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Eisai Co., Ltd. Revised: January 2010 (12th version) 1 Standard Commodity Classification No. of Japan 87449 - Drug for allergic diseases - Azeptin® Tablets 0.5mg Azeptin® Tablets 1mg <Azelastine hydrochloride preparation> Storage 1) AZEPTIN should be stored at room temperature. 2) AZEPTIN (1mg) package in the bottle should be protected from light and moisture once the bottle is opened. Expiration date AZEPTIN should be used before the expiration date indicated on the package or label. Approval No. Date of listing in the NHI reimbursement price Date of initial marketing in Japan Date of latest reexamination Date of latest approval of indications DESCRIPTION 1. Composition Tablets 0.5 mg: Each white, sugar coated tablet contains 0.5 mg of azelastine hydrochloride. It also contains powdered acacia, carnauba wax, hydrated silicon dioxide, microcrystalline cellulose, titanium oxide, stearic acid, calcium stearate, sucrose, talc, precipitated calcium carbonate, corn starch, lactose hydrate, white shellac, hydroxypropylcellulose, povidone and macrogol 6000 as inactive ingredients. Tablets 1 mg: Each white, sugar coated tablet contains 1 mg of azelastine hydrochloride. It also contains carnauba wax, hydrated silicon dioxide, microcrystalline cellulose, titanium oxide, stearic acid, calcium stearate, sucrose, talc, precipitated calcium carbonate, corn starch, lactose hydrate, white shellac, hydroxypropylcellulose, pullulan, povidone and macrogol 6000 as inactive ingredients. 2. Product description Brand name AZEPTIN Tablets 0.5mg AZEPTIN Tablets 1mg Dosage form and identification code Appearance Face Reverse Description Lateral White Sugercoated tablets 232 Diameter (mm) 6.2 Weight (mg) 100 Thickness (mm) 3.5 White Sugercoated tablets 233 INDICATIONS Bronchial asthma Allergic rhinitis Diameter (mm) 6.7 Weight (mg) 120 Thickness (mm) 3.7 Tablets 0.5 mg Tablets 1 mg 16100AMZ03237000 16100AMZ03238000 Jun 1986 Jun 1986 Jun 1986 Jun 1986 Sep 1993 Aug 1990 Urticaria, eczema/dermatitis, atopic dermatitis, pruritus and prurigo DOSAGE AND ADMINISTRATION 1. Bronchial asthma The usual adult dosage for oral use is 2 mg of azelastine hydrochloride twice a day after breakfast and at bedtime. The dosage may be adjusted depending on the patient’s age and symptoms. 2. Allergic rhinitis, urticaria, eczema/dermatitis, atopic dermatitis, pruritus and prurigo The usual adult dosage for oral use is 1 mg of azelastine hydrochloride twice a day after breakfast and at bedtime. The dosage may be adjusted depending on the patient’s age and symptoms. PRECAUTIONS 1. Important Precautions (1) Since AZEPTIN may induce drowsiness, patients should be cautioned against engaging in potentially hazardous activities requiring alertness, such as operating machinery or driving a car. (2) When a steroid is to be tapered off in a patient undergoing long-term steroid therapy, after initiation of AZEPTIN, the steroid dosage should be reduced slowly under close supervision. (3) If AZEPTIN is administered to patients with bronchial asthma, it should be explained to them that AZEPTIN is not a drug that rapidly relieves asthma attacks. (4) It is recommended that patients with seasonal allergic diseases be started on AZEPTIN immediately before the beginning of the unfavorable season and that the administration be continued until after its end. 2. Adverse Reactions Adverse reactions were reported in 439 of 14,365 patients. (At the end of the reexamination period) 2 Eisai Co., Ltd. 5% > ≥0.1% <0.1% Psychoneurologic Sleepiness and malaise Dizziness, headache and numbness of limbs Gastrointestinal Thirst and nausea/vomiting Oral and perioral roughness, anorexia, heart burn, stomach discomfort, abdominal pain, constipation and diarrhea Cardiovascular Facial hot flushes and palpitations Respiratory Nasal dryness and respiratory distress Hepatic Elevation of AST (GOT) and ALT (GPT), etc. Hypersensitivitynote) Rash Hematologic Bitter taste and