensitivity to ingredients contained in this product [Refer to the section of “2. Important Precautions.”] (4) Patients with a history of hypersensitivity to salicylic acid esters or salicylates [Cross allergy may develop.] DESCRIPTION Product description Brand name PENTASA Enema 1 g Active ingredient/ content Mesalazine 1 g per 100 mL in a container Inactive ingredients Sodium pyrosulfite, disodium edetate hydrate, sodium acetate hydrate, pH adjustment Description This product occurs as a white to pale yellow suspension. On standing, a white precipitate separates out to form a colorless to pale yellow supernatant. The precipitate disperses easily by shaking to form a suspension again. Appearance (Container) Identification code (Package material) KP-008 INDICATIONS Ulcerative colitis (excluding severe cases) There is no possible efficacy for inflammation in the sites distal to the splenic flexure. (Refer to the section of “PHARMA- COKINETICS”) DOSAGE AND ADMINISTRATION In general, the entire amount (1 g of mesalazine) of this product in a container is rectally administered once a day to adults. The dosage may be reduced according to patients’ ages and symptoms. PRECAUTIONS 1. Careful Administration (This product should be carefully administered to the following patients.) (1) Patients with reduced renal function [Excretion may be delayed to cause adverse reactions.] (2) Patients with reduced hepatic function 2 Kyorin Pharmaceutical Co., Ltd. [Metabolism may be delayed to cause adverse reactions.] (3) Patients with hypersensitivity to salazosulfapyridine (Refer to the clause (2) of the section of “2. Important Precautions.”) 2. Important Precautions (1) Mesalazine may induce hypersensitivity symptoms (fever,4) abdominal pain, 1)-3),5),15) diarrhea,1),3) eosinophilia,7) etc.), and aggravate ulcerative colitis.8),9) If any of abnormal findings is observed, appropriate therapeutic measures such as discontinuation of administration should be taken. (2) Administration of mesalazine tablets to patients with allergic symptoms to salazosulfapyridine induced a similar allergic symptom in three (7.7%) out of 39 cases in the domestic clinical studies,1),4)-6) and two (4.7%) out of 43 cases in the foreign clinical study.10) Therefore, this product should be carefully administered to patients with allergic symptoms to salazosulfapyridine. (3) Since mesalazine tablets have been reported to induce interstitial nephritis,11)-13) patients should be carefully monitored for laboratory test variables for renal function including creatinine during the period of treatment. If any of abnormal findings is observed, appropriate measures such as a reduction in the dose or discontinuation of administration should be taken. (4) Since mesalazine has been reported to induce hepati- tis,16)-18) hepatic dysfunction and jaundice, patients should be carefully monitored for laboratory variables for hepatic function such as AST (GOT) and ALT (GPT) during the period of treatment. If any of abnormal findings is observed, appropriate measures such as a reduction in the dose or discontinuation of administration should be taken. (5) When this product is co-administered with oral 5-amino- salicylic acid products such as mesalazine tablets, attention should be especially paid to the patients with reduced hepatic or renal function and elderly patients, taking an increase in the total dose of mesalazine into consideration. If any of abnormal findings is observed, appropriate measures such as a reduction in the dose or discontinuation of administration should be taken. 3. Drug Interactions Precautions for coadministration Since drug interactions have been reported in the literature, this product should be carefully administered in combination with the following drugs. Drug Sign or Symptom and Treatment Mechanism and Risk Factor Diuretics Steroids Changes in laboratory values (urine volume, and urinary excretions of sodium, potassium and chloride ions) should be monitored. A high dose (300 mg/kg) of mesalazine increased urine volume and urinary excretions of sodium, potassium and chloride ions in an animal study (rats)14) Azathioprine Mercapto- purine Decreased WBC may occur.19) This product has been reported to inhibit the metabolism of these drugs through suppression of thiopurine methyl- transferase activity.20),21) 4. Adverse Reactions Since there were no domestic clinical data on this product, the following adverse reactions were those found in the clinical studies and post-marketing surveillances from the launch in 1986 to 2000 in foreign countries, and those found in treatment with PENTASA Tablets 250mg.  