Package Insert Mobic This document is a translation from Japanese into English of the Enclosed Information (a package insert) of Meloxicam marketed in 2000 in Japan as Mobic(r) モービック(r) カプセル5mg モービック(r) カプセル10mg www.jouhoukoukai.com Created: December 2000 (first new version) Standard Commodity Classification No. of Japan 871149 Storage: Airtight containers Expiration Date: Indicated on the container and the outer carton Non-steroidal anti-inflammatory medicine * painkiller Powerful drug * prescription-only drug MOBIC(r) Capsules 5 mg MOBIC(r) Capsules 10 mg (Meloxicam medication) (r) = registered trademark Capsules 5 mg Capsules 10 mg Approval No. 21200 AMY 00245000 21200 AMY 00244000 Date of the listing in the NHI (National Health Insurance) reimbursement price list February 2001 February 2001 Date of the initial marketing in Japan February 2001 February 2001 Date of the international launch May 1995 May 1995 【CONTRAINDICATIONS】 (MOBIC IS CONTRAINDICATED FOR THE FOLLOWING PATIENTS) 1. Patients with peptic ulcer (Mobic may worsen a digestive ulcer due to a reduction of the protecting function of gastric mucosa by inhibition of prostaglandin synthesis. See paragraph 2 of "Careful Administration"). 2. Patients with severe blood disorder (Mobic may worsen the disorder). 3. Patients with severe liver disorder (Mobic may worsen the disorder). 4. Patients with severe renal dysfunction (Mobic may worsen the dysfunction due to reduction of renal blood flow volume, and disruption of the maintenance of balance of water and sodium, caused by inhibiting the prostaglandin synthesis). 5. Patients with severe heart failure (Mobic may worsen the heart failure due to reduction of renal blood flow volume, and disruption of the maintenance of balance of water and sodium, caused by inhibiting the prostaglandin synthesis). 6. Patients with severe hypertension (Mobic may increase blood due to reduction of renal blood flow volume, and disruption of the maintenance of balance of water and sodium, caused by inhibiting the prostaglandin synthesis). 7. Patients with, or with history of, hypersensitivity to ingredient of this product, salicylic acid salts (aspirin etc.) or other NSAIDs. 8. Patients with, or with history of, hypersensitivity to aspirin-triggered asthma (or induction of asthma attack by NSAIDs etc.). (Mobic may induce severe asthma attack) 9. Pregnant or expecting pregnancy (see "Use during Pregnancy, Delivery or Lactation"). 【DESCRIPTION】 Trade name Mobic Capsules 5 mg Mobic Capsules 10 mg Ingredients/Contents 1 capsule contains 5 mg meloxicam 1 capsule contains 10 mg meloxicam Additives Lauryl sodium sulphate Lauryl sodium sulphate Pharmaceutical form Solid capsules with light brown-yellow opacity Solid capsules with light brown-yellow opacity, and head with yellow opacity Internal content Powdered or granular pale yellow substance Powdered or granular pale yellow substance External form No. 4 No. 4 Length Approximately. 14 mm Approximately. 14 mm Diameters Approximately 5 mm Approximately 5 mm Weight Approximately 0.185 g Approximately 0.185 g Identification Code M05 M06 【INDICATIONS】   For anti-inflammatory effect and for pain relief in the following diseases and symptoms: * Chronic joint rheumatism * Deformations of the joints (osteoarthrosis) * Lumbago symptoms * Periarticular inflammation of the shoulder joint (scapulohumeral periarthritis) * Neck-shoulder-arm syndrome (brachialgia, cervicobrachial syndrom) 【DOSAGE AND ADMINISTRATION】 Usually, the dose of Mobic for adults is 10 mg meloxicam orally, once a day after meal. In addition to the above, depending on the age and symptoms, the dose may vary up to 15 mg as the maximum daily dose. Caution to DOSAGE AND ADMINISTRATION There is no safety profile established in this country (Japan) for doses exceeding 15 mg a day (due to the lack of experience)! 