[DESCRIPTION] Revised July 2017 (16th version) Standard Commodity Classification No. of Japan

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1 Revised July 2017 (1th version) Standard Commodity Classification No. of Prescription drug Caution: Use only as directed by a physician. An oral quinolone antibacterial agent Geninax Tablets 200 mg Garenoxacin mesilate hydrate Approval No AMX Date of listing in the NHI reimbursement price September 2007 Date of initial marketing in October 2007 Date of latest reexamination March 2017 International birth date July 2007 Storage: store at room temperature Expiration date: indicated on the package (3 years from manufacturing date) [CONTRAINDICATIONS (Geninax is contraindicated in the following patients.)] (1) Patients with a history of hypersensitivity to any of the ingredients of this product or quinolone antibacterial agents. (2) Pregnant women or women who may become pregnant (See. Use during Pregnancy, Delivery or Lactation section.) (3) Children (See 7. Pediatric Use section.) Brand name Ingredient/content (content per tablet) Inactive ingredient Color and dosage form Appearance Size (mm) [DESCRIPTION] Geninax Tablets 200 mg Garenoxacin mesilate hydrate mg (containing 200 mg of garenoxacin) Microcrystalline cellulose, light anhydrous silicic acid, carmellose calcium, magnesium stearate, hypromellose, titanium dioxide, triacetin, iron sesquioxide, yellow ferric oxide, carnauba wax Light-orange, film-coated tablet Diameter: approx. 8.mm Thickness: approx. 4.7mm Weight: approx. 30mg [INDICATIONS] <Indicated bacteria> Garenoxacin-susceptible bacteria: Staphylococcus sp., Streptococcus sp., Streptococcus pneumoniae (including penicillin resistant Streptococcus pneumoniae), Moraxella (Branhamella) catarrhalis, Escherichia coli, Klebsiella sp., Enterobacter sp., Haemophilus influenzae, Legionella pneumophila, Chlamydia pneumoniae and Mycoplasma pneumoniae. <Indications> Pharyngitis/laryngitis, tonsillitis (including peritonsillitis and peritonsillar abscess), acute bronchitis, pneumonia, secondary infections in chronic respiratory lesion, otitis media and sinusitis Streptococcus pneumoniae includes multidrug resistant Streptococcus pneumoniae. For details of indicated bacteria including resistant strains, see CLINICAL STUDIES and PHARMACOLOGY. [DOSAGE AND ADMINISTRATION] The usual adult dosage for oral use is 400 mg of garenoxacin once daily. <Precautions> (1) As a general rule, the duration of administration of Geninax should be limited to the minimum period required for the treatment of the patient s condition, after the susceptibility of the microorganism to this drug has been confirmed, in order to prevent the emergence of drug-resistant microorganisms. (2) It is desirable that this drug should be administered at low doses (200 mg) to underweight patients (under 40 kg) with advanced renal function disorder (Ccr is less than 30 ml/min) who do not receive dialysis. (See PHARMACOKINETICS.) [PRECAUTIONS] 1. Careful Administration (Geninax should be administered with care in the following patients.) (1) Patients with convulsive disorders, including epilepsy, or patients with a history of convulsive disorders [Convulsion may occur.] (2) Patients with QT prolonged [Ventricular arrhythmia (including Torsades de Pointes) and QT prolonged may be worsened.] (3) Patients with diabetes mellitus or abnormal glucose tolerance [Blood glucose level abnormalities may occur.] (4) Patients with systolic pressure of 90 mmhg or less [Blood pressure may decrease, which may result in worsening of hypotension.] (5) Patients with myasthenia gravis [Symptoms may be aggravated.] 2. Important Precautions (1) Since shock or anaphylaxis has been reported to occur with the use of this drug, patients should be carefully interviewed to see if they have a history of allergy or drug hypersensitivity before administration. (2) Since consciousness disturbed etc. may occur with the use of this drug, patients should be thoroughly instructed to pay attention when operating potentially hazardous machine such as driving. 3. Drug Interactions 1) Geninax is hardly metabolized by cytochrome P-450 (CYP). It does not inhibit the metabolic activity of CYP and does not induce CYP isozymes. (See PHARMACOKINETICS.) Precautions for coadministration (Geninax should be administered with care when coadministered with the following drugs.) - 1 -

