ZEDBAC Powder for solution for infusion Ref.[8683] Active ingredients: Azithromycin

Absorption

Bioavailability after oral administration is approximately 37%. Peak plasma concentrations are attained 2 to 3 hours after taking the medicinal product. The administration of azithromycin capsules after a substantial meal reduces bioavailability.

In patients hospitalized with community-acquired pneumonia treated with a single daily intravenous infusion of 500 mg azithromycin, over one hour, in a solution with a concentration of 2 mg/ml, for 2 to 5 days, the mean C_max ± D achieved was of 3.63 ± 1.60 µg/ml, while the trough levels concentration at 24 hours was 0.20 ± 0.15 µg/ml and the AUC₂₄ of 9.60 ± 4.80 µg.h/ml.

Mean C_max, trough levels concentration at 24 hours and AUC₂₄ values were of 1.14 ± 0.14 µg/ml, 0.18 ± 0.02 µg/ml and 8.03 ± 0.86 µg.h/ml, respectively, in normal volunteers receiving intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/ml, for 3 hours.

Distribution

Orally administered azithromycin is widely distributed throughout the body. In pharmacokinetic studies it has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times than those measured in plasma), which indicates that the agent strongly binds to tissues.

Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC90 for likely pathogen agents after a single dose of 500 mg. High azithromycin concentrations were detected in gynaecological tissue 96 hours after a single dose of 500 mg azithromycin.

In animal tests, high concentrations of azithromycin have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of azithromycin are released from inactive phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.

Biotransformation/Elimination

The terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2-4 days.

In a multiple-dose study in 12 normal volunteers using a 500 mg (1 mg/ml) one-hour intravenous dosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hours was about 11% after the 1^st dose and 14% after the 5^th dose. These values are higher than the reported 6% as being excreted unchanged in urine after oral administration of azithromycin. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also in bile, ten metabolites were detected, which were formed through N- and O- demethylation, hydroxylation of desosamine and aglycone rings and cleavage of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses carried has shown that the metabolites do not contribute to azithromycin microbiological activity.

Pharmacokinetics in special patient groups

Renal insufficiency

Following a single oral dose of azithromycin 1 g, mean C_max and AUC_0-120 increased by 5.1% and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR>80ml/min). In subjects with severe renal impairment, the mean C_max and AUC_0-120 increased 61% and 35% respectively compared to normal.

Hepatic insufficiency

In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.

Elderly

The pharmacokinetics of azithromycin in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred. In elderly volunteers (>65 years), higher (29%) AUC values were always observed after a 5-day course than in younger volunteers (<45 years). However, these differences are not considered to be clinically relevant; no dose adjustment is therefore recommended.

Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given multiple doses of azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of azithromycin treatment. The significance of the finding for animals and for humans is unknown.

Electrophysiological investigations have shown that azithromycin prolongs the QT interval.

Carcinogenic potential

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Mutagenic potential

There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.

Reproductive toxicity

In animal studies of the embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin dosages of 100 and 200 mg/kg/day led to mild retardation of foetal ossification and maternal weight gain. In peri- and post-natal studies in rats, mild retardation was observed following treatment with 50 mg/kg/day azithromycin and above.