【PRECAUTIONS】 1. Careful Administration (Mobic should be administered with care to the following patients): (1) Patients with peptic ulcer (Mobic may worsen a digestive ulcer due to a reduction of the protective functions of the gastric mucosa by inhibition of prostaglandin synthesis. See paragraph 2 of "Careful Administration") (2) Patients with NSAID-induced ulcer and having a concurrent treatment with misoprostol (Misoprostol has an indication for ulcer caused by NSAIDs, but there are some cases of ulcer showing resistance to the misoprostol treatment). Therefore, patients with, or with a history of, ulcer caused by NSAIDs, and who require long-term treatment with Mobic, should be carefully monitored and the drug administer with caution, since not all patients with such ulcers are cured after misoprostol therapy. (3) Patients treated with anti-coagulatants (such as warfarin, etc.).(See "Drug interaction") (4) Patients with, or with a history of, severe blood disorder (Mobic may worsen or reoccur the disorder). (5) Patients with, or with a history of, liver disorder (Mobic may worsen or reoccur the disorder). (6) Patients with, or with a history of, renal dysfunction (Mobic may worsen or reoccur the dysfunction due to reduction of renal blood flow volume, and due to a disruption - caused by inhibiting the prostaglandin synthesis, in the maintenance of the balance of water and sodium). (7) Patients with heart dysfunction (Mobic may worsen the dysfunction due to reduction of renal blood flow volume, and due to a disruption - caused by inhibiting the prostaglandin synthesis, in the maintenance of the balance of water and sodium). (8) Patients with hypertension (Mobic may increase blood pressure due to reduction of renal blood flow volume, and due to a disruption - caused by inhibiting the prostaglandin synthesis, in the maintenance of the balance of water and sodium). (9) Patients with bronchial asthma (Mobic may induce asthma attack). (10) Elderly (See "Use in Elderly"). (11) Patients immediately after a major operation accompanied by a loss of body fluids (Patients with reduced circulation of body fluids may have reduction of renal blood flow or renal dysfunction due to inhibition of prostaglandin synthesis). 2. Important Precautions (1) Mobic showed stronger inhibition of COX-2 than of COX-1 in in vitro tests. However, it was not confirmed its higher safety in any clinical study in Japanese subjects in comparison with NSAIDs which showed lower selectivity to COX-2. Therefore, especially for patients with high risk factors for causing a gastric dysfunction (patients having history of peptic ulcer, etc.), a careful observation is necessary, and monitoring for incidence of adverse events as well. (See "Clinical Effects" and "Clinical Pharmacology") (2) It should be aware that the treatment by Mobic is symptomatic treatment, but not ethiotropic treatment. Therefore, a consideration for (appropriate) ethiotropic treatment is necessary. (3) For long-term treatment by Mobic, regular laboratory tests (urinalysis, hematology tests, liver function tests, occult bleeding tests, etc.) should be performed. When abnormality is detected, a proper treatment such as reduction of the doses or discontinuation is needed. (4) The patient condition should be monitored carefully, and it should be paid a careful attention to the occurrence of side effects. In other countries, severe adverse reactions in gastro-intestinal system [peptic ulcer (in some cases perforative ulcer), gastrointestinal hemorrhage such as hematemesis, melena etc.] are reported. When abnormality is observed, the dosing should be discontinued, and proper treatment provided. (See "Adverse Reactions") (5) Due to the anti-inflammatory effect of meloxicam, an infection may not be manifested. In this aspect, the monitoring and administration of the drug should be carefully executed. (6) It is advised to avoid co-medication with other anti-inflammatory agents (It is reported that other NSAIDs enhance each others' side effects). (See "Drug interaction") (7) Symptoms of a central nervous system dysfunction - such as abnormal vision