2 Drugs Drugs containing aluminum, magnesium, calcium, iron and zinc: antacid, mineral containing vitamin preparation, etc. Nitroglycerin Isosorbide dinitrate Signs, Symptoms, and Treatment Since the effect of Geninax may be decreased, attention should be paid when administering Geninax with these drugs and appropriate measures, such as using them at intervals of two hours or more after administration of Geninax, should be taken. In clinical studies of injectable solutions conducted abroad, it has been confirmed that the incidence of hypotension tends to increase when coadministered with nitroglycerin or isosorbide dinitrate. Class IA QT prolonged and ventricular antiarrhythmic arrhythmia (including Torsades de agents Pointes) may occur. quinidine, procaine amide, etc. Class III antiarrhythmic agents amiodarone, sotalol, etc. Nonsteroidal Convulsion may occur. antiinflammatory drugs derived from phenylacetic acid or propionic acid Theophylline Aminophylline hydrate Warfarin Drugs with antihypertensive effects (antihypertensive drugs, diuretics, etc.) Hypoglycemic agents It has been confirmed that Cmax and AUC of theophylline are increased by about 20%. 3) Since poisoning symptoms caused by theophylline (gastrointestinal disorders, headache, arrhythmia, convulsion, etc.) may occur, patients should be carefully observed and their blood concentration should be monitored closely. The effects of warfarin may be increased, and haemorrhage and a prothrombin time prolonged may occur. Patients should be carefully observed, and caution should be exercised through blood coagulation tests. Antihypertensive effects may be increased in combination with these drugs. Hypoglycemic effects may be enhanced in combination with these drugs. Mechanism and Risk Factors Geninax may form insoluble chelates with metal ions, which could inhibit the absorption of Geninax. 2) When administered alone, these antiarrhythmic agents increase QT intervals. Geninax is thought to enhance the inhibition of the binding to GABA A receptors in the central nervous system. 4. Adverse Reactions In clinical studies conducted in before approval, adverse reactions to Geninax were observed in 132 (18.80%) of 702 patients evaluated for safety and laboratory test abnormalities were observed in 211 patients (30.0%). The major adverse reactions included diarrhea (23 patients/3.28%), headache (12 patients/1.71%), loose stool (10 patients/1.42%), etc. In addition, the major laboratory test abnormalities included ALT (GPT) increased (10.40%) (72/92), AST (GOT) increased (8.38%) (58/92), blood amylase increased (4.23%) (29/85), etc. In post-marketing surveillance (drug use surveillance and specified drug use surveillance) conducted in, adverse reactions to Geninax including laboratory test abnormalities were observed in 291 (4.00%) of 7283 patients evaluated for safety. The major adverse reactions included diarrhea (35 patients/0.48%), hepatic function abnormal (35 patients/0.48%), rash (27 patients/0.37%), etc. (1) Clinically significant adverse reactions 1) Shock or anaphylaxis (Incidence unknown): Since shock or anaphylaxis may occur with the use of this drug, patients should be carefully monitored. If dyspnea, blood pressure decreased, edema, redness, etc. occur, administration should be discontinued and appropriate measures should be taken. 2) Mucocutaneous ocular syndrome (Stevens-Johnson syndrome) (<0.1% Note1) ): Since mucocutaneous ocular syndrome (Stevens-Johnson syndrome) may occur with the use of this drug, patients should be carefully monitored. If any abnormality is observed, administration should be 3) Bradycardia, sinus arrest or atrioventricular block (Incidence unknown): Bradycardia, sinus arrest or atrioventricular block (initial symptoms: queasy, giddiness, syncope, etc.) may occur with the use of this drug. If any abnormality is observed, administration should be 4) QT prolonged, ventricular tachycardia (including Torsades de Pointes) and ventricular fibrillation (Incidence unknown): Since QT prolonged, ventricular tachycardia (including Torsades de Pointes) and ventricular fibrillation may occur with the use of this drug, patients should be carefully monitored. If any abnormality is observed, administration should be discontinued and appropriate measures should be taken. 