Cefuroxime Axetil (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Although 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.

14 CLINICAL STUDIES

14.1 Acute Bacterial Maxillary Sinusitis

One adequate and well-controlled trial was performed in subjects with acute bacterial maxillary sinusitis. In this trial, each subject had a maxillary sinus aspirate collected by sinus puncture before treatment was initiated for presumptive acute bacterial sinusitis. All subjects had radiographic and clinical evidence of acute maxillary sinusitis. In the trial, the clinical effectiveness of cefuroxime axetil in treating acute maxillary sinusitis was comparable to an oral antimicrobial agent containing a specific β-lactamase inhibitor. However, microbiology data demonstrated cefuroxime axetil to be effective in treating acute bacterial maxillary sinusitis due only to Streptococcus pneumoniae or non-β-lactamase–producing Haemophilus influenzae. Insufficient numbers of β-lactamase–producing Haemophilus influenzae and Moraxella catarrhalis isolates were obtained in this trial to adequately evaluate the effectiveness of cefuroxime axetil in treating acute bacterial maxillary sinusitis due to these 2 organisms.

This trial randomized 317 adult subjects, 132 subjects in the U.S. and 185 subjects in South America. Table 12 shows the results of the intent-to-treat analysis.

Table 12. Clinical Effectiveness of Cefuroxime Axetil Tablets in the Treatment of Acute Bacterial Maxillary Sinusitis
a 95% confidence interval around the success difference [-0.08, +0.32]. b 95% confidence interval around the success difference [-0.1, +0.16]. c Control was an antibacterial drug containing a β-lactamase inhibitor.
U.S. Subjects a South American Subjects b
Cefuroxime Axetil 250 mg Twice Daily (n = 49) Control c (n = 43) Cefuroxime Axetil 250 mg Twice Daily (n = 49) Control c (n = 43)
Clinical success (cure + improvement) 65% 53% 77% 74%
Clinical cure 53% 44% 72% 64%
Clinical improvement 12% 9% 5% 10%

In this trial and in a supporting maxillary puncture trial, 15 evaluable subjects had non-β-lactamase–producing Haemophilus influenzae as the identified pathogen. Of these, 67% (10/15) had this pathogen eradicated. Eighteen (18) evaluable subjects had Streptococcus pneumoniae as the identified pathogen. Of these, 83% (15/18) had this pathogen eradicated.

14.2 Early Lyme Disease

Two adequate and well-controlled trials were performed in subjects with early Lyme disease. All subjects presented with physician-documented erythema migrans, with or without systemic manifestations of infection. Subjects were assessed at 1 month posttreatment for success in treating early Lyme disease (Part I) and at 1 year posttreatment for success in preventing the progression to the sequelae of late Lyme disease (Part II).

A total of 355 adult subjects (181 treated with cefuroxime axetil and 174 treated with doxycycline) were randomized in the 2 trials, with diagnosis of early Lyme disease confirmed in 79% (281/355). The clinical diagnosis of early Lyme disease in these subjects was validated by 1) blinded expert reading of photographs, when available, of the pretreatment erythema migrans skin lesion, and 2) serologic confirmation (using enzyme-linked immunosorbent assay [ELISA] and immunoblot assay [“Western” blot]) of the presence of antibodies specific to Borrelia burgdorferi , the etiologic agent of Lyme disease. The efficacy data in Table 14 are specific to this “validated” patient subset, while the safety data below reflect the entire patient population for the 2 trials. Clinical data for evaluable subjects in the “validated” patient subset are shown in Table 13.

Table 13. Clinical Effectiveness of Cefuroxime Axetil Tablets Compared with Doxycycline in the Treatment of Early Lyme Disease
a 95% confidence interval around the satisfactory difference for Part I (-0.08, +0.05). b 95% confidence interval around the satisfactory difference for Part II (-0.13, +0.07). c n’s include subjects assessed as unsatisfactory clinical outcomes (failure + recurrence) in Part I (cefuroxime axetil — 11 [5 failure, 6 recurrence]; doxycycline — 8 [6 failure, 2 recurrence]). d Satisfactory clinical outcome includes cure + improvement (Part I) and success + improvement (Part II).
Part I (1 Month after 20 Days of Treatment) a Part II (1 Year after 20 Days of Treatment) b
Cefuroxime Axetil 500 mg Twice Daily (n = 125) Doxycycline 100 mg 3 Times Daily (n = 108) Cefuroxime Axetil 500 mg Twice Daily (n = 105 c) Doxycycline 100 mg 3 Times Daily (n = 83 c)
Satisfactory clinical outcome d 91% 93% 84% 87%
Clinical cure/success 72% 73% 73% 73%
Clinical improvement 19% 19% 10% 13%

Cefuroxime axetil and doxycycline were effective in prevention of the development of sequelae of late Lyme disease.

While the incidence of drug-related gastrointestinal adverse reactions was similar in the 2 treatment groups (cefuroxime axetil — 13%; doxycycline — 11%), the incidence of drug-related diarrhea was higher in the cefuroxime axetil arm versus the doxycycline arm (11% versus 3%, respectively).

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