Major adverse reactions found in treatment with PENTASA Tablets 250mg The number of cases of adverse reactions including laboratory test abnormalities was 277 (12.42%) out of 2230 cases. The major adverse reactions included diarrhea in 66 (2.96%), melena/hematochezia in 28 (1.26%), digestive symptoms including abdominal pain in 24 (1.08%), rash in 16 (0.72%), fever in 15 (0.67%), and hepatic dysfunction in 14 (0.63%). The major laboratory test abnormalities included increased CRP in 24 (1.08%), increased ALT (GPT) in 21 (0.94%), and increased WBC in 18 (0.81%). (at the application for approval of supplementing dosage and administration of PENTASA Tablets 250mg and 500mg)  Adverse reactions found in treatment with PENTASA Tablets 250mg in Japan, and those found in treatment with the oral, enema and suppository formulations of mesalazine in foreign post-marketing surveillances (1) Clinically significant adverse reactions 1) Hypersensitivity pulmonary disorders22)-29) ( 0.01 %) Pulmonary disorders including eosinophilic pneumonia,28) alveolitis,23),27) pneumonitis,25) interstitial pneumonia,22) and others24),26),29) have been reported. If any of symptoms such as fever, coughing, dyspnea, and abnormal findings in chest radiograms is observed, appropriate measures such as discontinuation of administration should be taken. 2) Myocarditis,31)-33) and pericarditis,30),32),34),35) (0.01% ≤ 0.1%), and pleurisy34),35) (incidence unknown) Myocarditis, pericarditis and pleurisy may occur. If any of symptoms such as pleural effusion, chest pain, and abnormal findings in electrocardiograms is Kyorin Pharmaceutical Co., Ltd. 3 observed, appropriate measures such as discon- tinuation of administration should be taken. 3) Interstitial nephritis,11)-13) nephrotic syndrome,36) and reduced renal function (0.01%), and acute renal failure (incidence unknown) Since interstitial nephritis, nephrotic syndrome, reduced renal function and acute renal failure may occur, patients should be carefully monitored for renal function variables during the period of treatment. If any of abnormal findings is observed, appropriate measures such as discontinuation of administration should be taken. 4) Aplastic anemia,43) pancytopenia,44) agranulocytosis and thrombocytopenia38),40) (0.01%)37),39),41),42) Since aplastic anemia, pancytopenia, agranulo- cytosis, and thrombocytopenia may occur, patients should be carefully monitored for hematological variables during the period of treatment. If any of abnormal findings is observed, appropriate measures such as discontinuation of administration should be taken. 5) Hepatitis (0.01%),16)-18) hepatic dysfunction and jaundice (incidence unknown) Since hepatitis, hepatic dysfunction with increased AST (GOT), ALT (GPT) and/or γ-GTP and jaundice may occur, patients should be carefully monitored for hepatic function variables during the period of treatment. If any of abnormal findings is observed, appropriate measures such as discontinuation of administration should be taken. 6) Pancreatitis45),46) (0.01%≤ 0.1%) Since pancreatitis may occur, patients should be carefully monitored for serum amylase levels during the period of treatment. If any of abnormal findings is observed, appropriate measures such as discontinua- tion of administration should be taken. The incidences of adverse ractions described in the above clauses 1) to 6) are based on the results of foreign post-marketing surveillances, with formula- tions undistinguished. (2) Other adverse reactions If any of the following adverse reactions is observed, appropriate measures such as discontinuation of the administration should be taken. Incidence of adverse reactions 1%≤ 0.01≤ 1% 0.01% Unknown Dermato -logic Rash, papule, urticaria erythe- ma Depilation 47) Itching Gastro- intestinal Diarrhea, abdomi- nal pain, nausea, vomiting Hemato- chezia,#1 melena,#1 Increased amylase, feeling of enlarged abdomen, #1 consti- pation,#1 mucous stool#1 Anorexia, stomatitis Hepatic Hepatic function abnormal such as increases in AST (GOT), ALT (GPT), -GTP, Al-P and bilirubin Renal Chroma- turia#1 Renal dysfunc- tions such as increases in creatinine, urinary NAG and urinary micro- globulin and urinary protein Hemato- logic Decreased WBC, anemia, eosino- philia7) Others Head- ache Increased