5) Hepatitis fulminant or hepatic function disorder (Incidence unknown): Since hepatitis fulminant or hepatic function disorder associated with marked increase of AST(GOT) and/or ALT(GPT), etc. may occur with the use of this drug, patients should be carefully monitored. If any abnormality is observed, administration should be discontinued and appropriate measures should be taken. ) Hypoglycemia (<0.1% Note1) ): Since hypoglycemia may occur with the use of this drug, patients (The elderly and patients with diabetes mellitus are more likely to develop hypoglycemia.) should be carefully monitored. If any abnormality is observed, administration should be 7) Pseudomembranous colitis (Clostridium colitis, less than 0.5%): Serious colitis associated with bloody stools, including pseudomembranous colitis may occur. If abdominal pain or frequent diarrhea occur, administration should be discontinued immediately and appropriate measures should be taken. 8) Agranulocytosis or thrombocytopenia (Incidence unknown): Since agranulocytosis or thrombocytopenia may occur with the use of this drug, patients should be carefully monitored. If any abnormality is observed, administration should be discontinued and appropriate measures should be taken. 9) Rhabdomyolysis (Incidence unknown): Rhabdomyolysis is characterized by myalgia, feelings of weakness, CK(CPK) increased, myoglobin blood increased and urine myoglobin increased. Since rhabdomyolysis associated with rapid worsening of renal function may occur with the use of this drug, patients should be carefully monitored. If any abnormality is observed, administration should be 10) Psychiatric symptoms including hallucination and delirium (Incidence unknown): Since hallucination, delirium, etc. may occur with the use of this drug, patients should be carefully monitored. If any abnormality is observed, administration should be discontinued and

3 appropriate measures should be taken. 11) Convulsion (Incidence unknown): Since convulsion may occur with the use of this drug, patients should be carefully monitored. If any abnormality is observed, administration should be discontinued and appropriate measures should be taken. 12) Interstitial pneumonia, eosinophilic pneumonia (<0.1% each Note1) ): Interstitial pneumonia, eosinophilic pneumonia, etc. accompanied by pyrexia, cough, dyspnea, chest X-ray abnormal, eosinophilia, etc. may occur with the use of this drug. If these symptoms occur, administration should be discontinued and appropriate measures, including administration of adrenal corticosteroid, should be taken. 13) Aggravation of myasthenia gravis (Incidence unknown): Since aggravation of symptoms may occur in patients with myasthenia gravis, patients should be carefully monitored. If any abnormality is observed, administration should be 14) Acute kidney injury (<0.1% Note1) ): Since serious renal disorder including acute kidney injury may occur with the use of this drug, patients should be carefully monitored. If any abnormality is observed, administration should be Incidence in post-marketing surveillance (2) Clinically significant adverse reactions (similar drugs) Since other quinolone antibacterial agents have been reported to cause the following serious adverse reactions, patients should be carefully monitored. If any abnormality is observed, administration should be discontinued and appropriate measures should be taken. 1) Toxic epidermal necrolysis: TEN 2) Interstitial nephritis 3) Hyperglycemia 4) Pancytopenia 5) Tendon disorders including Achilles tendonitis and tendon rupture ) Vasculitis (3) Other adverse reactions If the following adverse reactions occur, appropriate measures should be taken according to the symptoms. Hypersensitivity Hepatic Renal Gastrointestinal Hematologic 1% or Incidence unknown Rash, photosensitivity AST(GOT) increased, ALT(GPT) increased, -GTP increased, blood ALP increased, blood LDH increased, bilirubin increased Protein urine present, chromaturia Note2) Diarrhea, loose stool, constipation, blood amylase increased Eosinophil count increased, white blood cell count decreased, lymphocyte morphology abnormal 1%> 0.5% <0.5% Blood creatinine increased, glucose urine present Nausea, vomiting, abdominal pain, anorexia, abdominal distension, thirst, glossitis, cheilitis Platelet count increased, hemoglobin decreased, neutrophil count decreased