accommodation, sleepiness, etc. sometimes occurred. Enough care should be taken, as operating equipments or driving a car should be avoided by patients under treatment with this drug. 3. Drug Interactions Table. Cautions for co-medication Name of medication Clinical signs and symptoms or treatment Mode of action or risk factors Other NSAIDs or salicylic acid salts It is reported that co-medication with other NSAIDs cause an increase of the side effects (See "Important Precautions") It is considered that adverse effects are enhanced because both medications inhibit the prostaglandin synthesis. Cumarin type anticoagulants (warfarin etc.) This combination may increase the risk of bleeding. When the co-medication cannot be avoided, blood coagulation tests should be conducted, and the effects of these drugs should be carefully monitored. The reason is considered that both agents have anticoagulative effect. The metabolism by CYP2C9 may cause interaction between this medicine (meloxicam) and warfarin. Heparin Table (cont.) Cautions for co-medication Ticlopidine Risk of increase of the tendency for bleeding It is considered that Ticlopidine has inhibitory effect on platelet coagulation. Anti-thrombotics This is due to the anti-thrombotic effects of both agents. Cholestyramine Weakened this drug's effects It is considered that the clearance of this drug (meloxicam) can be shortened because cholestyramine absorbs other drugs. Oral anti-hyperglycemics Weakened this drug's (meloxicam) effects Mode of action is unknown, but glibenclamide was reported that it inhibited this drug's (meloxicam) metabolism (in vitro tests). Kinidine Weakened this drug's (meloxicam) effects Mode of action is not known, but kinidine was reported to increase this drug's (meloxicam) metabolism. Table (cont.) Cautions for co-medication Lithium The lithium concentration in the blood rises. Because there are reports that other NSAIDs lead to lithium poisoning, when Mobic is introduced the lithium concentration in the blood should be measured, the dose of Mobic reduced, and patients carefully observed. It is considered that the renal excretion of lithium is prolonged due to this drug's (meloxicam) inhibitory effect on the prostaglandin synthesis. Methotrexate This drug (meloxicam) has the risk of worsening the blood dysfunction caused by methotrexate. Hematology tests are required. It is considered that this drug (meloxicam) reduces the excretion of methotrexate at the renal duct due to inhibitory effect on the prostaglandin synthesis. Diuretics Patient on diuretics may have risks of acute renal failure when co-medicated with NSAIDs. Co-medication of this drug (meloxicam) should be started with special care on renal function. The reductions of renal blood flow volume, and the disruption of the maintenance of balance of water and sodium, are considered to be caused by the inhibition of the prostaglandin synthesis. Table (cont.) Cautions for co-medication Anti-hypotensive (beta-blockers, ACE inhibitors, blood vessel dilating medicines, diuretics, etc.) Other NSAIDs are reported to reduce anti-hypotensive drugs' effects. It is considered that inhibition of prostaglandin that expands blood vessels weaken the effect of reduction on the blood pressure of the anti-hypotensive agents. Cyclosporin NSAIDs are reported to enhance the renal toxicity of cyclosporin. Special care should be taken on the renal function. It is considered that reduction of renal blood flow is caused by inhibition of the prostaglandin synthesis. 