Cefuroxime Axetil

1 INDICATIONS AND USAGE Cefuroxime axetil tablet is a cephalosporin antibacterial drug indicated for the treatment of the following infections due to susceptible bacteria: (1) Pharyngitis/tonsillitis (adults and pediatric patients) ( 1.1 ) Acute bacterial otitis media (pediatric patients) ( 1.2 ) Acute bacterial maxillary sinusitis (adults and pediatric patients) ( 1.3 ) Acute bacterial exacerbations of chronic bronchitis (adults and pediatric patients 13 years and older) ( 1.4 ) Uncomplicated skin and skin-structure infections (adults and pediatric patients 13 years and older) ( 1.5 ) Uncomplicated urinary tract infections (adults and pediatric patients 13 years and older) ( 1.6 ) Uncomplicated gonorrhea (adults and pediatric patients 13 years and older) ( 1.7 ) Early Lyme disease (adults and pediatric patients 13 years and older) ( 1.8 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefuroxime axetil and other antibacterial drugs, cefuroxime axetil should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 1.1 Pharyngitis/Tonsillitis Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (13 years and older) with mild-to-moderate pharyngitis/tonsillitis caused by susceptible strains of Streptococcus pyogenes . Limitations of Use The efficacy of cefuroxime axetil in the prevention of rheumatic fever was not established in clinical trials. The efficacy of cefuroxime axetil in the treatment of penicillin-resistant strains of Streptococcus pyogenes has not been demonstrated in clinical trials. 1.2 Acute Bacterial Otitis Media Cefuroxime axetil tablets are indicated for the treatment of pediatric patients (who can swallow tablets whole) with acute bacterial otitis media caused by susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase–producing strains), Moraxella catarrhalis (including β-lactamase–producing strains), or Streptococcus pyogenes . 1.3 Acute Bacterial Maxillary Sinusitis Cefuroxime axetil tablets are indicated for the treatment of adult and pediatric patients (13 years and older) with mild-to-moderate acute bacterial maxillary sinusitis caused by susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae (non -β -lactamase–producing strains only). Limitations of Use The effectiveness of Cefuroxime axetil for sinus infections caused by β-lactamase–producing Haemophilus influenzae or Moraxella catarrhalis in patients with acute bacterial maxillary sinusitis was not established due to insufficient numbers of these isolates in the clinical trials [see Clinical Studies ( 14.1 )] . 1.4 Acute Bacterial Exacerbations of Chronic Bronchitis Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with mild-to-moderate acute bacterial exacerbations of chronic bronchitis caused by susceptible strains of Streptococcus pneumoniae , Haemophilus influenzae (β-lactamase–negative strains), or Haemophilus parainfluenzae (β-lactamase–negative strains). 1.5 Uncomplicated Skin and Skin-Structure Infections Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with uncomplicated skin and skin-structure infections caused by susceptible strains of Staphylococcus aureus (including β - lactamase–producing strains) or Streptococcus pyogenes. 1.6 Uncomplicated Urinary Tract Infections Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with uncomplicated urinary tract infections caused by susceptible strains of Escherichia coli or Klebsiella pneumoniae . 1.7 Uncomplicated Gonorrhea Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with uncomplicated gonorrhea, urethral and endocervical, caused by penicillinase-producing and non-penicillinase–producing susceptible strains of Neisseria gonorrhoeae and uncomplicated gonorrhea, rectal, in females, caused by non-penicillinase–producing susceptible strains of Neisseria gonorrhoeae . 1.8 Early Lyme Disease (erythema migrans) Cefuroxime axetil tablets are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with early Lyme disease (erythema migrans) caused by susceptible strains of Borrelia burgdorferi. 