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Preclinical Safety Data
Tramadol/Paracetamol Combination
There are no animal or laboratory studies on the combination product (tramadol and
paracetamol) to evaluate carcinogenesis, mutagenesis, or impairment of fertility.
No drug-related teratogenic effects were observed in the progeny of rats treated
orally with the combination of tramadol and paracetamol. The tramadol/paracetamol
combination product was shown to be embryotoxic and fetotoxic in rats at a
maternally toxic dose (50/434 mg/kg tramadol/paracetamol) 8.3 times the maximum
human dose but was not teratogenic at this dose level. Embryo and fetal toxicity
consisted of decreased fetal weights and increased supernumerary ribs. Lower and
less severe maternally toxic dosages (10/87 and 25/217 mg/kg tramadol/
paracetamol) did not produce embryo or fetal toxicity.
Tramadol Hydrochloride
Carcinogenicity/Mutagenicity
A slight but statistically significant increase in two common murine tumors,
pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly
in aged mice (dosing orally up to 30 mpg for approximately two years, although the
study was not done with the Maximum Tolerated Dose). This finding is not believed
to suggest risk in humans. No such finding occurred in a rat carcinogenicity study.
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal
activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the
absence of metabolic activation), dominant lethal mutation tests in mice,
chromosome aberration test in Chinese hamsters, and bone marrow micronucleus
tests in mice and Chinese hamsters.
Weakly mutagenic results occurred in the presence of metabolic activation in the mouse
lymphoma assay and micronucleus test in rats. Overall. the weight of evidence from
these tests indicates that tramadol does not pose a genotoxic risk to humans.
Impairment of Fertility/Effect on Reproduction
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg
in male rats and 75 mg/kg in female rats.
Tramadol was evaluated in pert- and post-natal studies in rats. Progeny of dams
receiving oral (gavage) dose levels of 50 mg/kg or greater had decreased weights,
and pup survival was decreased early in lactation at 80 mg/kg (6 to 10 times the
maximum human dose). No toxicity was observed for progeny of dams receiving 8,
10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels of tramadol
in this study, but effects on progeny were evident only at higher dose levels where
maternal toxicity was more severe.
PHARMACEUTICAL PARTICULARS
List of Excipients
Inactive ingredients in the tablet are powdered cellulose [(USP, EP)], pregelatinized
starch [(USP, EP)], sodium starch glycolate [(USP, EP)], starch [(USP, EP)]. purified
water [(USP, EP)], magnesium stearate [(USP, EP)], OPADRY Light Yellow, and
carnauba wax [(USP, EP)].
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