CEFIXIME

1 INDICATIONS AND USAGE Cefixime is a cephalosporin antibacterial drug indicated in the treatment of adults and pediatric patients six months and older with the following infections: Uncomplicated Urinary Tract Infections ( 1.1 ) Otitis Media ( 1.2 ) Pharyngitis and Tonsillitis ( 1.3 ) Acute Exacerbations of Chronic Bronchitis ( 1.4 ) Uncomplicated Gonorrhea (cervical/urethral) ( 1.5 ) Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefixime and other antibacterial drugs, cefixime for oral suspension and cefixime capsules should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. ( 1.6 ) 1.1 Uncomplicated Urinary Tract Infections Cefixime for oral suspension and cefixime capsule is indicated in the treatment of adults and pediatric patients six months of age or older with uncomplicated urinary tract infections caused by susceptible isolates of Escherichia coli and Proteus mirabilis . 1.2 Otitis Media Cefixime for oral suspension and cefixime capsule is indicated in the treatment of adults and pediatric patients six months of age or older with otitis media caused by susceptible isolates of Haemophilus influenzae , Moraxella catarrhalis , and Streptococcus pyogenes . (Efficacy for Streptococcus pyogenes in this organ system was studied in fewer than 10 infections.) Note: For patients with otitis media caused by Streptococcus pneumoniae , overall response was approximately 10% lower for cefixime than for the comparator [see Clinical Studies ( 14 )] . 1.3 Pharyngitis and Tonsillitis Cefixime for oral suspension and cefixime capsule is indicated in the treatment of adults and pediatric patients six months of age or older with pharyngitis and tonsillitis caused by susceptible isolates of Streptococcus pyogenes . (Note: Penicillin is the usual drug of choice in the treatment of Streptococcus pyogenes infections. Cefixime for oral suspension and cefixime capsule is generally effective in the eradication of Streptococcus pyogenes from the nasopharynx; however, data establishing the efficacy of cefixime for oral suspension and cefixime capsule in the subsequent prevention of rheumatic fever is not available.) 1.4 Acute Exacerbations of Chronic Bronchitis Cefixime for oral suspension and cefixime capsule is indicated in the treatment of adults and pediatric patients six months of age or older with acute exacerbations of chronic bronchitis caused by susceptible isolates of Streptococcus pneumoniae and Haemophilus influenzae . 1.5 Uncomplicated Gonorrhea (cervical/urethral) Cefixime for oral suspension and cefixime capsule is indicated in the treatment of adults and pediatric patients six months of age or older with uncomplicated gonorrhea (cervical/urethral) caused by susceptible isolates of Neisseria gonorrhoeae (penicillinase-and non-penicillinase-producing isolates). 1.6 Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug resistant bacteria and maintain the effectiveness of cefixime and other antibacterial drugs, cefixime for oral suspension and cefixime capsule should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antimicrobial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION Adults: 400 mg daily ( 2.1 ) Pediatric patients (6 months and older): 8 mg/kg/day ( 2.2 ) 2.1 Adults The recommended dose of cefixime is 400 mg daily. This may be given as a 400 mg capsule daily. For the treatment of uncomplicated cervical/urethral gonococcal infections, a single oral dose of 400 mg is recommended. The capsule may be administered without regard to food. In the treatment of