ADVERSE REACTIONS SECTION.

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/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 in 50 (less than 2%).GastrointestinalSeveral cases of documented pseudomembranous colitis were identified in clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after therapy. Hypersensitivity ReactionsAnaphylactic/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. HepaticTransient elevations in SGPT, SGOT, alkaline phosphatase, hepatitis, jaundice.RenalTransient elevations in BUN or creatinine, acute renal failure.Central Nervous SystemHeadaches, dizziness, seizures.Hemic and Lymphatic SystemTransient thrombocytopenia, leukopenia, neutropenia, prolongation in prothrombin time, elevated LDH, pancytopenia, agranulocytosis, and eosinophilia.Abnormal Laboratory TestsHyperbilirubinemia.Other Adverse Reactions Genital pruritus, vaginitis, candidiasis, toxic epidermal necrolysis.Adverse Reactions Reported for Cephalosporin-class DrugsAllergic 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Cefixime is semisynthetic cephalosporin antibacterial drug [see Microbiology 12.4)] . 12.3 Pharmacokinetics. Cefixime tablets and suspension, given orally, are about 40% to 50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food. single 200 mg tablet of cefixime produces an average peak serum concentration of approximately mcg/mL (range to mcg/mL); single 400 mg tablet produces an average peak concentration of approximately 3.7 mcg/mL (range 1.3 to 7.7 mcg/mL). The oral suspension produces average peak concentrations approximately 25% to 50% higher than the tablets, when tested in normal adult volunteers. Two hundred and 400 mg doses of oral suspension produce average peak concentrations of mcg/mL (range to 4.5 mcg/mL) and 4.6 mcg/mL (range 1.9 to 7.7 mcg/mL), respectively, when tested in normal adult volunteers. The area under the time versus concentration curve (AUC) is greater by approximately 10% to 25% with the oral suspension than with the tablet after doses of 100 to 400 mg, when tested in normal adult volunteers. This increased absorption should be taken into consideration if the oral suspension is to be substituted for the tablet. Crossover studies of tablet versus suspension have not been performed in children. The 400 mg capsule is bioequivalent to the 400 mg tablet under fasting conditions. However, food reduces the absorption following administration of the capsule by approximately 15% based on AUC and 25% based on max. Peak serum concentrations occur between and hours following oral administration of single 200 mg tablet, single 400 mg tablet or 400 mg of cefixime suspension. Peak serum concentrations occur between and hours following single administration of 200 mg of suspension. Peak serum concentrations occur between and hours following oral administration of single 400 mg capsule.DistributionSerum protein binding is concentration independent with bound fraction of approximately 65%. In multiple dose study conducted with research formulation which is less bioavailable than the tablet or suspension, there was little accumulation of drug in serum or urine after dosing for 14 days. Adequate data on CSF levels of cefixime are not available.Metabolism and ExcretionThere is no evidence of metabolism of cefixime in vivo. Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages to hours but may range up to hours in some normal volunteers. Special PopulationsGeriatrics: Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults. Differences in the pharmacokinetic parameters between 12 young and 12 elderly subjects who received 400 mg of cefixime once daily for days are summarized as follows: Pharmacokinetic Parameters (mean +- SD) for Cefixime in Both Young Elderly SubjectsPharmacokinetic parameterYoungElderlyCmax (mg/L) 4.74 +- 1.43 5.68 +- 1.83 Tmax (h) 3.9 +- 0.3 4.3 +- 0.6 AUC (mg.h/L) 34.9 +- 12.2 49.5 +- 19.1 1/2 (h) 3.5 +- 0.6 4.2 +- 0.4 ave (mg/L) 1.42 +-0.50 1.99 +- 0.75 Difference between age groups was significant. (p<0.05) However, these increases were not clinically significant [see Dosage and Administration 2)] Renal Impairment: In subjects with moderate impairment of renal function (20 to 40 mL/min creatinine clearance), the average serum half-life of cefixime is prolonged to 6.4 hours. In severe renal impairment (5 to 20 mL/min creatinine clearance), the half-life increased to an average of 11.5 hours. The drug is not cleared significantly from the blood by hemodialysis or peritoneal dialysis. However, study indicated that with doses of 400 mg, patients undergoing hemodialysis have similar blood profiles as subjects with creatinine clearances of 21 to 60 mL/min. 12.4 Microbiology. Mechanism of ActionAs with other cephalosporins, the bactericidal action of cefixime results from inhibition of cell wall synthesis. Cefixime is stable in the presence of certain beta-lactamase enzymes. As result, certain organisms resistant to penicillins and some cephalosporins due to the presence of beta-lactamases may be susceptible to cefixime. ResistanceResistance to cefixime in isolates of Haemophilus influenzae and Neisseria gonorrhoeae is most often associated with alterations in penicillin-binding proteins (PBPs). Cefixime may have limited activity against Enterobacteriaceae producing extended spectrum beta-lactamases (ESBLs). Pseudomonas species, Enterococcus species, strains of Group streptococci, Listeria monocytogenes, most strains of staphylococci (including methicillin-resistant strains), most strains of Enterobacter species, most strains of Bacteroides fragilis, and most strains of Clostridium species are resistant to cefixime. Antimicrobial ActivityCefixime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications And Usage 1). Gram-positive BacteriaStreptococcus pneumoniaeStreptococcus pyogenesGram-negative