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefuroxime axetil and other antibacterial drugs, cefuroxime axetil should be used only to treat or prevent 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 antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION Tablets and oral suspension are not bioequivalent and are therefore not substitutable on a milligram-per-milligram basis. ( 2.1 ) Administer tablets with or without food. ( 2.2 ) Administer cefuroxime axetil tablets as described in the dosage guidelines. ( 2.2 ) Dosage adjustment is required for patients with impaired renal function. ( 2.5 ) Adult Patients and Pediatric Patients Dosage Guidelines for Cefuroxime Axetil Tablets Infection Dosage Duration (Days) Adults and Adolescents (13 years and older) Pharyngitis/tonsillitis (mild to moderate) 250 mg every 12 hours 10 Acute bacterial maxillary sinusitis (mild to moderate) 250 mg every 12 hours 10 Acute bacterial exacerbations of chronic bronchitis (mild to moderate) 250 or 500 mg every 12 hours 10 Uncomplicated skin and skin-structure infections 250 or 500 mg every 12 hours 10 Uncomplicated urinary tract infections 250 mg every 12 hours 7 to 10 Uncomplicated gonorrhea 1,000 mg single dose Early Lyme disease 500 mg every 12 hours 20 Pediatric Patients younger than 13 years (who can swallow tablets whole ) Acute bacterial otitis media 250 mg every 12 hours 10 Acute bacterial maxillary sinusitis 250 mg every 12 hours 10 2.1 Important Administration Instructions Cefuroxime axetil tablets and cefuroxime axetil for oral suspension are not bioequivalent and are therefore not substitutable on a milligram-per-milligram basis [see Clinical Pharmacology ( 12.3 )]. Administer cefuroxime axetil tablets as described in the appropriate dosage guidelines [see Dosage and Administration ( 2.2 )]. Administer cefuroxime axetil tablets with or without food. Pediatric patients (aged 13 years and older) who cannot swallow the cefuroxime axetil tablets whole should receive cefuroxime axetil for oral suspension because the tablet has a strong, persistent bitter taste when crushed [see Dosage and Administration ( 2.2 )]. 2.2 Dosage for Cefuroxime axetil Tablets Administer cefuroxime axetil tablets as described in the dosage guidelines table below with or without food. Table 1. Adult Patients and Pediatric Patients Dosage Guidelines for Cefuroxime Axetil Tablets Infection Dosage Duration (Days) Adults and Adolescents (13 years and older) Pharyngitis/tonsillitis (mild to moderate) 250 mg every 12 hours 10 Acute bacterial maxillary sinusitis (mild to moderate) 250 mg every 12 hours 10 Acute bacterial exacerbations of chronic bronchitis(mild to moderate ) 250 or 500 mg every 12 hours 10a Uncomplicated skin and skin-structure infections 250 or 500 mg every 12 hours 10 Uncomplicated urinary tract infections 250 mg every 12 hours 7 to 10 Uncomplicated gonorrhea 1,000 mg single dose Early Lyme disease 500 mg every 12 hours 20 Pediatric Patients younger than 13 years (who can swallow tablets whole) b Acute bacterial otitis media 250 mg every 12 hours 10 Acute bacterial maxillary sinusitis 250 mg every 12 hours 10 a The safety and effectiveness of cefuroxime axetil administered for less than 10 days in patients with acute exacerbations of chronic bronchitis have not been established. b When crushed, the tablet has a strong, persistent bitter taste. Therefore, patients who cannot swallow the tablet whole should receive the oral suspension. 2.5 Dosage in Patients with Impaired Renal Function A dosage interval adjustment is required for patients whose creatinine clearance is less than 30 mL/min, as listed in Table 4 below, because cefuroxime is eliminated primarily by the kidney [see Clinical Pharmacology ( 12.3 )]. Table 4. Dosing in Adults with Renal Impairment Creatinine Clearance (mL/min) Recommended Dosage ≥30 No dosage adjustment 10 to ˂30 Standard individual dose given every 24 hours ˂10 (without hemodialysis) Standard individual dose given every 48 hours Hemodialysis A single additional standard dose should be given at the end of each dialysis