CK#1 Myalgia, arthral- gia, lupus- like syndrome 49),50) Fever, edema, general malaise, peripheral neuropathy,4 8) itching#2 and discomfort of the anus, defecation urgency 4 Kyorin Pharmaceutical Co., Ltd. The incidences of adverse reactions are based on the results of the domestic clinical studies and post-marketing surveillances of PENTASA Tablets 250mg and those of the foreign post-marketing surveillances, with formulations undistinhuished. The incidences from domestic and foreign spontaneous reportings are classified into the “unknown” category. #1: Adverse reactions found in treatment with PENTASA Tablets 250mg in Japan. #2: Adverse reactions reported only in foreign countries.  Bold typeface: Adverse reactions reported in both of the oral and enema formulations.  Italic typeface: Adverse reactions reported in the enema formulation alone. 5. Use in the Elderly Because elderly patients have generally reduced physiological functions (renal and hepatic functions, etc.), this product should be administered with a special care, such as a reduction in the dose. 6. Use during Pregnancy, Delivery or Lactation (1) This product should be administered to pregnant or possibly pregnant women only if the expected therapeutic benefits outweigh the potential risks associated with treatment. [No teratogenicity has been found in the animal studiy of mesalazine,51) but the safety of this product has not been established in pregnant women.] (2) Use of this product is not recommended in lactating women. If the use is judged to be essential, breast feeding must be discontinued during treatment. [Mesalazine has been reported to be excreted in the breast milk in humans.52),53)] 7. Pediatric Use The safety of this product has not been established in children because of the limited number of clinical experiences. 8. Precautions concerning Use (1) This product, a suspension charged in a polyethylene- made container, is packed in an aluminum-foil bag filled with nitrogen gas. Take out the container from the bag just before use. (2) How to use 1) Shake the container. 2) Open the container by rotating the nozzle toward the designated direction (Since the drug solution may spill out when the container is tightly grasped, grasp softly the container at opening). 3) Take the left lateral decubitus position. Then, insert the nozzle slowly into the anus (because of a possible damage to the rectal mucosa, insert the nozzle care- fully). 4) After insertion, inject the solution slowly while squeezing the container gradually. 5) After injection, remove the nozzle slowly from the anus while grasping the container. (3) This product must not be stored after opening of the aluminium-foil bag because mesalazine will be easily decomposed by light or oxygen. (4) This product occurs as a white or pale yellow suspension. Because mealazine will be easily oxidized to form colored degradations, the product with a super- natant colored more deeply than pale yellow must not be used. PHARMACOKINETICS [For reference] The excretion rates of mesalazine enema in urine and feces were examined when 100 mL (1g of mesalazine) of the enema was repeatedly administered twice a day for seven days to 11 foreign healthy adults. The total excretion rates of the unchanged and acetyl forms were about 15% of the doses in urine, and about 32% in feces.54) When mesalazine tablets (2 g of mesalazine) were orally administered in four divided doses a day for six days to 12 healthy adults, the total excretion rates were about 32% in urine, while about 27% in feces.55) After absorption, mesalazine is metabolized into its acetyl form, which is mainly excreted in the urine. The urinary excretion rate of the enema formulation is lower in than that of the oral formulation, indicating that the enema would have a low rate of absorption resulting in a low systemic exposure. The most distal sites of mesalazine delivered and their amounts in the colon were investigated, when 100 mL (1 g of mesalazine) of 99mTc-labeled mesalazine enema was rectally administered to eight healthy adults. Mesalazine remained in the rectum and sygmoid colon in one subject, and reached the splenic flexure in seven subjects, in four of which reached the transverse colon.56) CLINICAL STUDIES 1. Comparative Study with Steroid Enema[For reference] A double-blind, controlled study comparing the efficacy and safety between mesalazine and prednisolone enemas was conducted in patients (114 cases analyzed) with