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PHARMACOKINETICS
Absorption
After oral administration, the
absorption of Zaditen is almost complete. Bioavailability amounts to
approximately 50% owing to a first pass effect of about 50% in the liver.
Maximal plasma concentrations are reached within 2 to 4 hours.
Distribution
Protein binding is 75%.
Biotransformation
The main metabolite is the
practically inactive ketotifen-N-glucuronide.
The pattern of metabolism in children is the same as in adults, but the
clearance is higher in children. Children over the age of 3 years therefore
require the same daily dose regimen as adults.
Elimination
Ketotifen is eliminated
biphasically, with a short half-life of 3 to 5 hours and a longer one of 21
hours. About 1% of the substance is excreted unchanged in the urine within
48 hours and 60 to 70% as metabolites.
Slow release (SRO) formulation
The slow release of ketotifen
from Zaditen SRO tablets results in a smoother pharmacokinetic profile with
reduced daily variations in the plasma concentrations, which improves
tolerability and allows once-a-day administration. The peak plasma levels
attained with a single daily dose of Zaditen SRO are lower (76%) than those
found when the same daily amounts of ketotifen are given in 2 divided doses
of any of the other galenical forms. However, minimum plasma concentrations
(trough levels) and relative bioavailability (AUC) are the same for both
dose regimens.
Effect of food
The bioavailability of either
form of Zaditen is not influenced by the intake of food.
PRECLINICAL SAFETY DATA
Acute toxicity
Acute toxicity studies of
ketotifen in mice, rats. and rabbits revealed oral LD50 values
above 300 mg/kg body weight and between 5 and 20 mg/kg by the i.e. route.
Adverse effects induced by overdose were dyspnea and motor excitation
followed by spasms and drowsiness. Toxic signs appeared rapidly and
disappeared within hours: there was no evidence of cumulative or delayed
effects. Other studies yielded an oral LD50 value of ketotifen in
rats of 161 mg/kg and demonstrated that the toxicity of Zaditen syrup ( LD50
31.1 mg/kg ) was attributable to the sorbitol excipient alone. A total daily
dose of 10 mL administered to a child of 30 kg would be equivalent to 0.33
mL/kg Zaditen syrup and 0.07 mg/kg ketotifen base. Indicating a sufficiently
wide safety margin.
No evidence of skin sensitizing potential of ketotifen was obtained in
guinea pigs by intracutaneous injection.
Mutagenicity
Ketotifen and/or its metabolites
were devoid of genotoxic potential, when investigated in vitro for induction
of gene mutation in Salmonella typhimurium, for chromosome aberrations in
V79 Chinese hamster cells, or for primary DNA damage in rat hepatocyte
cultures. No clastogenic activity was observed in vivo ( cytogenetc analysis
of bone marrow cells in the Chinese hamster, bone marrow micronucleus assay
in mice ). Likewise, no mutagenic effects were evident on the germ cells of
male mice in the dominant lethal test.
Carcinogenicity
In rats treated continuously in
the diet for 24 months, maximum tolerated doses of 71 mg/kg ketotifen per
day revealed no carcinogenic potential. No evidence of tumorigenic effects
was obtained in mice treated with up to 88 mg/kg body weight in the diet for
74 weeks.
Reproductive toxicity
No embryotoxic or teratogenic
potential of ketotifen was revealed in rats or rabbits, In male rats treated
for 10 weeks ( i.e. more than a complete spermatogenic cycle ) before
mating, fertility was unaffected at a tolerated dose of 10 mg/kg per day.
The fertility of female rats as well as prenatal development, pregnancy
and weaning of the offspring were not adversely affected by ketotifen
treatment at oral dose levels of up to 50 mg/kg per day, although
non-specific toxicity to the pregnant females was observed at and above 10
mg/kg. Likewise, no adverse effect of treatment was found in the perinatal
phase. Due to the maternal toxicity. some decrease in pup survival and
weight gain was recorded during the first days of post-natal development at
the high dose level of 50 mg/kg per day.
EXCIPIENTS
Zaditen capsules : silicic acid;
fumaric acid; magnesium stearate; maize starch: mannitol; titanium dioxide;
gelatin.
Zaditen tablets : fumaric acid, magnesium stearate: maize starch; calcium
hydrogen phosphate; lactose.
Zaditen SRO tablets : magnesium stearate; silica; ethyl cellulose;
fumaric acid; polyvinylpyrrolidone; maize starch; glyceryl palmitostearate;
lactose; polyethylene glycol 6000; talc; methylhydroxy-propylcellulose; iron
oxide yellow; titanium dioxide.
Zaditen syrup : fumaric acid; banana or strawberry flavoring agent;
propyl p-hydroxybenzoate; methyl p-hydroxybenzoate; citric acid; disodium
hydrogen phosphate; maltitol liquid; water, demineralized. Some formulations
may contain ethanol.
Zaditen oral solution : fumaric acid; propyl parahydroxybenzoate; methyl
parahydroxybenzoate; citric acid; disodium hydrogen phosphate; maltitol
liquid; water, demineralized.
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