6 ADVERSE REACTIONS The following serious and otherwise important adverse reaction is described in greater detail in the Warnings and Precautions section of the label: Anaphylactic Reactions [see Warnings and Precautions ( 5.1 )]. The most common adverse reactions (≥3%) for cefuroxime axetil tablets are diarrhea, nausea/vomiting, Jarisch-Herxheimer reaction, and vaginitis (early Lyme disease). ( 6.1 ) 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 a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tablets Multiple-Dose Dosing Regimens with 7 to 10 Days’ Duration : In multiple-dose clinical trials, 912 subjects were treated with cefuroxime axetil (125 to 500 mg twice daily). It is noted that 125 mg twice daily is not an approved dosage. Twenty (2.2%) subjects discontinued medication due to adverse reactions. Seventeen (85%) of the 20 subjects who discontinued therapy did so because of gastrointestinal disturbances, including diarrhea, nausea, vomiting, and abdominal pain. The percentage of subjects treated with cefuroxime axetil who discontinued study drug because of adverse reactions was similar at daily doses of 1,000, 500, and 250 mg (2.3%, 2.1%, and 2.2%, respectively). However, the incidence of gastrointestinal adverse reactions increased with the higher recommended doses. The adverse reactions in Table 5 are for subjects (n = 912) treated with cefuroxime axetil in multiple-dose clinical trials. Table 5. Adverse Reactions (≥1%) after Multiple-Dose Regimens with Cefuroxime Axetil Tablets Adverse Reaction Cefuroxime Axetil (n = 912) Blood and lymphatic system disorders Eosinophilia 1% Gastrointestinal disorders Diarrhea 4% Nausea/Vomiting 3% Investigations Transient elevation in AST 2% Transient elevation in ALT 2% Transient elevation in LDH 1% The following adverse reactions occurred in less than 1% but greater than 0.1% of subjects (n = 912) treated with cefuroxime axetil in multiple-dose clinical trials. Immune System Disorders: Hives, swollen tongue. Metabolism and Nutrition Disorders: Anorexia. Nervous System Disorders: Headache. Cardiac Disorders: Chest pain. Respiratory Disorders: Shortness of breath. Gastrointestinal Disorders: Abdominal pain, abdominal cramps, flatulence, indigestion, mouth ulcers. Skin and Subcutaneous Tissue Disorders: Rash, itch. Renal and Urinary Disorders: Dysuria. Reproductive System and Breast Disorders: Vaginitis, vulvar itch. General Disorders and Administration Site Conditions: Chills, sleepiness, thirst. Investigations: Positive Coombs’ test. Early Lyme Disease with 20-Day Regimen: Two multicenter trials assessed cefuroxime axetil tablets 500 mg twice daily for 20 days. The most common drug-related adverse experiences were diarrhea (10.6%), Jarisch-Herxheimer reaction (5.6%), and vaginitis (5.4%). Other adverse experiences occurred with frequencies comparable to those reported with 7 to 10 days’ dosing. Single-Dose Regimen for Uncomplicated Gonorrhea: In clinical trials using a single 1,000-mg dose of cefuroxime axetil, 1,061 subjects were treated for uncomplicated gonorrhea. The adverse reactions in Table 6 were for subjects treated with a single dose of 1,000 mg cefuroxime axetil in U.S. clinical trials. Table 6. Adverse Reactions (≥1%) after Single-Dose Regimen with 1,000-mg Cefuroxime Axetil Tablets for Uncomplicated Gonorrhea Adverse Reaction Cefuroxime axetil (n = 1,061) Gastrointestinal disorders Nausea/Vomiting 7% Diarrhea 4% The following adverse reactions occurred in less than 1% but greater than 0.1% of subjects (n = 1,061) treated with a single dose of cefuroxime axetil 1,000 mg for uncomplicated gonorrhea in U.S. clinical trials. Infections and Infestations: Vaginal candidiasis. Nervous System Disorders: Headache, dizziness, somnolence. Cardiac Disorders: Tightness/pain in chest, tachycardia. Gastrointestinal Disorders: Abdominal pain, dyspepsia. Skin and Subcutaneous Tissue Disorders: Erythema, rash, pruritus. Musculoskeletal and Connective Tissue Disorders: Muscle cramps, muscle stiffness, muscle spasm of neck, lockjaw-type reaction. Renal and Urinary Disorders: Bleeding/pain in urethra, kidney pain. Reproductive System and Breast Disorders: Vaginal itch, vaginal discharge. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of cefuroxime axetil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders Hemolytic anemia, leukopenia, pancytopenia, thrombocytopenia. Gastrointestinal Disorders Pseudomembranous colitis [see Warnings and Precautions (5.2)] . Hepatobiliary Disorders Hepatic impairment including hepatitis and cholestasis, jaundice. Immune System Disorders Anaphylaxis, serum sickness-like reaction, acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction. Investigations Increased prothrombin time. Nervous System Disorders Seizure, encephalopathy. Renal and Urinary Disorders Renal dysfunction. Skin and Subcutaneous Tissue Disorders Angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.

