In studies of bupropion sustained-release, acute toxicity was tested in rats and mice.  The LD50 in mice was 544 mg/kg for males and 636 mg/kg for females.  In rats the LD50 was 607 kg/kg for males and 482 mg/kg for females.  Signs of acute toxicity included labored breathing, salivation, arched back, ptosis, ataxia, and convulsions.  A multidose toxicity  studies of bupropion sustained-release involved three month administration to rats of both degraded and undegraded compound.  Findings included dose-related salivation and increases in liver and thyroid weights due to reversible microsomal enzyme induction.  The findings in this study did not differ in any significant way from the findings in previous studies of bupropion immediate-release.

 

Lifetime carcinogenicity studies with bupropion immediate-release were performed in rats and mice at doses up to 300 and 150 mg/kg/day respectively.  There was an increase in nodular proliferative lesions at doses of 100 to 300 mg/kg/day in the rat.  Similar lesions were seen in the mouse.  No increase in malignant tumors of the liver and other organs was seen in either study.

 

The immediate release formulation produced a borderline positive response (two to three times control mutation rate) in some strains in the Ames bacterial mutagenecity test, and a high oral dose (300, but not 100 or 200 mg/kg) produced a low incidence of chromosomal aberrations in rats.  A similar response on the Ames test was seen with the bupropion sustained-release formulation.  Bupropion sustained-release did not induce chromosomal aberrations in rats during cytogenicity studies.

 

No evidence of impairment of fertility due to bupropion immediate-release at oral doses up to 300 mg/kg/day.  In the sponsor’s opinion, teratogenicity studies of both the immediate-release and sustained-release formulations were negative.

 

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