4. Adverse Reactions   Clinical studies were conducted domestically with patients with chronic joint rheumatism, osteoarthrosis, lumbago symptoms, scapulohumeral periarthritis, and cervicobrachial syndrome, and the safety results were reported. Adverse drug reactions were observed in 183 patients out of 1,128 patients (16.22%). Among these patients, 125 patients (11.08%) showed side effects in gastro-intestinal system. Major symptoms were gastric or epigastric discomfort with incidence of 36 cases (3.19%), stomach or epigastric pain in 28 cases (2.48%), exanthem/rash/drug-caused skin eruption in 23 cases (2.04%), abdomen or upper abdomen pain in 11 cases (0.98%), itchiness in 10 cases (0.89%) and so on. Laboratory tests did not show any tendency of alterations. (December 1996)      Clinical studies in other countries have been conducted in totally 5,500 subjects - healthy volunteers and patients with chronic joint rheumatism, osteoarthrosis, and ankylosing spondylitis. Among them, 7.5 mg and 15 mg meloxicam were administered orally in 3,750 patients. Major adverse drug reactions were dyspepsia (7.0%), nausea (4.6%), headache (4.0%), diarrhea (3.5%), rash (2.8%) and so on. (At time of marketing approval application in Europe) (1) Serious Adverse Events 1) Peptic ulcer (1% or less) (often with perforation), hematemesis (incidence is unknown), gastro-intestinal hemorrhage including melena (1% or less), colitis (less than 0.1%). Careful monitoring should be performed, and the therapy should be discontinued when abnormality appears and proper treatment should be administered. 2) Asthma (less than 0.1%). Careful monitoring should be performed, and the therapy should be discontinued when abnormality appears and proper treatment should be administered. 3) Acute renal failure (incidence is unknown). Careful monitoring should be performed, and the therapy should be discontinued when abnormality appears and proper treatment should be administered. 4) Agranulocytosis (incidence unknown), thrombocytopenia (1% or less). Careful monitoring should be conducted and hematology tests should be carried out regularly and when needed. The therapy should be discontinued when abnormality appears and proper treatment should be administered. Special care is required for co-medication with agents that reduce bone marrow function, such as methotrexate. (See "Drug Interaction") 5) Muco-cutaneo-ocular syndrome (Stevens-Johnson syndrome) (incidence unknown), epidermal toxic necrolysis (Lyell syndrome) (incidence unknown), blisters (incidence unknown) and erythema multiforme (incidence unknown). Careful monitoring should be performed, and the therapy should be discontinued when abnormality appears and proper treatment should be administered. 6) Anaphylaxis, anaphylactoid reaction (less than 0.1%). Careful monitoring should be performed and the therapy should be discontinued when abnormality appears and proper treatment should be administered. 7) Hepatitis (incidence unknown), severe lever dysfunction (1% or less) Careful monitoring should be conducted and laboratory tests should be carried out regularly and when needed. The therapy should be discontinued when abnormality appears and proper treatment should be administered. Note: The incidence figures cited here are taken from the results of the clinical studies conducted outside Japan. The incidence marked as "unknown" is based on the voluntary reports of PMS studies from overseas. (2) Serious Adverse Events (observed with the same class medicines)   Shock, aplastic anemia, bone marrow depression, nephrolysis syndromes have been observed with other NSAIDs. Physicians should carefully monitor, conduct regular laboratory tests as well as when needed, discontinue and provide proper treatment when abnormality occurs. (3) Other Adverse Events Table. Other Adverse Events More than 5% *Note 1 In range of 0.1-5% Note 1 Less than 0.1% Note 1 Negligible frequency Note 2 Circulatory organs Increase of blood pressure Hypotension, heart throbbing Digestive organs Stomachache Occult bleeding, gastric ulcer, vomiting, nausea / feeling like vomiting, anorexia, indigestion, mouth drying, stomatitis, angular stomatitis, eructation, diarrhea, flatulence crepitus Note 3, gullet flame Note 3 Abdominal fullness, constipation Gastritis Table (cont.) Other Adverse Events More than 5% *Note 1 In range of 0.1-5% Note 1 Less than 0.1% Note 1 Negligible frequency Note 2 Central Nervous System Headache, taste abnormality Sensory