Not applicable.
In 4-week-studies in animals, toxicity of Klaricid UDromycin was found to be related to the dose and to the duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which lesions were seen within 14 days in dogs and monkeys. The systemic levels of exposure, related to this toxicity, are not known in detail, but toxic doses were clearly higher than the therapeutic doses recommended for humans. Other tissues affected included the stomach, thymus and other lymphoid tissues as well as the kidneys. At near therapeutic doses conjunctival injection and lacrimation occurred only in dogs. At a dose of 400 mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema.
No mutagenic effects were found in in vitro- and in vivo -studies with Klaricid UDromycin
Studies on reproduction toxicity showed that administration of Klaricid UDromycin at doses 2x the clinical dose in rabbit (i.v.) and x10 the clinical dose in monkey (p.o.) resulted in an increased incidence of spontaneous abortions. These doses were related to maternal toxicity. No embryotoxicity or teratogenicity was noted in rat studies. Cardiovascular malformations were observed in rats treated with doses of 150 mg/kg/d. In mouse at doses x70 the clinical dose cleft palate occurred at varying incidence (3-30%).
Klaricid UDromycin has been found in the milk of lactating animals.
In 3-day old mice and rats, the LD50 values were approximately half those in adult animals. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported in some studies. Slight reductions in erythrocytes, platelets and leukocytes have also been found in juvenile animals.
Klaricid UDromycin has not been tested for carcinogenicity.
Absorption:
Klaricid UDromycin is rapidly and well absorbed from the gastrointestinal tract - primarily in the jejunum - but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of a 250-mg Klaricid UDromycin tablet is approximately 50%. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, Klaricid UDromycin tablets may be given without regard to food. Due to its chemical structure (6-O-Methylerythromycin) Klaricid UDromycin is quite resistant to degradation by stomach acid. Peak plasma levels of 1 - 2 μg/ml Klaricid UDromycin were observed in adults after oral administration of 250 mg twice daily. After administration of 500 mg Klaricid UDromycin twice daily the peak plasma level was 2.8 μg/ml. After administration of 250 mg Klaricid UDromycin twice daily the microbiologically active 14-hydroxy metabolite attains peak plasma concentrations of 0.6 μg/ml. Steady state is attained within 2 days of dosing.
Distribution:
Klaricid UDromycin penetrates well into different compartments with an estimated volume of distribution of 200-400 l. Klaricid UDromycin provides concentrations in some tissues that are several times higher than the circulating drug levels. Increased levels have been found in both tonsils and lung tissue. Klaricid UDromycin also penetrates the gastric mucus.
Klaricid UDromycin is approximately 70% bound to plasma proteins at therapeutic levels.
Biotransformation and elimination:
Klaricid UDromycin is rapidly and extensively metabolised in the liver. Metabolism is in the liver involving the P450 cytochrome system. Three metabolites are described: N-demethyl Klaricid UDromycin, decladinosyl Klaricid UDromycin and 14-hydroxy Klaricid UDromycin. The pharmacokinetics of Klaricid UDromycin is non-linear due to saturation of hepatic metabolism at high doses. Elimination half-life increased from 2-4 hours following administration of 250 mg Klaricid UDromycin twice daily to 5 hours following administration of 500 mg Klaricid UDromycin twice daily. The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration of 250 mg Klaricid UDromycin twice daily.
Approximately 20 -40% of Klaricid UDromycin is excreted as the unchanged active substance in the urine. This proportion is increased when the dose is increased. An additional 10% to 15% is excreted in the urine as 14-hydroxy metabolite. The rest is excreted in the faeces.Renal insufficiency increases Klaricid UDromycin levels in plasma, if the dose is not decreased. Total plasma clearance has been estimated to approximately 700 mL/min (11,7 mL/s), with a renal clearance of approximately 170 mL/min (2,8 mL/s).
Special populations:
Renal impairment: Reduced renal insufficiency function results in increased plasma levels of Klaricid UDromycin and the active metabolite levels in plasma.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