Eczema, erythema, dermatitis, pruritus, flushing, eyelid edema, allergic conjunctivitis, eye pruritus Urobilin urine present Pollakiuria, BUN increased, white blood cells urine positive, red blood cells urine positive, urinary casts Stomach and abdominal discomfort, dyspepsia, abnormal stools, stomatitis, coated tongue Red blood cell count decreased, hematocrit decreased, platelet count decreased, lymphocyte count increased, lymphocyte count decreased, monocyte count increased Metabolic disorders Cardiovascular 1% or Incidence unknown Blood potassium increased, blood glucose increased, blood glucose decreased 1%> 0.5% <0.5% Blood pressure decreased, electrocardiogram QT prolonged Blood chloride decreased, blood potassium decreased, blood sodium decreased Bradycardia, cardiac failure, atrial fibrillation, sinus arrhythmia, ventricular bigeminy, palpitations, chest discomfort, chest pain, blood pressure increased, electrocardiogram P wave abnormal, electrocardiogram ST-T change Note 3) Psychoneurologic Headache Somnolence, insomnia, dizziness Numbness, tremor Musculoskeletal Back pain Arthralgia, myalgia, muscle cramp, plantar fasciitis Respiratory Asthma, bloody sputum, nasal bleeding, nasal congestion, nasal passage irritation, pharyngolaryngeal pain, pneumothorax, rhinorrhoea, upper respiratory tract inflammation, nasopharyngitis, laryngopharyngitis Others Blood CK(CPK) Taste abnormality Malaise, feeling hot, increased, CRP feeling abnormal, increased, cold conjunctival agglutinins hemorrhage, eye pain, positive ocular hyperemia, defective colour vision, herpes simplex, pyrexia Note 3) Note 3), chills Incidence unknown Note 3) Incidence in post-marketing surveillance 5. Use in the Elderly 4) In clinical studies of Geninax, the types and incidence of adverse reactions to this drug were similar in both the elderly (5 to 94 years old) and non-elderly (18 to 4 years old) groups. However, since the elderly often have reduced physiological function, this drug should be administered with care to them while monitoring their general condition.. Use during Pregnancy, Delivery or Lactation (1) Geninax should not be administered to pregnant women or women who may possibly be pregnant. [The safety of this drug in pregnant women has not been established.] (2) If this drug is administered to nursing mothers, they should be instructed to discontinue lactation. [This drug has been reported to be excreted in human breast milk. 5) ] 7. Pediatric Use Since the safety of Geninax in children has not been established, this drug should not be administered to them. (See 10. Other Precautions.) 8. Overdosage For overdosage, induced emesis or gastric lavage should be performed to eliminate drugs from the stomach. If symptoms occur, appropriate supportive and symptomatic therapy should be initiated and plenty of water should be supplied. Geninax cannot be effectively eliminated from the body by hemodialysis and peritoneal dialysis. [Elimination rate of garenoxacin from the body: about 11% of the dosage can be eliminated from the body by hemodialysis (4 hours) and about 3% of the dosage eliminated by continuous ambulatory peritoneal dialysis (72 hours). ) ] - 3 -

4 Plasma concentration (μg/ml) 9. Precautions concerning Use Precautions regarding dispensing: For drugs that are dispensed in a press-through package (PTP), patients should be instructed 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, resulting in severe complications such as mediastinitis.] 10. Other Precautions 7)-11) (1) In the animal studies (immature dogs [three months old], young dogs [eight to nine months old]) and rats [six weeks old]), articular cartilage disorders have been reported to occur. (2) In the animal studies (mice, rats, dogs and cynomolgus monkeys), purple-red or purple reversible staining has been observed in the organs and tissues, such as oral mucosa, palpebral conjunctiva, skin, stomach, etc. [PHARMACOKINETICS] 1. Blood concentration (1) Single-dose administration 12) When single doses of 400 mg of garenoxacin were administered orally to 19 healthy adults under fasting conditions, the pharmacokinetic parameters were shown in the following table. Dose (mg) T max (hr) AUCinf ( g hr/ml) t 1/2 (hr) ± ± ± ± Serum protein binding rate 13) When single doses of 400 mg of garenoxacin were administered orally to 14 healthy adults under fasting conditions, the serum protein binding rate was 79 to 80% (ex vivo). 