disturbance, sleepiness, vertigo Confusion, disorientation Erethism, Hyper- sensitivity Rashes, skin itchiness, urticaria Contact dermatitis, photosensitivity Note 3 Sense organs Strange sensation in eye, eyeball sclera congestion, tinnitus Conjunctivitis, abnormal vision (sight obstacles), blurred vision Liver Increase of AST (GOT), ALT (GTP), LDH, A1-P in liver functional disorders, rise of total bilirubin value, urobilinogen Table (cont.) Other Adverse Events More than 5% *Note 1 In range of 0.1-5% Note 1 Less than 0.1% Note 1 Negligible frequency Note 2 Kidney BUN, creatinine, and uric acid values increase, total proteins, decrease of albumins, urine protein, urine glucose Decrease of the volume of urine Blood Increase of a white blood cells, decrease of red blood cells, white blood cells, hemoglobin, hematocrit value and lymphocytes, increase of neutrophils, eosinophils, basophils and monocytes, anemia 3) Table (cont.). Other Adverse Events More than 5% *Note 1 In range of 0.1-5% Note 1 Less than 0.1% Note 1 Negligible frequency Note 2 Others Oedema, fatigue, feeling bad, increase of urine sediment, urine occult bleeding, decrease of serum iron, rise of potassium Coughing, pain of the axilla or breast, rigors, hot flushes, fever, weakness in the lower extremities 5. Use in Elderly Elderly tend to suffer from adverse effects more often. The administration to elderly of this drug (meloxicam) should start with a careful monitoring of the patient's condition, for example, starting with low dose (5 mg once a day). In general, gastro-intestinal bleeding, ulcer and ulcer perforation in elderly will have more severe outcome, and in rare cases are reported as fatal digestive organ disorders. These events can happen at any treatment stage with or without history of serous digestive organ disorders. Physicians should carefully monitor patients (for digestive organ disorders especially gastro-intestinal bleeding), and when an abnormality is detected, to discontinue the administration and to provide appropriate treatment. 6. Use during Pregnancy, Delivery or Lactation (1) This drug should not be administered to women with pregnancy or expecting pregnancy since the following is found in animal studies (in rats and rabbits): 1) In studies with administration prior or at early stage of pregnancy in rats, it was observed a decrease of numbers of corpus lutea, implantations, survived fetuses and implantation rate, and an increase of death rate after implantation. 2) In studies with administration during the period of organogenesis in rats, it was observed a prolongation of pregnancy duration and an increase of the stillborns. 3) In studies with administration during the period of organogenesis in rabbits, an increase of death rate after implantation was observed, although not significant. 4) In studies with administration during the perinatal and lactation periods, extension of pregnancy duration, extension of birth delivery, an increase of stillbirths and mortality within the first four days after the birth were observed. (2) Dosing of lactating woman should be avoided. If the administration cannot be avoided, the lactation should be discontinued. [This drug is known to be excreted into milk in the pre-clinical animal tests (in rats)]. 7. Pediatric Use   Safety in newborns with low body weight, neonates, babies and infants is not established due to lack of experience. 8. Overdosage (1) Symptoms Overdose is rarely reported, and therefore the typical symptoms and treatment are not described. (2) Treatment When overdosed, according to general treatment, physician should wash stomach, and provide support treatment and symptomatic therapy. Cholestyramine is reported to shorten the effect of this drug 1). 9. Precautions Concerning the Use Taking the medicine   It is necessary to explain to patients to take out the tablets from PTP sheets for the drug in PTP package. (It is reported that if swallowed by a mistake, the hard edge of PTP sheets may perforate the mucous membrane of the esophagus, thus leading to mediastinitis and other severe complications) 10. Other Precautions   There is reported that other NSAIDs reduce contraception effects of the intrauterine devices. 