TOLERANCE AND SAFETY OF CEFMETAZOLE FOLLOWING INTRAMUSCULAR ADMINISTRATION TO HEALTHY MALE-VOLUNTEERS

The tolerance and safety of intramuscularly (IM) administered cefmetazole was examined in both a single-dose and a multiple-dose study. In the single-dose, escalating, randomized, double-blind, placebo-controlled study, cefmetazole sodium was given to 54 healthy male volunteers. Four different dose levels were studied sequentially: 375 mg, 750 mg, 1,000 mg, and 2,000 mg (the 2,000-mg dose was administered as two 1,000-mg injections). Local pain evaluations, assessment of adverse medical events (AMEs), measurement of vital signs, and analysis of blood and urine specimens were done at multiple times after drug dosing. All four dose levels caused dose-dependent local irritation that was well tolerated by most of the study volunteers. The only systemic AMEs reported in more than one volunteer were vasovagal reactions in three subjects (one in the 1,000-mg group and two in the 2,000-mg group on cefmetazole) and self-limited diarrhea in two subjects (1,000-mg group on cefmetazole). No clinically important changes in vital signs or laboratory parameters were noted. Cefmetazole was rapidly absorbed in most volunteers, with a mean (+/- SEM) time to maximum concentration in serum of 1.24 +/- 0.12 hour, and the mean maximum concentration in serum increased from 17.0 +/- 1.6-mu-g/ml to 74.2 +/- 9.5-mu-g/ml over the 0.375- to 2-gm dose range. Cefmetazole pharmacokinetics are linear after administration of a single intramuscular dose ranging from 0.375 to 2 gm. Clinically relevant concentrations of cefmetazole in serum (1 to 2-mu-g/ml) persist in a majority of volunteers for more than eight hours after administration of 0.750 gm or higher doses, and clinically relevant concentrations of cefmetazole continue to be excreted in urine eight to 12 hours after administration of 0.375- to 2-gm single doses. In the multiple-dose, randomized, double-blind, placebo-controlled study, 1- or 2-gm doses of cefmetazole or cefoxitin were administered twice a day for 7.5 consecutive days to 32 healthy male volunteers (16 on cefmetazole, eight on cefoxitin, and eight on placebo). All subjects completed the study and the medications were well tolerated at both dose levels. There were no clinically important changes in vital signs or laboratory assay results associated with IM cefmetazole administration. Higher proportions of subjects who received cefmetazole or cefoxitin experienced pain (subject's assessment), tenderness (investigator's assessment), and induration at one or both injection sites than did subjects who received placebo. There was less difference between treated and palcebo groups in the incidence of other local reactions at injection sites (erythema, swelling, ecchymosis, or bleeding). No petechia, necrosis, or atrophy was noted at injection sites of any subject in the study. Only two subjects reported AMEs (one event of loose stools each); both events were mild in intensity and resolved without intervention and despite continued treatment.