taste disorder 7. Other Precautions Because of the bitterness of the drug itself, a bitter taste and taste disorder may be experienced. PHARMACOKINETICS Elevation of Al-P Leucocytosis Urinary Others Incidence unknown Pollakiuria Dysuria and hematuria Edema Menstrual disorder 1. Blood concentration When AZEPTIN was administered orally to healthy male adult volunteers at a single doses of 1 mg (4 men), 2 mg (4 men), 3 mgnote) (6 men) and 4 mgnote) (4 men), the peak plasma concentrations were 0.6, 1.1, 2.0 and 2.1 ng/mL, respectively. The times to reach the peak plasma concentration were 4 hr after administration of 1 to 3note) mg and 6 hr after administration of 4 mg note). When AZEPTIN was repeatedly administered orally to 6 healthy male adult volunteers at dose of 3 mg twice a day, the plasma concentration reached a steady state within 6 days and the biological half-life was found to be about 16.5 hr. Note) In the event of such symptoms, treatment should be discontinued. 3. Use in the Elderly Since the elderly often have a physiological hypofunction, it is advisable to take measures, such as reduction in dosage, under careful supervision. 4. Use during Pregnancy, Delivery or Lactation (1) AZEPTIN should only be used in pregnant women or women suspected of being pregnant if the expected therapeutic benefits outweigh the possible risk of treatment. [AZEPTIN has been reported to be potentially teratogenic at large doses (greater than 370 times the recommended clinical dose) in an animal study (in rats). (2) It is advisable to avoid administration to nursing mothers. When AZEPTIN must be used, breast feeding should be discontinued during treatment. [It has been reported that AZEPTIN is excreted in breast milk in an animal study (in rats).] 5. Pediatric Use Safety in low birth weight infants, neonates, nursing infants and infants has not been established (insufficient clinical experience). 6. Precautions concerning Use Caution in handing over drug For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove the drug from the package prior to use. [It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, causing perforation and resulting in serious complications such as mediastinitis.] 2. Excretion When AZEPTIN was administered orally to 3 healthy male adult volunteers at a single dose of 4 mgnote), excretion of the unchanged drug in the urine within 72 hr of administration accounted for 2.5% and that in the feces for 1.2%. [References] When 4.4 mgnote) of 14C-azelastine hydrochloride was administered orally to healthy male adult volunteers outside Japan, excretion of radioactivity in the urine within 120 hr of administration accounted for 26.2% and that in the feces for 53.2%. Note) Single doses of 3, 4, and 4.4 mg are unapproved. CLINICAL STUDIES Clinical efficacy The efficacy rate (“remarkably effective+effective”) was 31.2% (138/443 patients) for broncial asthma. It increased 66.4% (294/443 patients) when fairly to remarkably effective was taken into account.1) The efficacy rate (“remarkably effective+effective”) was 49.8% (309/620 patients) for allergic rhinitis. It increased 80.2% (497/620 patients) when fairly to remarkably effective was taken into account.2,3) Eisai Co., Ltd. The efficacy rate (“remarkably effective+effective”) was 64.5% (142/220 patients) for dermatoses (urticaria, eczema/dermatitis, atopic dermatitis, pruritus cutaneous and prurigo). It increased 83.2% (183/220 patients) when fairly to remarkably effective was taken into account.4,5) The usefulness of AZEPTIN has been established in double blind clinical trials. 