【PHARMACOKINETICS】 1) Adsorption When 14C-meloxicam 30 mg Note)* was administered orally to healthy volunteers, absorption rate was estimated to be approximately 100 % 2). 2) Blood Concentration (1) Single dosage When meloxicam 5, 10, or 20 mg Note) were administered orally to healthy volunteers at after fasting, Cmax was observed at about 7 hours after dosing, as the peaks of the blood drug concentration showed two phases. Based on those findings, it is considered that this compound shows enteroenteric circulation from intestine to intestine, thus the drug is re-absorbed at the intestines after being excreted to intestines, or as a result of the intestine-liver circulation. Cmax and AUC showed a dose correlation. Table. Changes in the pharmacokinetic parameters after a single oral dose of meloxicam (administered after fasting) 3) Pharmacokinetic parameters 5 mg 10 mg 20 mg *Note) Cmax (?g/mL) 0.26 + 0.06 0.72+ 0.20 1.06+0.15 Tmax (h) 7.00+2.76 7.00+ 3.29 8.33+3.67 T1/2 (h) - 27.6+ 7.30 25.4+8.70 AUC 0-168 (?g *h/mL) 7.87+2.13 22.8+ 3.61 42.2+15.1 Cl tot (L/h) - 0.35+ 0.05 0.49+0.15 Vd (L) - 13.7+ 3.70 16.8+4.14 (Mean + S.D., n=6) (- For the assay limit, the calculation of pharmacokinetic parameters was impossible) Graph. Plasma concentration (?g/mL) of meloxicam after administration of various doses Time (hours) (2) Multiple dosage When meloxicam 10 mg was repeatedly administered to healthy volunteers 30 minutes after meal, T1/2 was approximately 17-22 hours. 4) (3) Effects of food Meloxicam was administered to healthy volunteers at a dose of 10 mg between meals (starving condition) or after meal, and the pharmacokinetic parameters were compared. As the results, Cmax was higher in groups dosed after meal and the AUCs were not differed between the groups. It was concluded that food did not affect the absorption of meloxicam. Table. Changes in the pharmacokinetic parameters after a single oral dose of meloxicam (administered before and after meal) 5) Pharmacokinetic parameters Cmax (?g/mL) Tmax (h) T1/2 (h) AUC 0-168 (?g *h/mL) Before meal 0.7410.101 8.08.0 28.75.6 26.65.0 After meal 0.8510.139 5.01.0 23.75.3 26.95.1 (Mean + S.D., n=12) 3) Distribution (a reference) When 14C-meloxicam 1 mg/kg was orally administered, its levels were high in blood, liver, kidney, lung, thymus, as well as in the intestines, but it was almost not detected at any level in the brain (in rats 6)). It was excreted in milk (in rats 7)). 4) Protein binding rate (1) In vivo studies When 14C-meloxicam 30 mg *Note) was orally administered in healthy volunteer, its biding rate to the serum proteins was more than 99% 2). (2) In vitro studies The biding rate of meloxicam to the human serum proteins was more than 99% 8), as the main binding protein was found to be the albumin 9). 5) Metabolism   When 14C-meloxicam 30 mg Note) was orally administered in healthy volunteers, the major form in the plasma was the unchanged parent compound (meloxicam), as metabolites were rarely detected 2). The unchanged compound was not found in urine. The major metabolites were 5'-hydroxymethyl meloxicam, 5'-carboxy meloxicam and an oxamic acid compound that resulted from the oxydative opening of the thiazine ring. The metabolism of meloxicam suggested that CYP2C9 of the liver cytochrome P-450 was mostly involved, and partially the CYP3A 10). 6) Excretion   When 14C-meloxicam 30 mg Note) was orally administered in healthy volunteers, the summarily level of the unchanged parent compound and its metabolites was approximately 43% in the urine at 168 hours after dosing, and approximately 47% in faces at 180 hours after dosing 2). 