infections due to Streptococcus pyogenes , a therapeutic dosage of cefixime should be administered for at least 10 days. 2.2 Pediatric Patients (6 months or older) The recommended dose is 8 mg/kg/day of the cefixime for suspension. This may be administered as a single daily dose or may be given in two divided doses, as 4 mg/kg every 12 hours. Note: A suggested dose has been determined for each pediatric weight range. Refer to Table 1. Ensure all orders that specify a dose in milliliters include a concentration, because cefixime for oral suspension is available in two different concentrations (100 mg/5 mL and 200 mg/5 mL). Table1. Suggested doses for pediatric patients PEDIATRIC DOSAGE CHART Doses are suggested for each weight range and rounded for ease of administration Cefixime for oral s uspension 100 mg/5 mL 200 mg/5 mL Patient Weight (kg) Dose/Day (mg) Dose/Day (mL) Dose/Day (mL) 5 to 7.5 50 2.5 -- 7.6 to 10 80 4 2 10.1 to 12.5 100 5 2.5 12.6 to 20.5 150 7.5 4 20.6 to 28 200 10 5 28.1 to 33 250 12.5 6 33.1 to 40 300 15 7.5 40.1 to 45 350 17.5 9 45.1 or greater 400 20 10 Pediatric patients weighing more than 45 kg or older than 12 years should be treated with the recommended adult dose. Otitis media should be treated with cefixime for oral suspension. Clinical trials of otitis media were conducted with the suspension, and the suspension results in higher peak blood levels than the tablet when administered at the same dose. Therefore, the cefixime tablet or cefixime capsule should not be substituted for the cefixime for oral suspension in the treatment of otitis media [see Clinical Pharmacology ( 12.3 )]. In the treatment of infections due to Streptococcus pyogenes , a therapeutic dosage of cefixime should be administered for at least 10 days. 2.3 Renal Impairment Cefixime may be administered in the presence of impaired renal function. Normal dose and schedule may be employed in patients with creatinine clearances of 60 mL/min or greater. Refer to Table 2 for dose adjustments for adults with renal impairment. Neither hemodialysis nor peritoneal dialysis removes significant amounts of drug from the body. Table2. Doses for Adults with Renal Impairment Renal Dysfunction Cefixime for Oral Suspension Creatinine Clearance (mL/min) 100 mg/5 mL 200 mg/5 mL Dose/Day (mL) Dose/Day (mL) 60 or greater Normal dose Normal dose 21 to 59 * OR renal hemodialysis * 13 6.5 20 or less OR continuous peritoneal dialysis 8.6 4.4 * The preferred concentrations of oral suspension to use are 200 mg/5 mL for patients with this renal dysfunction 2.4 Reconstitution Directions for Cefixime for Oral Suspension Table 3. Reconstitution Direction for Cefixime for Oral Suspension Strength Bottle Size Reconstitution Directions 200 mg/5 mL 75 mL To reconstitute, suspend with 51 mL water . Method: Tap the bottle several times to loosen powder contents prior to reconstitution. Add approximately half the total amount of water for reconstitution and shake well. Add the remainder of water and shake well. 100 mg/5 mL and 200 mg/5 mL 50 mL To reconstitute, suspend with 34 mL water . Method: Tap the bottle several times to loosen powder contents prior to reconstitution. Add approximately half the total amount of water for reconstitution and shake well. Add the remainder of water and shake well. After reconstitution, the suspension may be kept for 14 days either at room temperature, or under refrigeration, without significant loss of potency. Keep tightly closed. Shake well before using. Discard unused portion after 14 days.

