Section 5.2
Absorption
Following oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract. Absorption of pizotifen in man is fast (absorption half life 0.5 to 0.8 hours) and nearly complete. The mean absolute bioavailablility after oral administration is about 78 780%. Maximum blood levels are reached 5 hours after Following a single 1mg2mg oral administration of pizotifen (parent compound and N-glucuronide-conjugate measured together) the mean maximum plasma concentration (Cmax) of pizotifen and its metabolite measured together were about 5 ng/mL (Tmax: 5.5 hr). Following repeated administration of 1mg three times a day for six days, the mean maximum plasma concentration at steady state was observed at 4 hr post dose (Cmax,ss: 14 ng/mL) and the mean trough plasma concentration was about 11 ng/mL (Cmin,ss).
Distribution
Pizotifen is extensively and rapidly distributed throughout the body with the mean Protein binding of pizotifen in human plasma in vitro amounts to 91%. The distribution volume in man is of 833 L and 70 L for pizotifen the parent drug and its metabolite N-glucuronide, respectively. Approximately, 91% of the drug is bound to plasma proteins. The distribution and elimination kinetics have generally been described as a bi-exponential decay function using two-compartment model.
BiotransformationMetabolism
Pizotifen is extensively metabolised in the liver primarily by Gglucuronidation. is the main route of biotransformation and The main metabolite is the N-glucuronide-conjugate and accountings for at least 50% of the plasma exposure. and 60-70% of urinary excreted radioactivity.
Elimination
About one-third of an orally applied dose is excreted via the biliary route. into the faeces, aA significant proportion of the parent drug, corresponding to about 18% of the appliedadministered dose, is found in the faeces. The remaining fraction of the administered dose (about 55%) is primarily eliminated in the forms of metabolites in the urine. , representing parent drug, likely produced in the intestine after biliary excretion of the N-glucuronide-conjugate. Less than 1% of the administered dose of pizotifen is excreted unchanged in the urine through the kidneys. whereas up to 55% is excreted as metabolites. Pizotifen and its major metabolite is eliminated with a half life of approximately 23 hours (total radioactivity). Unchanged pizotifen and the N-glucuronide conjugate is eliminated with a half-life of approximately 23 hours. have, as estimated from the excretion in the urine, a comparable elimination half-life.
Special patient groupspopulation
Renal impairment
No specific pharmacokinetic studies were conducted in patients with renal impairment. Although pizotifen is primarily eliminated in the form of metabolites in the urine, the possibility of accumulation of inactive metabolites subsequently leading to the accumulation of the parent drug can not be ruled out. Caution is required in patients with renal impairment and dosage adjustment may be necessary.
In patients with kidney insufficiency dosage adjustment may be necessary.
Hepatic impairment
Although no specific pharmacokinetic studies were conducted in patients with hepatic impairment, pizotifen is extensively metabolized in liver and primarily eliminated in the form of glucuronides in the urine. Caution is required in patients with hepatic impairment and dosage adjustment may be necessary.
Section 5.3
There are no pre-clinical data of relevance to the prescriber, which are additional to that already included in other sections of the SPC.
Repeat-dose toxicity
Repeat-dose toxicity studies were performed in rats and dogs of up to 2 years duration. Target organs, based on histopathological findings, were liver, kidney and possibly thyroid in rats and liver, thyroid and spleen in dogs. The no-observed-effect level (NOEL) in both rats and dogs was 3 mg/kg which is over 30-fold greater than the maximum recommended human daily dose(corresponding to 18 mg/m2 in rats and to 60 mg/m2 in dogs) which is, respectively, 5- and 18-times the maximum recommended human daily dose of 3.33 mg/m2 based on body surface area comparisons.
Reproductive toxicity
Pizotifen hydrogen malate was evaluated in multiple reproductive and developmental toxicity studies in mice, rats and rabbits. for its effects on fertility and its embryotoxic, fetotoxic, teratogenic and developmental toxic potential. There were no effects on fertility or teratologic effects noted at all doses up to specific reproductive or developmental effects observed in mice, rats or rabbits up to the highest tested doses of 30 mg/kg/day. This dose level is greater than 300 times the daily maximum recommended adult human dose of 0.09 mg/kg.At 10 and 30 mg/kg/day in mice there was a small decrease in fetal body weight in the presence of increased maternal mortality and in rats at the highest dose there was evidence of fetotoxicity.
Mutagenicity
In vitro and in vivo mutagenicity tests were performed and did not reveal any mutagenic activity of pizotifen hydrogen malate.
Carcinogenicity
A 2-year rat toxicity study did not reveal any gross lesions or masses attributable to pizotifen hydrogen malate administration at dose levels of up to 27 mg/kg which is 300 fold greater than the maximum recommended human daily dose on a mg/kg basis.
Mutagenicity and Carcinogenicity
Pizotifen hydrogen malate was not genotoxic in standard in vitro and in vivo tests. Conventional rodent carcinogenicity studies have not been conducted.
|
