Question 18

There is a lot of data available demonstrating the tolerability and safety of the levofloxacin 500 mg schedule. Could you comment on the safety of the 750 mg dose in preclinical and clinical trials?

The safety of high-dose levofloxacin was demonstrated in early Phase II trials in healthy volunteers administered 500, 1,000 and 1,500 mg levofloxacin doses (48, 49). The incidence of adverse events was similar for all three doses. Therefore, it has been known since the early 1990s that a higher dose of levofloxacin would be well tolerated. Further detailed analysis of this has revealed that the safety profile of levofloxacin 750 mg, administered orally once daily for 5 days, was comparable with levofloxacin 500 mg once daily for 10 days (50). There were no notable differences in drug-related adverse events between the two treatment groups. Overall, 10.3% of subjects in the 750 mg group and 9.7% of subjects in the 500 mg group reported at least 1 drug-related adverse event. The most commonly reported drug-related events in the 750 mg group were nausea (3.3%) and diarrhea (1.8%) (Table 7). The types and rates of drug-related adverse events observed with both levofloxacin regimens were consistent with the known safety profile of levofloxacin.

Table 7. Levofloxacin 750 mg q.d. for 5 days provides comparable safety

Drug-related adverse events	No. (%) of patients
	750 mg q.d. for 5 days (n = 389)	500 mg q.d. for 10 days (n = 391)
Nausea	13 (3.3)	11 (2.8)
Diarrhea	7 (1.8)	9 (2.3)
Vomiting	4 (1.0)	3 (0.8)
Dizziness	4 (1.0)	2 (0.5)
Dry mouth	6 (1.5)	2 (0.5)
Dyspepsia	5 (1.3)	2 (0.5)
Abdominal pain	1 (0.3)	3 (0.8)
Genital moniliasis	3 (0.8)	6 (1.5)

Abbreviation: q.d. = once daily.
Adapted from reference (64).