3. Tissue distribution 13)-15) When single doses of garenoxacin 400 mg were administered orally, the tissue and body fluid distribution of garenoxacin were shown in the following table. Tissue and body fluid (time taken for collection) Paranasal mucosa ( hr) Palatine tonsil tissue ( hr) Middle ear mucosa ( hr) Saliva (2 hr) Sputum (3 hr) Note1) n=5, n=14 Plasma concentration Concentration in tissue and body fluid ( g/g or g/ml) The ratio of garenoxacin to plasma concentration ) 1)17) <Reference: foreign clinical data> When single doses of garenoxacin 00 mg were administered orally*, the tissue and body fluid distribution of garenoxacin were shown in the following table. Tissue and body fluid (time taken for collection) Lung parenchyma (4- hr) Bronchial mucosa (2-4 hr) Alveolar macrophages ( hr) Alveolar epithelial lining fluid ( hr) Breast milk (0- hr) Plasma concentrations Note1) n=8, n=, Note 3) n=3 Concentrations in tissues and body fluids ( g/g or g/ml) The ratio of garenoxacin to plasma concentrations Note 3) Note 3) <Reference: capsules> 13) When single doses of garenoxacin 400 mg were administered orally to healthy adults under fasting conditions, the pharmacokinetic parameters were similar to those obtained from healthy adults receiving 400 mg of garenoxacin tablets. (2) Repeated administration 13) <Reference: capsules> When 400 mg of oral garenoxacin was administered repeatedly once daily to healthy adults for 14 days, the pharmacokinetic parameters were shown in the following table. These parameters reached the steady state 7 days after the start of administration. Dose (mg) 400 Administration date Time (hr) T max AUC 0-24 Mean±S.D. (hr) ( g hr/ml) (hr) Day Day Day (3) Pharmacokinetics in patients 4) When 400 mg of garenoxacin was administered to 133 patients with chronic respiratory infection, Cmax and AUC 0-24 were g/ml and g hr/ml, respectively. [Population pharmacokinetics (PPK) analysis] t 1/ Metabolism 1)18) Major metabolites of garenoxacin in plasma, urine and feces were sulfate conjugates and glucuronides and oxidative metabolites formed by cytochrome P-450 (CYP) were present in very minor concentrations. In studies using human liver microsomes, the inhibitory effect of garenoxacin on metabolic activity of CYP1A2, 2A, 2C9, 2C19, 2D, 2E1 and 3A4 was weak at 200 μmol/l or less. In studies using human liver cells, CYP1A2, 2C9, 2C19, 2D, 2E1 and 3A4 were not induced. 5. Excretion 12) When single doses of 400 mg of garenoxacin were administered orally to 19 healthy adults under fasting conditions, the maximum urinary concentration of garenoxacin was 27.48± g/ml Note1) in the period between 0 to 4 hours after administration. In addition, the cumulative urinary excretion rates of garenoxacin were 34.1±4.% and 49.±5.7%, at 24 and 72 hours after administration, respectively. Note1) n=18 <Reference: foreign clinical data> When single doses of [ 14 C]-garenoxacin 00 mg were administered orally* to 8 healthy adults, the radioactivity recovery of [ 14 C]-garenoxacin was about the same in urine and feces and the rates of radioactivity recovered in urine and feces were, % and % at 7 days after administration,

5 Pneumonia respectively.. Blood concentrations in patients with renal function disorder (reference: foreign clinical data) ) When single doses of garenoxacin 00 mg were administered orally* to individuals with normal renal function, patients with severe renal function disorder who did not require dialysis, patients receiving hemodialysis (HD) and patients receiving continuous ambulatory peritoneal dialysis (CAPD), Cmax decreased by 20 to 52% in patients with severe renal function disorder compared with individuals with normal renal function. Furthermore, AUC increased by 51% in patients with severe renal function disorder who did not require dialysis and AUC increased by 1.2 to 21% in patients with severe renal function disorder who were receiving HD or CAPD. Degree of renal function disorder (Ccr: ml/min) Normal (Ccr>80) Patients with severe renal function disorder who do not require dialysis (Ccr<30) Patients receiving hemodialysis (HD) Patients receiving continuous ambulatory peritoneal dialysis (CAPD) N 12. [30.3] 10.1 [37.0] Note 4).0 7 [23.] Note 5) 9.2 [24.0] 7.1 [2.7] AUC ( g hr/ml) 13.4 [20.1] [3.4] [37.4] 15.5 [34.] 