Overdosage of cephalosporins can cause cerebral irritation leading to convulsions or encephalopathy. Serum levels of cefuroxime can be reduced by hemodialysis and peritoneal dialysis.
CEFTIN is contraindicated in patients with a known hypersensitivity (e.g., anaphylaxis) to CEFTIN or to other β-lactam antibacterial drugs (e.g., penicillins and cephalosporins).
The following serious and otherwise important adverse reaction is described in greater detail in the Warnings and Precautions section of the label:
Anaphylactic Reactions
Clinical Trials ExperienceBecause 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’ DurationIn multiple-dose clinical trials, 912 subjects were treated with CEFTIN (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 CEFTIN 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 CEFTIN in multiple-dose clinical trials.
Table 5: Adverse Reactions (≥1%) after
Multiple-Dose Regimens with CEFTIN Tablets
| Adverse Reaction | CEFTIN (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 CEFTIN 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 RegimenTwo multicenter trials assessed CEFTIN 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 GonorrheaIn clinical trials using a single 1,000-mg dose of CEFTIN, 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 CEFTIN in U.S. clinical trials.
Table 6: Adverse Reactions (≥1%) after Single-Dose
Regimen with 1,000-mg CEFTIN Tablets
for Uncomplicated Gonorrhea
| Adverse Reaction | CEFTIN (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 CEFTIN 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.
Oral SuspensionIn clinical trials using multiple doses of CEFTIN, pediatric subjects (96.7% were younger than 12 years) were treated with CEFTIN (20 to 30 mg/kg/day divided twice daily up to a maximum dose of 500 or 1,000 mg/day, respectively). Eleven (1.2%) U.S. subjects discontinued medication due to adverse reactions. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea or vomiting. Thirteen (1.4%) U.S. pediatric subjects discontinued therapy due to the taste and/or problems with drug administration.
The adverse reactions in Table 7 are for U.S. subjects (n = 931) treated with CEFTIN in multiple-dose clinical trials.
Table 7: Adverse Reactions (>1%) after
Multiple-Dose Regimens with CEFTIN for Oral Suspension
| Adverse Reaction | CEFTIN (n = 931) |
| Gastrointestinal disorders | |
| Diarrhea | 9% |
| Dislike of taste | 5% |
| Nausea/vomiting | 3% |
| Skin and subcutaneous tissue disorders | |
| Diaper rash | 3% |
The following adverse reactions occurred in less than 1% but greater than 0.1% of U.S. subjects (n = 931) treated with CEFTIN for oral suspension in multiple-dose clinical trials.
Infections and Infestations: Gastrointestinal infection, candidiasis, viral illness, upper respiratory infection, sinusitis, urinary tract infection.
Blood and Lymphatic System Disorders: Eosinophilia.
Psychiatric Disorders: Hyperactivity, irritable behavior.
Gastrointestinal Disorders: Abdominal pain, flatulence, ptyalism.
Skin and Subcutaneous Tissue Disorders: Rash.
Musculoskeletal and Connective Tissue Disorders: Joint swelling, arthralgia.
Reproductive System and Breast Disorders: Vaginal irritation.
General Disorders and Administration Site Conditions: Cough, fever.
Investigations: Elevated liver enzymes, positive Coombs' test.
Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of CEFTIN. 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 DisordersHemolytic anemia, leukopenia, pancytopenia, thrombocytopenia.
Gastrointestinal DisordersPseudomembranous colitis.
Hepatobiliary DisordersHepatic impairment including hepatitis and cholestasis, jaundice.
Immune System DisordersAnaphylaxis, serum sickness-like reaction.
Investigations
Increased prothrombin time.
Nervous System DisordersSeizure, encephalopathy.
Renal and Urinary DisordersRenal dysfunction.
Skin and Subcutaneous Tissue DisordersAngioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria.
CEFTIN 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.
CEFTIN for oral suspension is indicated for the treatment of pediatric patients aged 3 months to 12 years with mild-to-moderate pharyngitis/tonsillitis caused by susceptible strains of Streptococcus pyogenes.
Limitations Of UseCEFTIN 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.
CEFTIN for oral suspension is indicated for the treatment of pediatric patients aged 3 months to 12 years 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.
Acute Bacterial Maxillary SinusitisCEFTIN 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).
CEFTIN for oral suspension is indicated for the treatment of pediatric patients aged 3 months to 12 years 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 UseThe effectiveness of CEFTIN 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.
Acute Bacterial Exacerbations Of Chronic BronchitisCEFTIN 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 para influenzae (β-lactamase-negative strains).
Uncomplicated Skin And Skin-Structure InfectionsCEFTIN 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.
Uncomplicated Urinary Tract InfectionsCEFTIN 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.
Uncomplicated GonorrheaCEFTIN 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.
Early Lyme Disease (erythema migrans)CEFTIN 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.
ImpetigoCEFTIN for oral suspension is indicated for the treatment of pediatric patients aged 3 months to 12 years with impetigo caused by susceptible strains of Staphylococcus aureus (including Plactamase- producing strains) or Streptococcus pyogenes.
UsageTo reduce the development of drug-resistant bacteria and maintain the effectiveness of CEFTIN and other antibacterial drugs, CEFTIN 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.
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 CEFTIN tablets to adults are shown in Table 8.