3 DOSAGE FORMS AND STRENGTHS Oral Suspension: 100 mg/5 mL and 200 mg/5 mL ( 3 ) Capsules: 400mg ( 3 ) Cefixime for oral suspension USP is available for oral administration in a powder for oral suspension, when reconstituted, provides either 100 mg/5 mL or 200 mg/5 mL of cefixime as trihydrate. The powder has an off white to pale yellow color and is strawberry flavored. Cefixime capsule is available for oral administration as capsules which provide 400 mg of cefixime as trihydrate. These are size "0" capsules with pink opaque cap and pink opaque body, imprinted with "LU" on the cap and "U43" on the body in black ink. Capsules contain white to yellowish white granular powder.

4 CONTRAINDICATIONS Cefixime capsules are contraindicated in patients with known allergy to cefixime or other cephalosporins. Contraindicated in patients with known allergy to cefixime or other cephalosporins. ( 4 )

6 ADVERSE REACTIONS Most common adverse reactions are gastrointestinal such as diarrhea (16%), nausea (7%), loose stools (6%), abdominal pain (3%), dyspepsia (3%), and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/m edwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most commonly seen adverse reactions in U.S. trials of the tablet formulation were gastrointestinal events, which were reported in 30% of adult patients on either the twice daily or the once daily regimen. Five percent (5%) of patients in the U.S. clinical trials discontinued therapy because of drug-related adverse reactions. Individual adverse reactions included diarrhea 16%, loose or frequent stools 6%, abdominal pain 3%, nausea 7%, dyspepsia 3%, and flatulence 4%. The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in pediatric patients receiving the suspension was comparable to the incidence seen in adult patients receiving tablets. 6.2 Post-marketing Experience The following adverse reactions have been reported following the post-approval use of cefixime. Incidence rates were less than 1 in 50 (less than 2%). Gastrointestinal Several cases of documented pseudomembranous colitis were identified in clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after therapy. Hypersensitivity Reactions Anaphylactic/anaphylactoid reactions (including shock and fatalities), skin rashes, urticaria, drug fever, pruritus, angioedema, and facial edema. Erythema multiforme, Stevens-Johnson syndrome, and serum sickness-like reactions have been reported. Hepatic Transient elevations in SGPT, SGOT, alkaline phosphatase, hepatitis, jaundice. Renal Transient elevations in BUN or creatinine, acute renal failure. Central Nervous System Headaches, dizziness, seizures. Hemic and Lymphatic System Transient thrombocytopenia, leukopenia, neutropenia, prolongation in prothrombin time, elevated LDH, pancytopenia, agranulocytosis, and eosinophilia. Abnormal Laboratory Tests Hyperbilirubinemia. Other Adverse Reactions Genital pruritus, vaginitis, candidiasis, toxic epidermal necrolysis. Adverse Reactions Reported for Cephalosporin-class Drugs Allergic reactions, superinfection, renal dysfunction, toxic nephropathy, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and colitis. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced [see Dosage and Administration ( 2 ) and Overdosage ( 10 )] . If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

7 DRUG INTERACTIONS · Elevated carbamazepine levels have been reported in postmarketing experience when cefixime is administered concomitantly. ( 7.1 ) · Increased prothrombin time, with or without clinical bleeding, has been reported when cefixime is administered concomitantly with warfarin and anticoagulants. ( 7.2 ) 7.1 Carbamazepine Elevated carbamazepine levels have been reported in postmarketing experience when cefixime is administered concomitantly. Drug monitoring may be of assistance in detecting alterations in carbamazepine plasma concentrations. 7.2 Warfarin and Anticoagulants Increased prothrombin time, with or without clinical bleeding, has been reported when cefixime is administered concomitantly. 7.3 Drug/Laboratory Test Interactions A false-positive reaction for ketones in the urine may occur with tests using nitroprusside but not with those using nitroferricyanide. The administration of cefixime may result in a false-positive reaction for glucose in the urine using Clinitest ®** , Benedict’s solution, or Fehling’s solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix ®** or TesTape ®** ) be used. A false-positive direct Coombs test has been reported during treatment with other cephalosporins; therefore, it should be recognized that a positive Coombs test may be due to the drug. **Clinitest ® and Clinistix ® are registered trademarks of Ames Division, Miles Laboratories, Inc. Tes-Tape ® is a registered trademark of Eli Lilly and Company.

