PIZOTIFEN Film-coated tablet Ref.[9288] Active ingredients:

Absorption

Following oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract. The mean absolute bioavailablility after oral administration is about 78%. Following a single 1mg oral administration of pizotifen the mean maximum plasma concentration (C_max) of pizotifen and its metabolite measured together were about 5 ng/mL (T_max: 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 (C_max,ss: 14 ng/mL) and the mean trough plasma concentration was about 11 ng/mL (C_min,ss).

Distribution

Pizotifen is extensively and rapidly distributed throughout the body with the mean distribution volume of 833 L and 70 L for 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 twocompartment model.

Metabolism

Pizotifen is extensively metabolised in the liver primarily by glucuronidation. The main metabolite is the N-glucuronide-conjugate and accounts for at least 50% of the plasma exposure.

Elimination

About one-third of an orally applied dose is excreted via the biliary route. A significant proportion of the parent drug, corresponding to about 18% of the administered 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. Less than 1% of the administered dose of pizotifen is excreted unchanged through the kidneys. Pizotifen and its major metabolite the N-glucuronide conjugate is eliminated with a half-life of approximately 23 hours.

Special population

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.

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.

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 (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 reproductive and developmental toxicity studies in mice, rats and rabbits. There were no effects on fertility or teratologic effects noted at all doses up to 30 mg/kg/day. 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 and Carcinogenicity

Pizotifen hydrogen malate was not genotoxic in standard in vitro and in vivo tests. Conventional rodent carcinogenicity studies have not been conducted.