ROZEX Cream Ref.[27696] Active ingredients: Methronidazole

Absorption

Metronidazole is rapidly and nearly totally absorbed after oral administration. The drug is not significantly bound to serum proteins and distributes well to all body compartments with the lowest concentration found in the fat.

Distribution

Bioavailability studies with a topical 1g application of Rozex Cream to the face of normal subjects resulted in mean maximum serum concentrations of 32.9ng/ml (range 14.8 to 54.4ng/ml) which is approximately 100 times less than those attained after a single oral dose of 250 mg (mean C_max = 7248ng/ml; range 4270–13970 ng/ml). The peak concentration occurred between 0.25–4 hours after oral dosing, and 6 to 24 hours after cutaneous application of Rozex Cream.

Following topical application of Rozex Cream, serum concentrations of the major metabolite (the hydroxymetabolite 2-hydroxymethylmetronidazole) were below the quantifiable limit of the assay (<9.6ng/ml) at most of the time points, ranging to a maximum of 17.5ng/ml peak concentration between 8 and 24 hours after application. In comparison, the peak concentration following a 250mg oral dose ranged from 626 to 1788ng/ml between 4 and 12 hours after dosing.

The extent of exposure (Area under the curve, AUC) from a 1g application of metronidazole administered topically was 1.36% of the AUC of a single oral 250mg metronidazole dose (mean + 912.7ng.hr/ml and approximately 67207ng.ml/hr respectively).

Elimination

Metronidazole is excreted primarily in the urine as parent drug, oxidative metabolites and conjugates.

No evidence for a primary dermal irritation was observed in rabbits following a single 24-hour cutaneous application of Rozex Cream to abraded and non-abraded skin, under occlusion.

Metronidazole has shown mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-response increase in the frequency of micronuclei was observed in mice after intraperitoneal injection and an increase in chromosome aberrations have been reported in patients with Crohn’s disease who were treated with 200 to 1200mg/day of oral metronidazole for 1 to 24 months. However, the preponderance of evidence from these studies suggests that although metronidazole has a potential for producing mutations, this should not occur in well oxygenated mammalian cells, i.e., under normal aerobic conditions.

The carcinogenicity of metronidazole by the oral route of administration has been evaluated in rats, mice and hamsters. These studies showed that oral metronidazole caused an increased incidence of pulmonary tumours in mice and possibly other tumours, including liver tumours, in the rat. Conversely, two lifetime studies in hamsters produced negative results. Moreover, one study showed a significant enhancement of UV-induced skin tumours in hairless mice treated with metronidazole intraperitoneally (15μg per g body weight and per day for 28 weeks).

Although the significance of these results to the cutaneous use of metronidazole for the treatment of rosacea is unclear, patients should be advised to avoid or minimise exposure of metronidazole cream-treated sites to sun. After several decades of systemic use, no evidence has been published to suggest that metronidazole is associated with carcinogenic potential in humans.