Ultram

[Tramadol]

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.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/ kg (300 mg/ m 2 ) in male rats and 75 mg/ kg (450 mg/ m 2 ) in female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage of 246 mg/ m 2 , respectively.

Pregnancy, Teratogenic Effects

Pregnancy

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Category C

Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/ kg or 360 mg/ m 2 ), rats ( 25 mg/ kg or 150 mg/ m 2 ) and rabbits ( 75 mg/ kg or 900 mg/ m 2 ) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on a mg/ m 2 basis are 1.4, 0.6, and 3.6 times the maximum daily human dosage (246 mg/ m 2 ) for mouse, rat and rabbit, respectively. No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/ kg or 420 mg/ m 2 ), rats (up to 80 mg/ kg or 480 mg/ m 2 ) or rabbits (up to 300 mg/ kg or 3600 mg/ m 2 ) treated with tramadol by various routes.

Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/ kg (3600 mg/ m 2 ), a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the maximum daily human dosage (246 mg/ m 2 ), respectively.

Non-teratogenic Effects

Tramadol was evaluated in peri-and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/ kg (300 mg/ m 2 or 1.2 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/ kg (480 mg/ m 2 or 1.9 and higher the maximum daily human dose).

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