CINNARON Hard capsule Ref.[28182] Active ingredients: Cinnarizine

Absorption

Maximum absorption levels of cinnarizine reached 1 to 3 hours after intake.

Distribution

The binding of cinnarizine to plasma proteins is 91%.

Biotransformation

Cinnarizine is extensively metabolised mainly via the CYP2D6.

The reported excretion half-life of cinnarizine ranges from 4 to 24 hours. Metabolites are excreted approximately ⅓ in the urine and ⅔ in the faeces.

The LD₅₀ values of single dose in various animal models showed a wide range of security on a mg/kg base compared to the maximum recommended human dose (MRHD) of 225 mg/day or 4.5 mg/kg based on a 50 kg person. LD₅₀ values in mice were 1000 mg/kg after oral, subcutaneous and intraperitoneal advances. Similarly, the LD₅₀ values in rats and dogs was 640 mg/kg and 160 mg/kg, respectively for the three routes of administration. The levels of LD₅₀ after intravenous administration in mice and rats were 22 mg/kg and 2 mg/kg, respectively. The LD₅₀ in rats was 40 mg/kg after oral and subcutaneous administrations. The effects of acute oral, subcutaneous and intraperitoneal toxicity in mice and rats with dihydrochloride salt were similar to the parent compound.

Toxicity studies form repeated oral doses (administered with food) in rats showed some reduction in food consumption and changes in serum chemistry (inorganic phosphorus reduction, increase of calcium/phosphorus levels), body weight (decrease in spleen and heart, increase in liver, kidneys, and in brain) and histopathology (chronic degeneration associated with the central part of the pod and changes of pancreas). These observations were generally in the high dose group (320 mg/kg or approximately 72 x MRHD) and were more intense after 10 months of treatment. After 3 or 12 months of oral dosing in dogs, all observations were similar to controls except some weight reduction (after 3 months at 80 mg/kg or approximately 18 x MRHD) or some limited histopathological findings (focal nuclear vacuolation and glial cell aggregation around neurons in the CNS hydropic aspect of the liver, pancreatic lymphoid modifications, inhibition of spermatogenesis and atrophy of genital tract of female), after 12 months at the high dose of 20 mg/kg (~5 x MRHD).

In reproduction studies in rats, rabbits, and dogs, there were no effects on fertility and no teratogenicity was presented. At very high doses (80 to 320 mg/kg, approximately 18 72 x MRHD) in rats, maternal toxicity has resulted in reduced size in newborn rats, an increase in the absorption rate and a reduction in the weight of the embryo at birth.

The in-vitro mutagenicity study in Salmonella typhimurium indicated that the parent compound is not mutagenic up to 10 μmol/petri dish. However, after reacting with nitrates and forming the nitrate product, a weak mutagenic effect was observed. Carcinogenicity has not been specifically assessed. However, pre-neoplastic changes were not evident during oral administration of 18 months in rats up to a dose of 72 times the maximum human dose level.