FOMICYT Powder for solution for infusion Ref.[6865] Active ingredients: Fosfomycin

Pharmacokinetics

A single intravenous infusion of 4 g and 8 g of fosfomycin in young healthy males resulted in maximum serum concentrations (C_max) of approx. 200 and 400 μg/ml, respectively. The serum half-life was approx. 2 hours. In elderly and/or critically ill male and female subjects, single intravenous doses of 8 g of fosfomycin resulted in mean C_max and half-lives in plasma of approximately 350–380 µg/ml and 3.6–3.8 h, respectively.

Distribution

The apparent volume of distribution of fosfomycin is approx. 0.30 l/kg body weight. Fosfomycin is distributed well to tissues. High concentrations are reached in eyes, bones, wound secretions, musculature, cutis, subcutis, lungs and bile. In patients with inflamed meninges, cerebrospinal fluid concentrations reach approx. 20–50% of the corresponding serum levels. Fosfomycin passes the placental barrier. Low quantities were found in human milk (about 8% of the serum concentrations). The plasma protein binding is negligible.

Metabolism

Fosfomycin is not metabolised by the liver and does not undergo enterohepatic circulation. No accumulation is therefore to be expected in patients with hepatic impairment.

Elimination

80–90% of the quantity of fosfomycin administered to healthy adults is eliminated renally within 10 hours after a single intravenous administration. Fosfomycin is not metabolised, i.e. the biologically active compound is eliminated. In patients with normal or mildly to moderately impaired renal function (creatinine clearance ≥40 ml/min), approximately 50–60% of the overall dose is excreted within the first 3-4 hours.

Linearity

Fosfomycin shows linear pharmacokinetic behaviour after intravenous infusion of therapeutically used doses.

Special populations

Very limited data are available in special populations.

Elderly

No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should be reduced if there is evidence of renal impairment (see section 4.2).

Paediatric population

The pharmacokinetics of fosfomycin in children and adolescents aged 3–15 years as well as in term newborns with normal renal function are generally similar to those of healthy adult subjects. However, in renally healthy neonates and infants up to 12 months, the glomerular filtration rate is physiologically decreased compared to older children and adults. This is associated with a prolongation of the elimination half-life of fosfomycin in dependence on the stage of renal maturation.

Renal insufficiency

In patients with impaired renal function, the elimination half-life is increased proportionally to the degree of renal insufficiency. Patients with creatinine clearance values of 40 ml/min or less require dose adjustments (see also section 4.2. “Dosage in renal insufficiency” for further details).

In a study investigating 12 patients under CVVHF customary polyethylene sulfone haemofilters with a membrane surface of 1.2 m² and a mean ultrafiltration rate of 25 ml/min were employed. In this clinical setting, the mean values of plasma clearance and elimination half-life in plasma were 100 ml/min, and 12 h, respectively.

Hepatic insufficiency

There is no requirement for dosage adjustments in patients with hepatic insufficiency since the pharmacokinetics of fosfomycin remains unaffected in this patient group.

Subacute and chronic toxicity

The toxicity of fosfomycin following repeated administration for up to 6 months was evaluated in rats, dogs, rabbits and monkeys. At high intra-peritoneal doses of fosfomycin (>500 mg/kg/day), rats developed respiratory arrest, tetanic cramps, anaemia, a reduction of blood protein levels, increased serum cholesterol and reduced blood glucose. Furthermore, dogs and monkeys experienced diarrhoea due to antibiotic-related changes in the intestinal flora following intravenous administration of doses of higher than 250 mg/kg/day and 500 mg/kg/day, respectively. In the rabbit, no toxicity was observed following intravenous administration of 400 mg/kg/day for a period of 1 month.

Reproductive toxicity

Fertility

In male and female rats, following repeated administration (via a pharyngeal tube) of up to 1400 mg/kg/day reduced fertility was observed at the maximum dose tested.

Teratogenicity

Fosfomycin was administered to mice, rats and rabbits via pharyngeal tube at maximum doses of 2 × 120 mg/kg/day, 1400 mg/kg/day and 420 mg/kg/day, respectively or intravenously to mice and rabbits at 55.3 mg/kg/day, and up to 250 mg/kg/day, respectively. There was no evidence of embryotoxicity or teratogenicity.

Perinatal and postnatal toxicity

In rats, a maximum dose of 2800 mg/kg/day was administered via a pharyngeal tube. There was no evidence of foetal or peri- and postnatal toxicity.

Mutagenicity

In-vitro tests were performed to test the alkylating capacity and the mutagenic effect of fosfomycin. Fosfomycin showed no alkylating effect. In the Ames test, no mutagenic effect was seen in test strains of Salmonella typhimurium (TA 98, TA 100, TA 1535, TA 1537 and TA 1538, with and without addition of rat-liver homogenate) after exposure to fosfomycin at up to 1600 µg/ml.