mild to moderate active episodes of ulcerative colitis from seven institutions in Denmark.57) Mesalazine enema at a dose of 1 g/100 mL and prednisolone enema at a dose of 25 mg/100 mL were administered once a day for four weeks. (1) Efficacy In an overall judgment in combination with clinical response and sigmoidoscopy, the rates of remitted and improved categories were similar between the mesalazine and prednisolone groups, with 77 and 72%, respectively. (2) Safety In 123 patients participating in the study, adverse reactions developed in 13 (21.3%) of the mesalazine group and in six (9.7%) of the prednisolone group, with no statistically significant difference between the two groups. The most common adverse reactions in the mesalazine group were feeling of abdomen enlarged and abdominal pain in three patients (4.9%) each. 2. Dose (Concentration) Comparative Study [For reference] A double-blind placebo controlled study of mesalazine enema was conducted in patients (287 cases analyzed) with mild to moderate active episodes of ulcerative colitis from Kyorin Pharmaceutical Co., Ltd. 5 18 institutions in the United States.58) Mesalazine enema at a dose of 1, 2 or 4 g/100 mL was administered once a day for eight weeks. (1) Efficacy 1) Overall judgment by investigator The efficacy responses of mealazine enema in the 1, 2 and 4 g/100 mL groups were 67, 65 and 75%, respectively, as compared with 27% of the placebo group, demonstrating significant differences between the mesalazine groups and placebo group. However, there were no significant differences among the mesalazine groups. 2) Judgment with endoscopical scores The endoscopical scores were improved by 5.8, 5.9 and 6.4 points in the 1 g/100 mL, 2 g/100 mL and 4 g/100 mL groups,respectively, as compared with 1.8 point in the placebo group, demonstrating significant differences between the mesalazine groups and placebo group. However, there were no significant differences among the mesalazine groups. (2) Safety The incidences of adverse reactions were 14% in the mesalazine groups, as compared with 10% in the placebo group, indicating no dose-dependent variations. PHARMACOLOGY 1. Effect on Experimental Animal Model Administration of mesalazine enema significantly decreased the ulcerative areas in the rat acetic acid-induced ulcerative colitis model at doses of 6.25 mg/kg or more,59) and the lesions in the rat TNBS-induced colitis model at a dose of 25.0 mg/kg.60) 2. Mechanism of Action61) An in vitro study showed that mesalazine had a free radical (DPPHL)-reducing action, hydrogen peroxide-eliminating action, hypochlorous ion-eliminating action, and lipid peroxide-suppressing action (also in vivo). In addition, mesalazine suppressed the biosynthesis of leukotriene B4 (LTB4) in rat neutrophils (in vitro). These results indicate that the major mechanisms of mesalazine would include elimination of active oxygen species released from inflammatory cells, suppressions of the progress of inflammation and impairment of the tissues, and suppression of biosynthesis of LTB4 resulting in supression of infiltration of inflammatory cells into the tissues. Separately, mesalazine may also participate in suppressions of histamine released from the mast cells, biosynthesis of platelet activating factor (PAF), and production of interleukin-1 (IL-1) (in vitro). PHYSICOCHEMISTRY Nonproprietary name: Mesalazine (JAN, INN) Chemical name: 5-Aminosalicylic acid Molecular formula: C7H7NO3 Molecular weight: 153.14 Structural formula: Melting point: 270 to 275ºC (Decomposition) Description: Mesalazine occurs as a grayish white to pale grayish yellow needle-like crystal or crystalline powder. It is odorless or has a characteristic odor. It has a sour taste with a slightly sweet aftertaste. It is slightly soluble in water, very slightly soluble in methanol and ethanol (99.5), and practically insoluble in diethyl ether and chloroform. PACKAGING PENTASA Enema 1 g 100 mL x 7 REFERENCES 1) Munakata A. et al., Jpn. Pharmacol. Therap., 22 (Suppl.10), S2509 (1994) 2) Munakata A. et al., Jpn. Pharmacol. Therap., 22 (Suppl.10), S2531 (1994) 3) Munakata A. et al., Jpn. Pharmacol. Therap., 22 (Suppl.10), S2555 (1994) 4) Munakata A. et al., Jpn. Pharmacol. Therap., 22 (Suppl.10), S2585 (1994) 5) Munakata A. et al., Jpn. Pharmacol. Therap., 22 (Suppl.10), S2607 (1994) 6) Munakata A. et al., Jpn. Pharmacol. Therap., 22 (Suppl.10), S2625 (1994) 7) Morice A.H. et al., Lancet, 350, 1105 (1997) 8) K