12.3 Pharmacokinetics Absorption After oral administration, cefuroxime axetil is absorbed from the gastrointestinal tract and rapidly hydrolyzed by nonspecific esterases in the intestinal mucosa and blood to cefuroxime. Serum pharmacokinetic parameters for cefuroxime following administration of cefuroxime axetil tablets to adults are shown in Table 8. Table 8. Pharmacokinetics of Cefuroxime Administered in the Postprandial State as Cefuroxime Axetil Tablets to Adults a Doseb (Cefuroxime Equivalent) Peak Plasma Concentration (mcg/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) AUC (mcg•h/mL) 125 mg 2.1 2.2 1.2 6.7 250 mg 4.1 2.5 1.2 12.9 500 mg 7 3 1.2 27.4 1,000 mg 13.6 2.5 1.3 50 a Mean values of 12 healthy adult volunteers. b Drug administered immediately after a meal. Effect of Food: Absorption of the tablet is greater when taken after food (absolute bioavailability increases from 37% to 52%). Despite this difference in absorption, the clinical and bacteriologic responses of subjects were independent of food intake at the time of tablet administration in 2 trials where this was assessed. All pharmacokinetic and clinical effectiveness and safety trials in pediatric subjects using the suspension formulation were conducted in the fed state. No data are available on the absorption kinetics of the suspension formulation when administered to fasted pediatric subjects. Lack of Bioequivalence : Oral suspension was not bioequivalent to tablets when tested in healthy adults. The tablet and oral suspension formulations are NOT substitutable on a milligram-per-milligram basis. The area under the curve for the suspension averaged 91% of that for the tablet, and the peak plasma concentration for the suspension averaged 71% of the peak plasma concentration of the tablets. Therefore, the safety and effectiveness of both the tablet and oral suspension formulations were established in separate clinical trials. Distribution Cefuroxime is distributed throughout the extracellular fluids. Approximately 50% of serum cefuroxime is bound to protein. Metabolism The axetil moiety is metabolized to acetaldehyde and acetic acid. Excretion Cefuroxime is excreted unchanged in the urine; in adults, approximately 50% of the administered dose is recovered in the urine within 12 hours. The pharmacokinetics of cefuroxime in pediatric subjects have not been studied. Until further data are available, the renal elimination of cefuroxime axetil established in adults should not be extrapolated to pediatric subjects. Specific Populations Patients with Renal Impairment: In a trial of 28 adults with normal renal function or severe renal impairment (creatinine clearance <30 mL/min), the elimination half-life was prolonged in relation to severity of renal impairment. Prolongation of the dosage interval is recommended in adult patients with creatinine clearance <30 mL/min [see Dosage and Administration ( 2.5 )]. Geriatric Patients : In a trial of 20 elderly subjects (mean age = 83.9 years) having a mean creatinine clearance of 34.9 mL/min, the mean serum elimination half-life was prolonged to 3.5 hours; however, despite the lower elimination of cefuroxime in geriatric patients, dosage adjustment based on age is not necessary [see Use in Specific Populations ( 8.5 )]. Drug Interaction Studies Concomitant administration of probenecid with cefuroxime axetil tablets increases the cefuroxime area under the serum concentration versus time curve and maximum serum concentration by 50% and 21%, respectively [see Drug Interactions( 7.2 )].