CEFIXIME

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: Cefixime is available for oral administration as 400 mg film coated tablets. Inactive ingredients contained in the cefixime tablets, USP 400 mg are: dibasic calcium phosphate, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, titanium dioxide, and triacetin. Cefixime Structure

Cefixime tablets are cephalosporin antibacterial drug indicated in the treatment of adults and pediatric patients weighing more than 45 kg or older than 12 years with the following infections: Uncomplicated Urinary Tract Infections ( 1.1 ) Pharyngitis and Tonsillitis ( 1.3 ) Acute Exacerbations of Chronic Bronchitis ( 1.4 ) Uncomplicated Gonorrhea (cervical/urethral) ( 1.5 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefixime tablets and other antibacterial drugs, cefixime tablets 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 tablets are indicated in the treatment of adults and pediatric patients weighing more than 45 kg or older than 12 years with uncomplicated urinary tract infections caused by susceptible isolates of Escherichia coli and Proteus mirabilis. 1.3 Pharyngitis and Tonsillitis Cefixime tablets are 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 tablets are generally effective in the eradication of Streptococcus pyogenes from the nasopharynx; however, data establishing the efficacy of cefixime tablets in the subsequent prevention of rheumatic fever is not available.) 1.4 Acute Exacerbations of Chronic Bronchitis Cefixime tablets are indicated in the treatment of adults and pediatric patients weighing more than 45 kg or older than 12 years with acute exacerbations of chronic bronchitis caused by susceptible isolates of Streptococcus pneumoniae and Haemophilus influenzae . 1.5 Uncomplicated Gonorrhea (cervical/urethral) Cefixime tablets are indicated in the treatment of adults and pediatric patients weighing more than 45 kg or older than 12 years with uncomplicated gonorrhea (cervical/urethral) caused by susceptible isolates of Neisseria gonorrhoeae (penicillinase-and non-penicillinase-producing isolates). 1.6 Usage To reduce the development of drug resistant bacteria and maintain the effectiveness of cefixime tablets and other antibacterial drugs, cefixime tablets 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.

Adults: 400 mg daily ( 2.1 ) Children: weighing more than 45 kg or older than 12 years should be treated with recommended adults dose ( 2.2 ) 2.1 Adults The recommended dose of cefixime is 400 mg daily. This may be given as a 400 mg tablet daily or the 400 mg tablet may be split and given as one half tablet every 12 hours. For the treatment of uncomplicated cervical/urethral gonococcal infections, a single oral dose of 400 mg is recommended. The tablet 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 (weighing more than 45 kg or older than 12 years) Children weighing more than 45 kg or older than 12 years should be treated with the recommended adult dose. Clinical trials of otitis media were conducted with the chewable tablets or suspension, and the chewable tablets or suspension results in higher peak blood levels than the tablet when administered at the same dose. Therefore, the tablet should not be substituted for the chewable tablets or 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. Table 2. Doses for Adults with Renal Impairment Renal Dysfunction Tablet Creatinine Clearance (mL/min) 400 mg Dose/Day 60 or greater Normal dose 21 to 59 OR renal hemodialysis Not Appropriate 20 or less OR continuous peritoneal dialysis 0.5 tablet

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

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 Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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%. 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.

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.