Taisho Toyama Pharmaceutical Co., Ltd. 1 Revised: June 2005 (10th version, Revisions associated with the amendment of Standard Commodity Classification No. of Japan the Pharmaceutical Affairs Law) 876132 - Cephem antibiotic product for oral use - TOMIRONÒ Fine granules 100 for pediatric < Cefteram pivoxil granules > Designated drug/prescription drugnote) Storage Approval No. (02EM)0110 Store in a dry location at room temperature. Date of listing in the NHI reimbursement price Aug 1990 [See ²PRECAUTIONS FOR HANDLING² section] Date of initial marketing in Japan Sep 1990 Date of latest reexamination Dec 1996 Expiration date Date of latest reevaluation Sep 2004 Do not use after the expiration date indicated on the package or the label. CONTRAINDICATIONS (TOMIRON® is contraindi- spp., Morganella morganii, Providencia spp. and Haemophilus cated in the following patients.) influenzae Patients with a history of shock following exposure to any <Indications> of the ingredients in the product. ·Pharyngitis or laryngitis, tonsillitis (including peritonsilli- tis and peritonsillar abscess), acute bronchitis and pneu- monia RELATIVE CONTRAINDICATIONS (As a general ·Cystitis and pyelonephritis rule, TOMIRON® is contraindicated in the following pa- Otitis media and sinusitis ® · tients. If the use of TOMIRON is considered essential, ·Scarlet fever it should be administered with care.) Patients with a history of hypersensitivity to any of the in- DOSAGE AND ADMINISTRATION gredients in the product or other cephem antibiotics. For oral use, the usual pediatric dosage is 9 - 18 mg (potency) of cefteram pivoxil per kg daily in 3 divided doses. DESCRIPTION The dosage may be adjusted according to the patient's age and ® Brand name TOMIRON Fine granules 100 for pediatric symptoms. Active ingredient Cefteram pivoxil (JP) Content (per 1 g) 100 mg (Potency) <Precautions> Inactive Refined sugar, Sucrose esters of fatty acids, 1. The drug must be used with care, and the dose or dosing ingredient Carmellose calcium, Crystalline cellulose/ interval should be adjusted in patients with severe renal Carmellose sodium, Aspartame (L-phenyl- dysfunction. [See ²PHARMACOKINETICS² section.] alanine compound), Polydimethylsiloxane, 2. As a general rule, the duration of administration of the Sorbitan fatty acid esters, Fatty acid esters of glycerol, Carmellose sodium, flavor, FD&C drug should be limited to the minimum period required Yellow No. 6 (Sunset Yellow FCF) for the treatment of the patient¢s condition, after Color/dosage Light orange fine granules with a smell and susceptibility of the microorganism to the drug has been form sweet flavor confirmed, in order to prevent the emergence of drug- Identification 0.25g ´ 240 packets 0.5g ´ 240 packets resistant microorganisms. code (packets) PRECAUTIONS · The drug may be seen as white granules on rare occasions ® because of unbalanced coloring. 1. Careful Administration (TOMIRON should be ad- ministered with care in the following patients.) INDICATIONS (1) Patients with a history of hypersensitivity to penicillin <Indicated bacteria> antibiotics Cefteram -susceptible bacteria; Streptococcus spp., Streptococ- [Patients should be interviewed carefully because cus pneumoniae, Escherichia coli, Klebsiella spp., Proteus shock may develop.] note) Prescription drug: Caution -- Use only as directed by a physician. 2 Taisho Toyama Pharmaceutical Co., Ltd. (2) Patients who or whose parents or siblings have a pre- should be discontinued and appropriate therapeutic disposition to develop allergic reactions such as bron- measures should be taken. chial asthema, rash and urticaria. 3) Serious nephropathy such as acute renal failure [The patient with allergic predisposition should be (incidence unknown) may develop. The patients carefully interviewed because he/she is more likely to should be carefully monitored, and periodic renal develop hypersensitivity.] function tests should be performed. If any abnormal (3) Patients with severe renal dysfunction findings are observed, administration should be dis- [Persistently elevated blood concentrations may de- continued and appropriate therapeutic measures velop. (See ²PHARMACOKINETICS² section.)] should be taken. (4) Patients with poor oral food intake or who are receiving 4) Serious colitis with bloody stool such as pseudo- parenteral alimentation, and patients in poor general membranous colitis (incidence unknown) may de- health. velop. If abdominal pain or frequent diarrhoea is ob- [Patients who are unable to take vitamin K through served, appropriate therapeutic measures, such as food should be observed carefully because vitamin K immediate discontinuing administration, should be deficiency may develop. (See ²(3) Other adverse reac- taken. tions² in ²3. Adverse Reactions² section.)] 