Moxifloxacin Hydrochloride (Page 7 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals to determine the carcinogenic potential of moxifloxacin have not been performed. Moxifloxacin was not mutagenic in 4 bacterial strains (TA 98, TA 100, TA 1535, TA 1537) used in the Ames Salmonella reversion assay. As with other fluoroquinolones, the positive response observed with moxifloxacin in strain TA 102 using the same assay may be due to the inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay. An equivocal result was obtained in the same assay when v79 cells were used.

Moxifloxacin was clastogenic in the v79 chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no evidence of genotoxicity in vivo in a micronucleus test or a dominant lethal test in mice.

Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as 500 mg/kg/day, approximately 12 times the maximum recommended human dose based on body surface area) or at intravenous doses as high as 45 mg/kg/day, approximately equal to the maximum recommended human dose based on body surface area). At 500 mg/kg orally there were slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats.

13.2 Animal Toxicology and/or Pharmacology

Fluoroquinolones have been shown to cause arthropathy in immature animals. In studies in juvenile dogs oral doses of moxifloxacin 30 mg/kg/day or more (approximately 1.5 times the maximum recommended human dose based upon systemic exposure) for 28 days resulted in arthropathy. There was no evidence of arthropathy in mature monkeys and rats at oral doses up to 135 and 500 mg/kg/day, respectively.

Moxifloxacin at an oral dose of 300 mg/kg did not show an increase in acute toxicity or potential for CNS toxicity (for example, seizures) in mice when used in combination with NSAIDs such as diclofenac, ibuprofen, or fenbufen. Some fluoroquinolones have been reported to have proconvulsant activity that is exacerbated with concomitant use of NSAIDs.

A QT-prolonging effect of moxifloxacin was found in dog studies, at plasma concentrations about five times the human therapeutic level. The combined infusion of sotalol, a Class III antiarrhythmic agent, with moxifloxacin induced a higher degree of QTc prolongation in dogs than that induced by the same dose (30 mg/kg) of moxifloxacin alone.

Electrophysiological in vitro studies suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (IKr) as an underlying mechanism.

No signs of local intolerability were observed in dogs when moxifloxacin was administered intravenously. After intra- arterial injection, inflammatory changes involving the peri-arterial soft tissue were observed suggesting that intra-arterial administration of moxifloxacin hydrochloride should be avoided.

14 CLINICAL STUDIES

14.1 Acute Bacterial Sinusitis

In a controlled double-blind study conducted in the US, moxifloxacin hydrochloride Tablets (400 mg once daily for ten days) were compared with cefuroxime axetil (250 mg twice daily for ten days) for the treatment of acute bacterial sinusitis. The trial included 457 patients valid for the efficacy analysis. Clinical success (cure plus improvement) at the 7 to 21 day post- therapy test of cure visit was 90% for moxifloxacin hydrochloride and 89% for cefuroxime.

An additional non-comparative study was conducted to gather bacteriological data and to evaluate microbiological eradication in adult patients treated with moxifloxacin hydrochloride 400 mg once daily for seven days. All patients (n = 336) underwent antral puncture in this study. Clinical success rates and eradication/presumed eradication rates at the 21 to 37 day follow- up visit were 97% (29 out of 30) for Streptococcus pneumoniae , 83% (15 out of 18) for Moraxella catarrhalis , and 80% (24 out of 30) for Haemophilus influenzae.

14.2 Acute Bacterial Exacerbation of Chronic Bronchitis

Moxifloxacin hydrochloride Tablets (400 mg once daily for five days) were evaluated for the treatment of acute bacterial exacerbation of chronic bronchitis in a randomized, double-blind, controlled clinical trial conducted in the US. This study compared moxifloxacin hydrochloride with clarithromycin (500 mg twice daily for 10 days) and enrolled 629 patients. Clinical success was assessed at 7-17 days post-therapy. The clinical success for moxifloxacin hydrochloride was 89% (222/250) compared to 89% (224/251) for clarithromycin.

Table 12: Clinical Success Rates at Follow-Up Visit for Clinically Evaluable Patients by Pathogen (Acute Bacterial Exacerbation of Chronic Bronchitis)

PATHOGEN	Moxifloxacin hydrochloride	Clarithromycin
Streptococcus pneumoniae	16/16 (100%)	20/23 (87%)
Haemophilus influenzae	33/37 (89%)	36/41 (88%)
Haemophilus parainfluenzae	16/16 (100%)	14/14 (100%)
Moraxella catarrhalis	29/34 (85%)	24/24 (100%)
Staphylococcus aureus	15/16 (94%)	6/8 (75%)
Klebsiella pneumoniae	18/20 (90%)	10/11 (91%)

The microbiological eradication rates (eradication plus presumed eradication) in moxifloxacin hydrochloride treated patients were Streptococcus pneumoniae 100%, Haemophilus influenzae 89%, Haemophilus parainfluenzae 100%, Moraxella catarrhalis 85%, Staphylococcus aureus 94%, and Klebsiella pneumoniae 85%.