3 PHYSICOCHEMISTRY Nonproprietary name: Azelastine Hydrochloride Chemical name: 4-[(4-Chlorophenyl)methyl]-2-[(4RS)-(1-methylazepan-4yl)]phthalazin –1(2H)-one monohydrochloride Molecular formula: C22H24ClN3O ⋅ HCl Molecular weight: 418.36 Structural formula: PHARMACOLOGY 1. Mechanisms of Action (1) Inhibition of the production and release of leukotrienes and antagonism to leukotrienes Azelastine hydrochloride inhibits the production and release of leukotrienes C4, D4 and B4 in guinea pig lung sections and human neutrophils and eosinophils. Its inhibitory action is considered to reside in its ability to inhibit calcium ion influx into the cell, inhibit 5-lipoxygenase activity, increase intracellular cyclic AMP and stabilize the cell membrane, etc. Azelastine hydrochloride has also been shown to inhibit the contraction of isolated guinea pig ileum and bronchial muscle induced by leukotrienes C4 and D4, and the migration of neutrophils induced by leukotriene B4.6-9) (2) Inhibition of histamine release and antagonism to histamine Azelastine hydrochloride inhibits histamine release from human and rabbit basophils, and rat mast cells, and exhibits an antihistaminic action in the contraction reaction of guinea pig bronchial muscle and ileum.9-14) (3) Inhibition of the migration and infiltration of inflammatory cells and production of active oxygen Azelastine hydrochloride inhibits the migration of human neutrophils induced by leukotriene B4, and the migration and infiltration of guinea pig eosinophils induced by PAF. Azelastine hydrochloride also exhibits a marked inhibitory effect on the production of active oxygen in guinea pig neutrophils.8,15,16) 2. Inhibition of experimental allergic reactions Azelastine hydrochloride inhibits the following over a long period of time at low oral doses: passive cutaneous anaphylactic reactions (PCA) in guinea pigs and rats, experimental asthma in guinea pigs due to the inhalation of leukotriens, PAF and histamine, experimental allergy rhinitis in dogs and Arthus reaction (type III allergy reaction) in guinea pigs.17-19) 3. Reduction of hypersensitivity in airways and nasal mucosa It has been demonstrated in airways and nasal mucosal hypersensitivity tests that azelastin hydrochloride reduces airway and nasal mucosal hypersensitivity in patients with asthma or allergic rhinitis.20,21) And enantiomer Description: Azelastine hydrochloride occurs as a white crystalline powder. It is soluble in formic acid, slightly soluble in water and in ethanol (99.5). Azelastine hydrochloride shows no optical rotation. Melting point: about 225°C (decomposition) PACKAGING AZEPTIN Tablets 0.5 mg: Boxes of 100 and 500 in press-through packages AZEPTIN Tablets 1 mg: Boxes of 100, 280 (28 Tabs. × 10), 500, 1,000, 1,400 (28 Tabs. × 50) and 3,000 tablets in press-through packages, and bottles of 500 REFERENCES 1) Makino S. et al.: Jpn. J.Clin. Exp. Med, 62, 1623, 1985. 2) Okuda M. et al.: Oto-rhino-Laryngol. Tokyo, 26(S,6), 563, 1983. 3) Okuda M. et al.: ibid., 26(S,6), 606, 1983. 4) Kameda H. et al.: Jpn. J. Clin. Exp. Med., 58, 2719, 1981. 5) Nisimoto M. et al.: J. New Remed. Clin., 35, 2111, 1986. 6) Katayama S. et al.: Prog. Med., 6, 1173, 1986. 7) Matsumura. M. et al.: Respiration Res., 9, 206, 1990. 8) Origasa E. et al.: Prog. Med., 9, 2272, 1989. 9) Tomooka M. et al.: Jpn. J. Allergol. 37, 213, 1988. 10) Little M. M. et al.: J. Allergy Clin. Immunol., 79, 204, 1987. 11) Chand N. et al.: Eur. J. Pharmacol., 96, 227, 1983. 12) Chand N. et al.: Int. Archs. Allergy Appl. immunol., 77, 451, 1985. 13) Yamanaka T. et al.: Arzneim.-Forsch., 31, 1203, 1981. 14) Akagi M. et al.: Pharmacometrics, 26, 191, 1983. 15) Takahashi R. et al.: Prog. Med., 9, 2479, 1989. 16) Yamai T. et al.: 2th Azeptin Research Report, 2, 12, 1989. 17) Tasaka K. et al.: Arzneim.-Forsch., 29, 488, 1979. 18) Katayama S. et al.: ibid., 31, 1196, 1981. 19) Tanigawa T.et al.: ibid., 31, 1212, 1981. 4 Eisai Co., Ltd. 20) Iwata M. et al.: Jpn. J. Allergol. 39, 428, 1989. 21) Harada I. et al.: Oto-Rhino-Laryngol. Tokyo, 35(S,6), 469, 1992. REQUEST FOR LITERATURE SHOULD BE MADE TO: Safety Management Department Fax: 03-3811-2710 Eisai Co., Ltd. REQUEST FOR PRODUCT INFORMATION SHOULD BE MADE TO: Customer Information Service Free Dial: 0120-419-497 Eisai Co., Ltd. Manufactured and marketed by: Eisai Co., Ltd. 6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, 112-8088