【CLINICAL STUDIES】 1. Clinical Effects Results of double-blind comparison studies in patients with chronic joint rheumatism, osteoarthrosis, lumbago symptoms, scapulohumeral periarthritis and cervicobrachial syndrome revealed the effectiveness of Mobic. Among the total 955 patients at 280 sites, including those in domestic double-blind comparison studies, the trial results from 636 patients with the approved indications and doses are shown below. Table. Clinical effectiveness Target indications Number of effective cases/Number of evaluated cases Efficacy rate (more than gradual improvement) Chronic joint rheumatism 102/306 33.3 % Deformations of the joints (osteoarthrosis) 20/166 72.3 % Lumbago symptoms 48/57 84.2 % Periarticular inflammation of the shoulder joint (scapulohumeral periarthritis) 37/55 67.3 % Neck-shoulder-arm syndrome (brachialgia, cervicobrachial syndrom) 42/52 80.8 % 2. Safety (results of double-blind comparison study) 1. The results of double-blind comparison studies in patients with chronic joint rheumatism comparing Mobic with piroxicam capsules 20 mg (administered one per day) demonstrated equivalency in the overall safety ratings between Meloxicam and piroxicam 11). 2. The results of double-blind comparison studies in patents with osteoarthrosis comparing Mobic with diclofenac tablets 25 mg (administered 3 times per day) proved the significant superiority of meloxicam in overall safety ratings against diclofenac tablets 12). 3. The double-blind comparison studies with indomethacin capsules 25 mg (3 times dosing per day) in patients with lumbago symptoms, scapulohumeral periarthritis, or cervicobrachial syndrome showed equivalency in overall safety ratings between the two medicines 13). 【PHARMACOLOGY】 1. Anti-inflammatory effects Meloxicam showed almost equivalent to the indomethacin anti-inflammatory effect in caoline-induced foot oedema (in rats). In adjuvant arthritis (in rats 14, 15)), meloxicam in some cases exerted stronger effects compared to indomethacin, piroxicam or diclofenac. Meloxicam demonstrated anti-inflammatory effects in carrageenen-induced foot oedema model (in rats 16)), in cotton-ball-induced granulation model (in rats 14)) and in carrageenen-induced pleurisy model (in rats 14, 17)). 2. Analgesia Meloxicam demonstrated an effect equivalent to indomethacin or piroxicam in foot oedema with inflammatory pain test (in rats 14) Randall-Selitto method), in pain in adjuvant arthritis models (in rats 16)), and in acetic acid writhing test (in mice 16)). 3. Effects on gastrointestinal tract Meloxicam showed weaker effects than piroxicam or indomethacin in gastric mucosa dysfunction effect (in rats 11, 17)), and in intestinal ulcer induced effects (in rats 16)). Piroxicam caused significant enhancement of HCl-induced gastric mucosa damage (in rats), while meloxicam did not produced any enhancement 18). 4. Inhibition activity on Cyclooxygenase (COX)-1 and COX-2 Meloxicam has shown stronger inhibition activity for COX-2 than COX-1 in enzyme assay 17) and cell assay 19). Table. Inhibition ratio of COX-2 vs. COX-1 in in vitro assays 17, 19) Enzyme assay 17) Cell assay 19) IC50(COX-2/COX-1) 0.0825 0.33 5. Mode of action Based on the results, it is considered that meloxicam inhibits the cyclooxygenase (COX) activity (in vitro 17, 19)), inhibits the local synthesis of prostaglandin in focal inflammation (in rats, mice 20)), and shows anti-inflammatory and analgesic effects. 【PHYSICOCHEMISTRY】 Nonproprietary name: Merokishikamu* (JAN)    Meloxicam (JAN) Chemical name: 4-hydroxy -2-methyl -N -(5-methyl -2-thiazolyl)-2 H -1,2- benzothiazine -3-carboxamide 1,1-dioxide Structural formula Molecular formula: C14H13N3O4S2 Molecular weight: 351.41 Description: It is a pale yellow, odorless powder. It is highly soluble in strong acids and bases, slightly soluble in methanol or ethanol (95%), and practically insoluble in water or diethyl ether. Melting point: 241 Co (resolution) 【PACKAGING】 Capsules 5 mg: 100 capsules (10 capsules x 10) PTP 700 capsules (14 capsules x 50) PTP 1000 capsules (10 capsules x 100) PTP 250 capsules in bottle Capsules 10 mg: 100 capsules (10 capsules x 10) PTP 700 capsules (14 