15.0 [27.7] t 1/2 Note 3) T max (hr) (hr) [0.50, 1.50] [0.50, 2.05] [0.75, 3.00] [0.50, 2.00] [0.75, 4.00] Geometric mean [CV%] Mean S.D. Note 3) Median [min, max] Note 4) HD was performed 3 hours after administration of garenoxacin 00 mg (for 4 hours). Note 5) Immediately after the completion of HD, 00 mg of garenoxacin was administered and HD was performed 8 hours after administration (for 4 hours). <Reference> When 400 mg of garenoxacin was administered repeatedly to underweight patients (under 40 kg) with advanced renal function disorder (Ccr was less than 30 ml/min) who did not receive dialysis, the average AUC 0-24 was 219 g hr/ml (calculated value). 4 ) 7. Blood concentrations in patients with hepatic function disorder (reference: foreign clinical data) When single doses of garenoxacin 00 mg were administered orally* to individuals with normal hepatic function and patients with mild, moderate or severe hepatic function disorder (Child-Pugh A, B and C), Cmax was slightly reduced in patients with moderate or severe hepatic function disorder in comparison with that of individuals with normal hepatic function and patients with mild hepatic function disorder showed no decrease in Cmax. Furthermore, when compared with individuals with normal hepatic function, no significant changes in AUC were observed in patients with mild, moderate or severe hepatic function disorder. Note 3) Degree of hepatic AUC t N 1/2 T max function disorder ( g hr/ml) (hr) (hr) Normal [29.0] [25.8] [0.50, 3.00] Mild (Child-Pugh A) [18.9] [45.7] [0.75, 3.00] Moderate (Child-Pugh B) [17.5] [14.1] [0.50, 2.00] Severe (Child-Pugh C) [1.4] [37.1] [0.50, 0.75] Geometric mean [CV%], Mean S.D., Note 3) Median [min, max] [CLINICAL STUDIES] 1. Efficacy rate by disease The following table shows the efficacy rate by disease in Phase II and III studies (including double-blind tests), which were conducted in both and foreign countries, in patients with respiratory infections and infections in the otorhinolaryngological field who received 400 mg of garenoxacin once a day. Disease Effective cases/ cases evaluated for efficacy Efficacy rate Note4) (%) Abroad (reference) Effective cases/ cases evaluated for efficacy Efficacy rate Note5) (%) Pharyngitis/laryngitis 17/ Tonsillitis 20/ Note ) Note ) Acute bronchitis 21/ Bacterial pneumonia 227/ / Mycoplasma pneumonia 22/ / Chlamydial pneumonia 12/ / Legionella pneumonia 0 / Secondary infections in Note3) chronic respiratory lesion 139/ / Otitis media 41/ Note ) Note ) Sinusitis 23/ / Including peritonsillitis and peritonsillar abscess. Including one patient with acute chlamydial bronchitis. Note 3) : including chronic bronchitis, diffuse panbronchiolitis, bronchiectasis, bronchial asthma, emphysema, old pulmonary tuberculosis, pulmonary fibrosis, etc. Abroad: chronic bronchitis Note 4) Evaluated at the completion of administration Note 5) Evaluated 7 days after completion of administration Note ) No clinical studies have been conducted on this disease. 2. Bacterial eradication rate by bacterial strain The following table shows bacterial eradication rates against each bacterial strain collected from patients in the Phase II and III studies (of respiratory infections and infections in the otorhinolaryngological field) conducted in both and foreign countries. The bacterial eradication rates against MRSA, which was a type of Staphylococcus bacterium and for which garenoxacin was indicated, were.7% (2/3) and 87.5% (14/1), respectively, in studies conducted in both and foreign countries and the results of other strains were as follows: penicillin resistant Streptococcus pneumoniae (100% (27/27) and 85.7%(12/14)), multidrug resistant Streptococcus pneumoniae (100%(81/81) and 91.4% (32/35)), -lactamase-producing strains of Moraxella catarrhalis (100% (29/29) and 93.3% (125/134) and BLNAR strains of Haemophilus influenzae (100% (49/49) in studies conducted in ). Abroad (reference) No. of strains Bacterial No. of strains Bacterial Bacterial strains and eradicated/ eradication eradicated/ eradication species No. of strains rate No. of strains rate isolated (%) isolated (%) Staphylococcus sp. 53/ / MRSA 2/3.7 14/ Streptococcus sp. 20/ / Streptococcus pneumoniae 122/ / Penicillin resistant Streptococcus 27/ / pneumoniae Multidrug resistant Streptococcus 81/ / pneumoniae Note 3) Moraxella (Branhamella) 32/ / catarrhalis -lactamaseproducing strains 29/ / Escherichia coli 0/0 40/ Klebsiella sp. 9/ / Enterobacter sp. 2/ / Haemophilus influenzae 111/ / BLNAR 49/49 100