Bacteria Escherichia coli Haemophilus influenzaeMoraxella catarrhalis Neisseria gonorrhoeaeProteus mirabilis The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefixime against isolates of similar genus or organism group. However, the efficacy of cefixime in treating clinical infections caused by to these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive BacteriaStreptococcus agalactiaeGram-negative BacteriaCitrobacter amalonaticusCitrobacter diversusHaemophilus parainfluenzaeKlebsiella oxytocaKlebsiella pneumoniaePasteurella multocidaProteus vulgarisProvidencia species Salmonella species Serratia marcescensShigella species Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adults: 400 mg daily 2.1) 2.1 Adults. The recommended dose of cefixime is 400 mg daily. This may be given as 400 mg capsule daily. For the treatment of uncomplicated cervical/urethral gonococcal infections, 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, therapeutic dosage of cefixime should be administered for at least 10 days. 2.2 Pediatric Patients (6 months or older). The recommended dose is mg/kg/day of the suspension. This may be administered as single daily dose or may be given in two divided doses, as mg/kg every 12 hours. Note: suggested dose has been determined for each pediatric weight range. Refer to Table 1. Ensure all orders that specify dose in milliliters include concentration, because cefixime for oral suspension is available in three different concentrations (100 mg/5 mL, 200 mg/5 mL, and 500 mg/5 mL). Table 1. Suggested doses for pediatric patients PEDIATRIC DOSAGE CHARTDoses are suggested for each weight range and rounded for ease of administration Cefixime for Oral Suspension100 mg/5 mL 200 mg/5 mL 500 mg/ mL Patient Weight (kg) Dose/Day (mg) Dose/Day (mL) Dose/Day (mL) Dose/Day (mL)5 to 7.5 50 2.5 -- 7.6 to 10 80 2 10.1 to 12.5 100 2.5 12.6 to 20.5 150 7.5 1.5 20.6 to 28 200 10 2 28.1 to 33 250 12.5 2.5 33.1 to 40 300 15 7.5 40.1to 45 350 17.5 3.5 45.1 or greater 400 20 10 The preferred concentrations of oral suspension to use are 100 mg/5 mL or 200 mg/5 mL for pediatric patients in these weight ranges. Children weighing more than 45 kg or older than 12 years should be treated with the recommended adult dose. In the treatment of infections due to Streptococcus pyogenes, therapeutic dosage of cefixime should be administered for at least 10 days. 2.3 Renal Impairment. Normal dose and schedule may be employed in patients with creatinine clearances of 60 mL/min or greater. Neither hemodialysis nor peritoneal dialysis removes significant amounts of drug from the body.

DRUG INTERACTIONS SECTION.

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. 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 false-positive reaction for glucose in the urine using Clinitest (R), Benedicts solution, or Fehlings solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix (R) or TesTape (R)) be used. false-positive direct Coombs test has been reported during treatment with other cephalosporins; therefore, it should be recognized that positive Coombs test may be due to the drug. Clinitest (R) and Clinistix (R) are registered trademarks of Ames Division, Miles Laboratories, Inc. Tes-Tape (R) is registered trademark of Eli Lilly and Company.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Cefixime is cephalosporin antibacterial drug indicated in the treatment of adults and pediatric six months and older 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) Uncomplicated Urinary Tract Infections 1.1) Pharyngitis and Tonsillitis 1.3) Acute Exacerbations of Chronic Bronchitis 1.4) Uncomplicated Gonorrhea (cervical/urethral) 1.5) 1.1 Uncomplicated Urinary Tract Infections. Cefixime 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. 1.3 Pharyngitis and Tonsillitis. Cefixime capsules 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 capsules are generally effective in the eradication of Streptococcus pyogenes from the nasopharynx; however, data establishing the efficacy of cefixime capsules in the subsequent prevention of rheumatic fever is not available.) 1.4 Acute Exacerbations of Chronic Bronchitis. Cefixime capsules 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 capsules 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 the development of drug resistant bacteria and maintain the effectiveness of cefixime capsules and other antibacterial drugs, cefixime capsules 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Information for Patients. Patients should be counseled that antibacterial drugs, including cefixime, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefixime is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefixime or other antibacterial drugs in the future.Diarrhea is common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.Repackaged and Distributed By:Remedy Repack, Inc.625 Kolter Dr. Suite Indiana, PA 1-724-465-8762.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Cefixime tablets and suspension, given orally, are about 40% to 50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food. single 200 mg tablet of cefixime produces an average peak serum concentration of approximately mcg/mL (range to mcg/mL); single 400 mg tablet produces an average peak concentration of approximately 3.7 mcg/mL (range 1.3 to 7.7 mcg/mL). The oral suspension produces average peak concentrations approximately 25% to 50% higher than the tablets, when tested in normal adult volunteers. Two hundred and 400 mg doses of oral suspension produce average peak concentrations of mcg/mL (range to 4.5 mcg/mL) and 4.6 mcg/mL (range 1.9 to 7.7 mcg/mL), respectively, when tested in normal adult volunteers. The area under the time versus concentration curve (AUC) is greater by approximately 10% to 25% with the oral suspension than with