8 USE IN SPECIFIC POPULATIONS Pediatric Use: Efficacy and safety in pediatric patients younger than 6 months of age have not been established. ( 8.4 ) Geriatric Use: Clinical studies did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. ( 8.5 ) Renal Impairment: Cefixime may be administered in the presence of impaired renal function. Dose adjustment is required in patients whose creatinine clearance is less than 60 mL/min. ( 8.6 ) 8.1 Pregnancy Risk Summary Available data from published observational studies, case series, and case reports over several decades with cephalosporin use, including cefixime, in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Reproduction studies have been performed in mice and rats at doses equivalent to 40 and 80 times, respectively, the adult human recommended dose and have revealed no evidence of harm to the fetus due to cefixime (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Maternal gonorrhea may be associated with preterm birth, low neonatal birth weight, chorioamnionitis, intrauterine growth restriction, small for gestational age and premature rupture of membranes. Perinatal transmission of gonorrhea to the offspring can result in infant blindness, joint infections, and bloodstream infections. Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified a consistent association with cephalosporin use, including cefixime, during pregnancy, and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodological limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data The results of embryo-fetal development studies in mice and rats show that cefixime, at doses up to 3200 mg/kg/day administered during the period of organogenesis did not adversely affect development. In these studies, in mice and rats, cefixime did not affect postnatal development or reproductive capacity of the F 1 generation or fetal development of the F 2 generation. In an embryo-fetal development study in rabbits, cefixime at doses of 3.2, 10 or 32 mg/kg given daily during the period of organogenesis (gestation days 6 through 18) resulted in abortions and/or maternal deaths at doses > 10 mg/kg (typically associated with the administration of antibiotics in this species), but no malformations were reported at lower doses. A pre- and post-natal development study of cefixime at oral doses up to 3200 mg/kg/day in rats demonstrated no effect on the duration of pregnancy, process of parturition, development and viability of offspring, or reproductive capacity of the F 1 generation and development of their fetuses (F 2 ). 8.2 Lactation Risk Summary There are no available data on the presence of cefixime in human milk, the effects on the breast-fed infant, or the effects on milk production. Cefixime is present in animal milk (see Data). When a drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for cefixime and any potential adverse ef …

12.1 Mechanism of Action Cefixime is a semisynthetic cephalosporin antibacterial drug [see Microbiology ( 12.4 )] .

11 DESCRIPTION Cefixime is a semisynthetic, cephalosporin antibacterial for oral administration. Chemically, it is ( 6R , 7R )-7-[2-(2-Amino-4-thiazolyl)glyoxylamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, 7 2 -( Z )-[ O -(carboxy methyl) oxime] trihydrate. Molecular weight = 507.50 as the trihydrate. Chemical Formula is C 16 H 15 N 5 O 7 S 2 .3H 2 O The structural formula for cefixime is: Inactive ingredients contained in the cefixime powder for oral suspension USP are colloidal silicon dioxide, sodium benzoate, strawberry flavor, sucrose, and xanthan gum. Inactive ingredients contained in the cefixime capsules 400 mg are colloidal silicon dioxide, croscarmellose sodium, low substituted hydroxy propyl cellulose, magnesium stearate, and mannitol. The capsule shell contains the following inactive ingredients: ferric oxide black, ferric oxide red, gelatin, potassium hydroxide, propylene glycol, shellac, sodium lauryl sulfate, and titanium dioxide. Cefixime USP

10 OVERDOSAGE Gastric lavage may be indicated; otherwise, no specific antidote exists. Cefixime is not removed in significant quantities from the circulation by hemodialysis or peritoneal dialysis. Adverse reactions in small numbers of healthy adult volunteers receiving single doses up to 2 g of cefixime did not differ from the profile seen in patients treated at the recommended doses.

16 HOW SUPPLIED/STORAGE AND HANDLING Cefixime for oral suspension USP, 100 mg/5 mL is an off-white to pale yellow colored powder. After reconstituted as directed, each 5 mL of reconstituted suspension contains 100 mg of cefixime as the trihydrate and is supplied as follows: NDC 68180-405-01 - 50 mL Bottle Prior to reconstitution : Store drug powder at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. After reconstitution : Store at room temperature or under refrigeration. Keep tightly closed. Cefixime for oral suspension USP, 200 mg/5 mL is an off-white to pale yellow colored powder. After reconstituted as directed, each 5 mL of reconstituted suspension contains 200 mg of cefixime as the trihydrate and is supplied as follows: NDC 68180-407-03 - 50 mL Bottle NDC 68180-407-04 - 75 mL Bottle Prior to reconstitution : Store drug powder at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. After reconstitution : Store at room temperature or under refrigeration. Keep tightly closed. Cefixime capsules, 400 mg is size "0" capsule with pink opaque cap and pink opaque body, imprinted with "LU" on cap and "U43" on body in black ink, containing white to yellowish white granular powder containing 400 mg of cefixime as the trihydrate and is supplied as follows: NDC 68180-423-08 - Bottle of 50 capsules NDC 68180-423-11 - Unit dose Package of 10 (1 blister of 10 capsules) Store at 20 °C to 25°C (68°F to 77°F) [See USP Controlled Temperature].