6 Mycoplasma pneumoniae 8/ /0 Bacterial eradication rate measured at the completion of administration Bacterial eradication rate measured 7 days after completion of administration Note 3) Multidrug resistant Streptococcus pneumoniae: strains resistant to two or more drugs including quinolone (levofloxacin, MIC 8 g/ml), -lactam (cefuroxime, MIC 2 g/ml), macrolide (erythromycin, MIC 1 g/ml), tetracycline (MIC 8 g/ml) and trimethoprim/sulfamethoxazole (MIC 4/7 g/ml). [PHARMACOLOGY] 1. Antibacterial activity 19) Garenoxacin has a broad antibacterial spectrum against gram-positive, gram-negative and atypical bacteria and showed strong antibacterial activity against Staphylococcus sp. (including MRSA), Streptococcus sp., Streptococcus pneumoniae, Moraxella (Branhamella) catarrhalis (including -lactamase-producing strains), Escherichia coli, Klebsiella sp., Enterobacter sp., Haemophilus influenzae (including BLNAR), Legionella pneumophila, Chlamydia pneumoniae and Mycoplasma pneumoniae. Particularly, garenoxacin exhibited strong antibacterial activity against Streptococcus pneumonia, including penicillin resistant Streptococcus pneumoniae and multidrug resistant Streptococcus pneumoniae, which caused respiratory infection. 2. Mechanism of action 19) Garenoxacin inhibits DNA gyrase and topoisomerase IV of bacteria and has bactericidal activity. On the other hand, it exhibited weak inhibitory activity against topoisomerase II derived from eukaryotic cells and selectively inhibited type II topoisomerase derived from bacteria. [PHYSICOCHEMISTRY] Nonproprietary name: Garenoxacin Mesilate Hydrate Abbreviation: GRNX Chemical name: 1-Cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl- 2,3-dihydro-1H-isoindol-5-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid monomethanesulfonate monohydrate Structural formula: Molecular formula: C 23 H 20 F 2 N 2 O 4 CH 4 O 3 S H 2 O Molecular weight: Description: Garenoxacin mesilate hydrate is a white powder. It is freely soluble in N, N-dimethylformamide, soluble in methanol, sparingly soluble in water, slightly soluble in acetonitrile and ethanol (95) and very slightly soluble in 2-propanol. Melting point: About 277 C (decomposition) [PACKAGING] 100 tablets (10 tablets x 10) and 500 tablets (10 tablets x 50) [REFERENCES AND REQUEST FOR LITERATURE SHOULD BE MADE TO:] 1. REFERENCES 1) Nakamura T., et al.: Chemotherapy 55(S-1): 87, [GEN-0022] 2) Krishna G., et al.: Pharmacotherapy 27: 93, [GEN-00212] 3) Niki Y., et al.: Chemotherapy 55(S-1): 20, [GEN-00235] 4) Kobayashi H., et al.: Chemotherapy 55(S-1): 144, [GEN-00230] 5) Amsden G.W. et al.: J. Clin. Pharmacol., 44: 188, [GEN-00135] ) Krishna G. et al.: Curr. Med. Res. Opin., 23: 49, [GEN-00200] 7) Nagai A. et al.: J. Toxicol. Sci., 27: 219, [GEN-00071] 8) internal document (Toxicity study: dogs) (DIR07007) 9) internal document (Toxicity study: rats) (DIR070077) 10) Nagasawa M., et.al.: Chemotherapy 55(S-1): 34, [GEN-00220] 11) Kizawa K., et al.: Chemotherapy 55(S-1): 42, [GEN-00221] 12) internal document (Bioequivalence study) (DIR130073) 13) Uchida E.: Chemotherapy 55(S-1): 95, [GEN-00227] 14) Baba S., et al: Chemotherapy 55(S-1): 194, [GEN-00234] 15) Watanabe A., et al.: Chemotherapy 55(S-1): 12, [GEN-00231] 1) Krishna G., et al.: Curr. Med. Res. Opin., 23: 1841, [GEN-00242] 17) Andrews J. et al.: J. Antimicrob. Chemother., 51:727, [GEN-00102] 18) Hayakawa H. et al.: Drug Metab. Dispos., 31:1409, [GEN-00109] 19) Takahata M., et al.: Chemotherapy 55(S-1): 1, [GEN-00217] 2. REQUEST FOR LITERATURE AND PRODUCT INFORMATION SHOULD BE MADE TO: Please request for the internal documents as well as literature cited in the REFERENCE to the following companies: Medical information Center Astellas Pharma Inc. 5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo Toll-Free Medical information Center Taisho Toyama Pharmaceutical Co., Ltd , Takada, Toshima-ku, Tokyo , Toll-Free Distributed by: Astellas Pharma Inc. 5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo Copromoted by: Taisho Toyama Pharmaceutical Co., Ltd , Takada, Toshima-ku, Tokyo, Manufactured and Marketed by: TOYAMA CHEMICAL CO., LTD. 2-5, Nishishinjuku 3-chome, Shinjuku-ku, Tokyo, - -