the tablet after doses of 100 to 400 mg, when tested in normal adult volunteers. This increased absorption should be taken into consideration if the oral suspension is to be substituted for the tablet. Crossover studies of tablet versus suspension have not been performed in children. The 400 mg capsule is bioequivalent to the 400 mg tablet under fasting conditions. However, food reduces the absorption following administration of the capsule by approximately 15% based on AUC and 25% based on max. Peak serum concentrations occur between and hours following oral administration of single 200 mg tablet, single 400 mg tablet or 400 mg of cefixime suspension. Peak serum concentrations occur between and hours following single administration of 200 mg of suspension. Peak serum concentrations occur between and hours following oral administration of single 400 mg capsule.DistributionSerum protein binding is concentration independent with bound fraction of approximately 65%. In multiple dose study conducted with research formulation which is less bioavailable than the tablet or suspension, there was little accumulation of drug in serum or urine after dosing for 14 days. Adequate data on CSF levels of cefixime are not available.Metabolism and ExcretionThere is no evidence of metabolism of cefixime in vivo. Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages to hours but may range up to hours in some normal volunteers. Special PopulationsGeriatrics: Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults. Differences in the pharmacokinetic parameters between 12 young and 12 elderly subjects who received 400 mg of cefixime once daily for days are summarized as follows: Pharmacokinetic Parameters (mean +- SD) for Cefixime in Both Young Elderly SubjectsPharmacokinetic parameterYoungElderlyCmax (mg/L) 4.74 +- 1.43 5.68 +- 1.83 Tmax (h) 3.9 +- 0.3 4.3 +- 0.6 AUC (mg.h/L) 34.9 +- 12.2 49.5 +- 19.1 1/2 (h) 3.5 +- 0.6 4.2 +- 0.4 ave (mg/L) 1.42 +-0.50 1.99 +- 0.75 Difference between age groups was significant. (p<0.05) However, these increases were not clinically significant [see Dosage and Administration 2)] Renal Impairment: In subjects with moderate impairment of renal function (20 to 40 mL/min creatinine clearance), the average serum half-life of cefixime is prolonged to 6.4 hours. In severe renal impairment (5 to 20 mL/min creatinine clearance), the half-life increased to an average of 11.5 hours. The drug is not cleared significantly from the blood by hemodialysis or peritoneal dialysis. However, study indicated that with doses of 400 mg, patients undergoing hemodialysis have similar blood profiles as subjects with creatinine clearances of 21 to 60 mL/min.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Cefixime should be used during pregnancy only if clearly needed. 8.1) Nursing Mothers: Consideration should be given to discontinuing nursing temporarily during treatment with cefixime. 8.3) Children: Efficacy and safety in infants aged less than six months 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. Pregnancy Category BPregnancy Category B. Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and have revealed no evidence of harm to the fetus due to cefixime. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.. 8.2 Labor and Delivery. Cefixime has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.. 8.3 Nursing Mothers. It is not known whether cefixime is excreted in human milk. Consideration should be given to discontinuing nursing temporarily during treatment with this drug.. 8.4 Pediatric Use. Safety and effectiveness of cefixime in children aged less than six months old have not been established. The incidence of gastrointestinal adverse reactions, including diarrhea and loose stools, in the pediatric patients receiving the suspension, was comparable to the incidence seen in adult patients receiving tablets.. 8.5 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. pharmacokinetic study in the elderly detected differences in pharmacokinetic parameters [see Clinical Pharmacology 12.3)] These differences were small and do not indicate need for dosage adjustment of the drug in the elderly. 8.6 Renal Impairment. The dose of cefixime should be adjusted in patients with renal impairment as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Patients on dialysis should be monitored carefully [see Dosage and Administration 2.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity reactions including shock and fatalities have been reported with cefixime. Discontinue use if reaction occurs. 5.1) Clostridium difficile associated diarrhea: Evaluate if diarrhea occurs. 5.2) 5.1 Hypersensitivity Reactions. Anaphylactic/anaphylactoid reactions (including shock and fatalities) have been reported with the use of cefixime.Before therapy with cefixime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross hypersensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with history of penicillin allergy. If an allergic reaction to cefixime occurs, discontinue the drug.. 5.2 Clostridium difficile-Associated Diarrhea. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefixime, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins and which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.3 Dose Adjustment in Renal Impairment. The dose of cefixime should be adjusted in patients with renal impairment as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD). Patients on dialysis should be monitored carefully [see DOSAGE AND ADMINISTRATION 2)] . 5.4 Coagulation Effects. Cephalosporins, including cefixime, may be associated with fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin administered as indicated.. 5.5 Development of Drug-Resistant Bacteria. Prescribing cefixime in the absence of proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.