Source: Υπουργείο Υγείας (CY) Revision Year: 2016 Publisher: Remedica Ltd, Aharnon Str., Limassol Industrial Estate, 3056 Limassol, Cyprus
Pharmacotherapeutic group: Analgesics; Antimigraine preparations
ATC code: N02CX01
Pizotifen is characterized by its polyvalent inhibitory effect on biogenic amines, such as serotonin, histamine and tryptamine. It is suitable for the prophylactic treatment of migraine, reducing the frequency of attacks.
Pharmacodynamic studies demonstrate pizotifen to have powerful anti-serotonin and anti-tryptaminic properties, marked anti-histaminic effects and some antagonistic activity against kinins. It also possesses weak anti-cholinergic effects and sedative properties.
Pizotifen also possesses appetite-stimulating properties.
The prophylactic effect of pizotifen in migraine is associated with its ability to modify the humoral mechanisms of headache. It inhibits the permeability-increasing effect of serotonin and histamine on the affected cranial vessels, thereby checking the transudation of plasmakinin so that the pain threshold of the receptors is maintained at ‘normal’ levels. In the sequence of events leading to migraine attack, depletion of plasma serotonin contributes to loss of tone in the extracranial vessels. Pizotifen inhibits serotonin re-uptake by the platelets, thus maintaining plasma serotonin and preventing the loss of tone and passive distension of the extracranial arteries.
Following oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract. The mean absolute bioavailability after oral administration is about 80%. Following a single 2-mg oral administration of pizotifen 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 1 mg 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 through plasma concentration was about 11 ng/mL (Cmin,ss).
Pizotifen is extensively metabolized in the liver primarily by glucuronidation. The main metabolite is the N-glucuronide-conjugate and accounts for at least 50% of the plasma exposure.
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 two-compartment model.
About one-third of an orally administered 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, N-glucuronide conjugate, is eliminated with a half-life of approximately 23 hours.
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.
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 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.
Pizotifen hydrogen malate was evaluated in multiple reproductive and developmental toxicity studies for its effects on fertility and its embryotoxic, fetotoxic, teratogenic and developmental toxic potential. There were no specific reproductive or developmental effects observed in mice, rats or rabbits up to the highest tested doses of 30 mg/kg. This dose level is greater than 300 times the daily maximum recommended adult human dose of 0.09 mg/kg.
In vitro and in vivo mutagenicity tests were performed and did not reveal any mutagenic activity of pizotifen.
A 2-year rat toxicity study did not reveal any gross lesions or masses attributable to pizotifen 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.
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