capsules x 50) PTP 1000 capsules (10 capsules x 100) PTP 250 capsules in bottle 【REFERENCES】 1) Busch U et al: Eur J Clin Pharmacol 48: 269, 1995 2) Schmid J et al: Drug Metab Dispos 23: 1206, 1995 3) Azuma J et al: Clinical Reports 30 (12): 3189, 1996 4) Azuma J et al: Clinical Reports 30 (12): 3211, 1996 5) Irie Sh et al: Clinical Reports 30 (12): 3249, 1996 6) Ooiwa Youko et al: Drug Metabolism 12 (2): 108, 1997 7) Busch U: Drug Metab Dispos 26 (6): 576, 1998 8) Busch U: Internal communication 9) Turck D et al: Arzneim-Forsch 47 (1): 253, 1997 10) Chesne C et al: Xenobiotica 28 (1): 1, 1998 11) Mizushima Y et al: Clinical Reports 31 (3): 1115, 1997 12) Aoki T et al : J. Clin Therapeutics & Medicine 13 (4): 973, 1997 13) Sakurai M et al: Clinical Reports 31 (3): 1201, 1997 14) Engelhardt G et al: Inflamm Res 44: 423, 1995 15) Engelhardt G et al: Inflamm Res 44: 548, 1995 16) Yoshida M et al: Adv Drug Reactions 53: 351, 1997 17) Ogino K et al: Pharmacology 55 (1): 44, 1997 18) Schierok H J: Internal communication 19) Engelhardt G et al: Biochem Pharmacol 51: 21, 1996 20) Engelhardt G et al: Biochem Pharmacol 51: 29, 1996 【REQUESTS FOR INFORMATION】 Nippon Boehringer Ingelheim Co., Ltd. Scientific Information Department 3-10-1 Yato, Kawanishi-shi, Hyogo, Japan 666-0193 【INFORMATION ABOUT LONG TERM ADMINISTRATION】   This medicine (meloxicam) has been categorized as a "Drug with New Active Ingredient" (Ministry of Health and Welfare Notification No. 73 (dated March 17, 2000) and it is not permitted to be prescribed to the patients for a treatment period exceeding 30 days per prescription. This restriction shall be effective for one year after the date of listing the product (for reimbursement) in the National Health Insurance tariff list. 【NAME AND ADDRESS OF THE MANUFACTURER AND DISTRIBUTOR】 Manufacturer Nippon Boehringer Ingelheim Co., Ltd. 3-10-1 Yato, Kawanishi-shi, Hyogo-ken, Japan 666-0193 Co-distributor (co-marketer) Dai-Ichi Pharmaceutical Co., Ltd. 3-14-10 Nihonbashi, Chuo-ku, Tokyo * Note 1 Incidence figures are taken from domestic clinical test results. Note 2 The incidence marked as "unknown" is based on the voluntary reports of PMS studies from overseas (those adverse drug effects were not observed in domestic clinical studies). Note 3 On the basis of foreign clinical test results (those adverse effects that were not observed in domestic clinical trials). * Note 1 Incidence figures are taken from domestic clinical test results. Note 2 The incidence marked as "unknown" is based on the voluntary reports of PMS studies from overseas (those adverse drug effects were not observed in domestic clinical studies). Note 3 On the basis of foreign clinical test results (those adverse effects that were not observed in domestic clinical trials). * Note 1 Incidence figures are taken from domestic clinical test results. Note 2 The incidence marked as "unknown" is based on the voluntary reports of PMS studies from overseas (those adverse drug effects were not observed in domestic clinical studies). Note 3 On the basis of foreign clinical test results (those adverse effects that were not observed in domestic clinical trials). * Note 1 Incidence figures are taken from domestic clinical test results. Note 2 The incidence marked as "unknown" is based on the voluntary reports of PMS studies from overseas (those adverse drug effects were not observed in domestic clinical studies). Note 3 On the basis of foreign clinical test results (those adverse effects that were not observed in domestic clinical trials). * Reference 2) - from foreign data Note): Approved dose and dosages of this product is 10 mg as meloxicam, taken orally once per day after meal. * Note): Approved dose and dosages of this product is 10 mg as meloxicam, taken orally once per day after meal. * Note): Approved dose and dosages of this product is 10 mg as meloxicam, taken orally once per day after meal. * Japanese phonetic transcription Mobic Copyright (c) 2001-2002 by JKS LLC Page 18 of 33