METRONIDAZOLE Solution for infusion Ref.[6987] Active ingredients: Methronidazole

Distribution

After administration of a single 500 mg dose, mean Metronidazole peak plasma concentrations of ca. 14–18 μg/ml are reached at the end of a 20 minute infusion. 2-hydroxy-metabolite peak plasma concentrations of ca. 3 μg/ml are obtained after a 1 g single i.v. dose. Steady state Metronidazole plasma concentrations of about 17 and 13 μg/ml are reached after administration of Metronidazole every 8 or 12 hours, respectively.

Plasma protein binding is less than 10%, and the volume of distribution 1.1 ± 0.4 l/kg.

Metabolism

Metronidazole is metabolised in the liver by hydroxylation, oxidation and glucuronidation. The major metabolites are a 2-hydroxy- and an acetic acid metabolite.

Elimination

More than 50% of the administered dose is excreted in the urine, as unchanged Metronidazole (ca. 20% of the dose) and its metabolites. About 20% of the dose is excreted with faeces. Clearance is 1.3 ± 0.3 ml/min/kg, while renal clearance is about 0.15 ml/min/kg. The plasma elimination half-life of Metronidazole is ca. 8 hours, and of the 2-hydroxy-metabolite ca. 10 hours.

Special patient groups

The plasma elimination half-life of Metronidazole is not influenced by renal impairment, however this may be increased for 2-hydroxy- and an acetic acid metabolite. In the case of haemodialysis, Metronidazole is rapidly excreted and the plasma elimination half-life is decreased to ca. 2.5 h. Peritoneal dialysis does not appear to affect the elimination of Metronidazole or its metabolites compared to patients with renal impairment.

In patients with impaired liver function, the metabolism of Metronidazole is expected to decrease, leading to an increase in the plasma elimination half-life. In patients with severe liver impairment, clearance may be decreased up to ca. 65%, resulting in an accumulation of Metronidazole in the body.

Metronidazole has been shown to be non-mutagenic in mammalian cells in vitro and in vivo.

Metronidazole and a metabolite have been shown to be mutagenic is some tests with non mammalian cells.

Although Metronidazole has been shown to be carcinogenic in certain species of mice, it was not carcinogenic in either rats or guinea pigs. There is no suspicion of carcinogenicity in man.

Daily peroral metronidazole at 5-times the maximum human daily dose for greater than 4 weeks caused testicular toxicity and infertility in male rats. Fertility was restored in most subjects by 8 weeks after cessation of treatment, whereas the lower testicular and epididymal weights and sperm counts had improved but were still observed.

Daily peroral metronidazole at approximately 6-times the maximum human daily dose for ≥2 weeks caused testicular toxicity in male mice. Most indices of testicular toxicity were restored within 2 months after cessation of treatment, whereas the lower testicular and epididymal weights had improved but were still observed.

These studies demonstrate that the adverse effects of metronidazole on the male reproductive system are wholly or partially reversible after treatment withdrawal (see section 4.6).