Table 8: Pharmacokinetics of Cefuroxime Administered
in the Postprandial State as CEFTIN Tablets to Adultsa
| 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 | 7.0 | 3.0 | 1.2 | 27.4 |
| 1,000 mg | 13.6 | 2.5 | 1.3 | 50.0 |
| a Mean values of 12 healthy adult volunteers. b Drug administered immediately after a meal. |
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 BioequivalenceOral suspension was not bioequivalent to tablets when tested in healthy adults. The tablet and oral suspension formulations are NOT substitutable on a milligram-permilligram 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.
DistributionCefuroxime is distributed throughout the extracellular fluids. Approximately 50% of serum cefuroxime is bound to protein.
MetabolismThe axetil moiety is metabolized to acetaldehyde and acetic acid.
ExcretionCefuroxime 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.
Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, CEFTIN should be used during pregnancy only if clearly needed.
Reproduction studies have been performed in mice at doses up to 3,200 mg/kg/day (14 times the recommended maximum human dose based on body surface area) and in rats at doses up to 1,000 mg/kg/day (9 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to cefuroxime axetil.
Included as part of the PRECAUTIONS section.
PRECAUTIONS Anaphylactic ReactionsSerious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on β-lactam antibacterials. These reactions are more likely to occur in individuals with a history of β-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. CEFTIN is contraindicated in patients with a known hypersensitivity to CEFTIN or other β-lactam antibacterial drugs. Before initiating therapy with CEFTIN, inquire about previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, discontinue CEFTIN and institute appropriate therapy.
Clostridium Difficile-Associated DiarrheaClostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CEFTIN, 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 A and B which contribute to the development of CDAD. Hypertoxinproducing strains 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 antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Potential For Microbial OvergrowthThe possibility of superinfections with fungal or bacterial pathogens should be considered during therapy.
Development Of Drug-Resistant BacteriaPrescribing CEFTIN either in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
PhenylketonuriaCEFTIN for oral suspension 125 mg/5 mL contains phenylalanine 11.8 mg per 5 mL (1 teaspoonful) of reconstituted suspension. CEFTIN for oral suspension 250 mg/5 mL contains phenylalanine 25.2 mg per 5 mL (1 teaspoonful) of reconstituted suspension.
Interference With Glucose TestsA false-positive result for glucose in the urine may occur with copper reduction tests, and a false-negative result for blood/plasma glucose may occur with ferricyanide tests in subjects receiving CEFTIN.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityAlthough lifetime studies in animals have not been performed to evaluate carcinogenic potential, no mutagenic activity was found for cefuroxime axetil in a battery of bacterial mutation tests. Positive results were obtained in an in vitro chromosome aberration assay; however, negative results were found in an in vivo micronucleus test at doses up to 1.5 g/kg. Reproduction studies in rats at doses up to 1,000 mg/kg/day (9 times the recommended maximum human dose based on body surface area) have revealed no impairment of fertility.
Use In Specific Populations PregnancyPregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, CEFTIN should be used during pregnancy only if clearly needed.
Reproduction studies have been performed in mice at doses up to 3,200 mg/kg/day (14 times the recommended maximum human dose based on body surface area) and in rats at doses up to 1,000 mg/kg/day (9 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to cefuroxime axetil.
Nursing MothersBecause cefuroxime is excreted in human milk, caution should be exercised when CEFTIN is administered to a nursing woman.
Pediatric UseThe safety and effectiveness of CEFTIN have been established for pediatric patients aged 3 months to 12 years for acute bacterial maxillary sinusitis based upon its approval in adults. Use of CEFTIN in pediatric patients is supported by pharmacokinetic and safety data in adults and pediatric patients, and by clinical and microbiological data from adequate and well-controlled trials of the treatment of acute bacterial maxillary sinusitis in adults and of acute otitis media with effusion in pediatric patients. It is also supported by postmarketing adverse events surveillance.
Geriatric UseOf the total number of subjects who received CEFTIN in 20 clinical trials, 375 were aged 65 and older while 151 were aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects. Reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.
Cefuroxime is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Renal ImpairmentReducing the dosage of CEFTIN is recommended for adult patients with severe renal impairment (creatinine clearance <30 mL/min).
Administer CEFTIN tablets as described in the dosage guidelines table below with or without food.
Table 1: Adult Patients and Pediatric Patients Dosage
Guidelines for CEFTIN 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 CEFTIN
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. |
||
Administer CEFTIN for oral suspension as described in the dosage guidelines table below with food.
Table 2: Pediatric Patients (3 Months to 12 Years)
Dosage Guidelines for CEFTIN for Oral Suspension
| Infection | Recommended Daily Dosea | Maximum Daily Dose | Duration (Days) |
| Pharyngitis/tonsillitis | 20 mg/kg | 500 mg | 10 |
| Acute bacterial otitis media | 30 mg/kg | 1,000 mg | 10 |
| Acute bacterial maxillary sinusitis | 30 mg/kg | 1,000 mg | 10 |
| Impetigo | 30 mg/kg | 1,000 mg | 10 |
| a Recommended daily dose given twice daily divided in equal doses. |
Prepare a suspension at the time of dispensing as follows:
Table 3: Amount of Water Required for Reconstitution
of Labeled Volumes of CEFTIN for Oral Suspension
| Oral Suspension | Amount of Water Required for Reconstitution | Labeled Volume after Reconstitution |
| 125 mg/5 mL | 37 mL | 100 mL |
| 250 mg/5 mL | 19 mL | 50 mL |
| 35 mL | 100 mL |
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.
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 |
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.