14.3 Community Acquired Pneumonia

A randomized, double-blind, controlled clinical trial was conducted in the US to compare the efficacy of moxifloxacin hydrochloride Tablets (400 mg once daily) to that of high-dose clarithromycin (500 mg twice daily) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 474 patients (382 of whom were valid for the efficacy analysis conducted at the 14–35 day follow-up visit). Clinical success for clinically evaluable patients was 95% (184/194) for moxifloxacin hydrochloride and 95% (178/188) for high dose clarithromycin.

A randomized, double-blind, controlled trial was conducted in the US and Canada to compare the efficacy of sequential intravenous/oral moxifloxacin hydrochloride 400 mg once a day for 7–14 days to an intravenous/oral fluoroquinolone control (trovafloxacin or levofloxacin) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 516 patients, 362 of whom were valid for the efficacy analysis conducted at the 7-30 day post-therapy visit. The clinical success rate was 86% (157/182) for moxifloxacin hydrochloride therapy and 89% (161/180) for the fluoroquinolone comparators.

An open-label ex-US study that enrolled 628 patients compared moxifloxacin hydrochloride to sequential intravenous/oral amoxicillin/clavulanate (1.2 gram intravenously every 8 hours/625 mg orally every 8 hours) with or without high-dose intravenous/oral clarithromycin (500 mg twice a day). The intravenous formulations of the comparators are not FDA approved. The clinical success rate at Day 5–7 for moxifloxacin hydrochloride therapy was 93% (241/258) and demonstrated superiority to amoxicillin/clavulanate ± clarithromycin (85%, 239/280) [95% C.I. of difference in success rates between moxifloxacin and comparator (2.9%, 13.2%)]. The clinical success rate at the 21–28 days post-therapy visit for moxifloxacin hydrochloride was 84% (216/258), which also demonstrated superiority to the comparators (74%, 208/280) [95% C.I. of difference in success rates between moxifloxacin and comparator (2.6%, 16.3%)].

The clinical success rates by pathogen across four CAP studies are presented in Table 13.

Table 13: Clinical Success Rates By Pathogen (Pooled CAP Studies)

PATHOGEN	Moxifloxacin hydrochloride
Streptococcus pneumoniae	80/85	(94%)
Staphylococcus aureus	17/20	(85%)
Klebsiella pneumoniae	11/12	(92%)
Haemophilus influenzae	56/61	(92%)
Chlamydophila pneumoniae	119/128	(93%)
Mycoplasma pneumoniae	73/76	(96%)
Moraxella catarrhalis	11/12	(92%)

Community Acquired Pneumonia caused by Multi-Drug Resistant Streptococcus pneumoniae (MDRSP)*

Moxifloxacin hydrochloride was effective in the treatment of community acquired pneumonia (CAP) caused by multi-drug resistant Streptococcus pneumoniae MDRSP* isolates. Of 37 microbiologically evaluable patients with MDRSP isolates, 35 patients (95%) achieved clinical and bacteriological success post-therapy. The clinical and bacteriological success rates based on the number of patients treated are shown in Table 14.

* MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin resistant S. pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin (MIC ≥ 2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Table 14: Clinical and Bacteriological Success Rates for moxifloxacin hydrochloride-Treated MDRSP CAP Patients (Population: Valid for Efficacy)

Screening Susceptibility	Clinical Success		Bacteriological Success
	n/Na	%	n/Nb	%
Penicillin-resistant	21/21	100%c	21/21	100%c
2nd generation cephalosporin-resistant	25/26	96%c	25/26	96%c
Macrolide-resistantd	22/23	96%	22/23	96%
Trimethoprim/sulfamethoxazole-resistant	28/30	93%	28/30	93%
Tetracycline-resistant	17/18	94%	17/18	94%
a)n = number of patients successfully treated; N = number of patients with MDRSP (from a total of 37 patients)b)n = number of patients successfully treated (presumed eradication or eradication); N = number of patients with MDRSP (from a total of 37 patients)c)One patient had a respiratory isolate that was resistant to penicillin and cefuroxime but a blood isolate that was intermediate to penicillin and cefuroxime. The patient is included in the database based on the respiratory isolate.d)Azithromycin, clarithromycin, and erythromycin were the macrolide antimicrobials tested.

Not all isolates were resistant to all antimicrobial classes tested. Success and eradication rates are summarized in Table 15.

Table 15: Clinical Success Rates and Microbiological Eradication Rates for Resistant Streptococcus pneumoniae (Community Acquired Pneumonia)

S . pneumoniae with MDRSP	Clinical Success	Bacteriological Eradication Rate
Resistant to 2 antimicrobials	12/13 (92.3 %)	12/13 (92.3 %)
Resistant to 3 antimicrobials	10/11 (90.9 %)a	10/11 (90.9 %)a
Resistant to 4 antimicrobials	6/6 (100%)	6/6 (100%)
Resistant to 5 antimicrobials	7/7 (100%)a	7/7 (100%)a
Bacteremia with MDRSP	9/9 (100%)	9/9 (100%)
a)One patient had a respiratory isolate resistant to 5 antimicrobials and a blood isolate resistant to 3 antimicrobials. The patient was included in the category resistant to 5 antimicrobials.