5) Hepatic function disorder and jaundice (incidence (5) Elderly patients unknown) may develop. The patients should be care- (See ²4. Use in the Elderly² section.) fully monitored. If any abnormal findings are ob- served, administration should be discontinued and 2. Important Precautions appropriate therapeutic measures should be taken. The patients should be carefully interviewed because shock 6) Agranulocytosis and thrombocytopenia (incidence may develop. unknown) may develop. The patients should be care- fully monitored. If any abnormal findings are ob- 3. Adverse Reactions served, administration should be discontinued and Adverse reactions (including abnormal laboratory data) to appropriate therapeutic measures should be taken. the drug were reported in 51 (7.20%) of 708 patients who had been observed at time of approval. And they were re- (2) Clinically significant adverse reactions (similar ported in 71 (1.29%) of 5,510 patients who had been ob- drugs) served during the 4 years after approval (June 1990 to June 1) Hemolytic anemia has been reported in patients 1994). treated with other cephem antibiotics (cefalotin so- Adverse reactions to the drug were reported in 122 (1.96%) dium, cefaloridine, etc.). If any abnormal findings are of 6,218 patients at completion of reexamination. A total of observed, appropriate therapeutic measures, such as 144 cases of adverse reactions were reported. The major discontinuing administration, should be taken. adverse reactions were diarrhoea in 72 cases (1.16%), eo- 2) Interstitial pneumonia and PIE syndrome with fe- sinophilia in 13 cases (0.21%), increased AST (GOT) in 13 ver, cough, dyspnea, chest X-ray abnormalities, cases (0.21%) and increased ALT (GPT) in 11 cases and eosinophilia have been reported in patients (0.18%). treated with other cephem antibiotics. If such symp- For TOMIRON® tablet, which contain the same active in- toms are observed, administration should be discon- gredient as TOMIRON® fine granules 100 for pediatric, tinued and appropriate therapeutic measures, such as adverse reactions (including abnormal laboratory data) administration of adrenocortical hormones, should be were reported in 317 (1.90%) of 16,703 patients at com- taken. pletion of reexamination. A total of 456 cases of adverse reactions were reported. (3) Other adverse reactions Adverse reactions with unknown incidence developed after If the following adverse reactions are observed, appro- approval are also included in the data presented in this sec- priate therapeutic measures should be taken according tion. to the patient¢s condition. (1) Clinically significant adverse reactions Type 2% > ³ 0.1% or < 0.1% 1) Shock and anaphylactoid reactions (including incidence unknown dyspnoea, etc.) (incidence unknown) may develop. Hypersensitivity Rash, arthralgianote1) Urticarianote2), erythema, The patients should be carefully monitored. If any pruritus, fevernote2), edema, signs of shock or anaphylactoid reactions are ob- swollen lymph nodesnote2) served, administration should be discontinued and Hematologic Eosinophilia Granulocytopenia, appropriate therapeutic measures should be taken. thrombocytopenia 2) Toxic epidermal necrolysis (Lyell syndrome) and Hepatic Increased AST(GOT), Increased Al-P, Muco-cutaneo-ocular syndrome (Stevens-Johnson increased ALT(GPT), increased LDH syndrome) (incidence unknown) may develop. The Jaundicenote1) patients should be carefully monitored. If any signs of these syndromes are observed, administration Taisho Toyama Pharmaceutical Co., Ltd. 3 Type 2% > ³ 0.1% or < 0.1% (2) Positive results may develop in the direct Coombs¢test. incidence unknown Therefore, caution is required. Gastrointestinal Diarrhoea/ loose stools, Nausea/ vomiting, feeling 8. Other Precautions 1) stomach discomfortnote2), of enlarged abdomennote2), The drug has been reported to decrease serum carnitine . anorexianote2) heartburnnote2), abdominal Therefore, it is recommended that the drug not be used in pain, epigastric painnote2) children for periods longer than 2 weeks. Microbial - Stomatitisnote2), candidiasis substitution PHARMACOKINETICS Vitamin Vitamin K deficiency 1. Blood concentration ® deficiency symptoms When 3 mg and 6 mg per kg of TOMIRON were orally (hypoprothrombinemia, administered to children after meals, mean peak blood con- bleeding tendency, centrations of cefteram, the metabolite with antibacterial etc.)note1), vitamin B - activity, were seen 3 to 4 hours after the medication was complex deficiency taken, and those peak concentrations were, respectively, symptoms (glossitis, 1.3 mg/mL and 2.2 mg/mL. The half-life was 1.2 to 1.3 2) stomatitis, anorexia, hours . neuritis, etc.)note1) Others increased CK(CPK)note1) Headachenote2), Dizzinessnote2), 6mg/kg (n=3)