|
NDA 20-358 |
12 |
SUMMARY
Bupropion (B) is currently marked as an immediate release formulation; the usual animal toxicity studies were performed and reviewed under NDA 18-644 (Original Summary of 6/15/82). The new sustained release formulation contains 2 new degradation products at proposed limits of 2% each, as well as apparently increased amounts of other degradation products/impurities with limits ranging from 1 to 5% each, with a total limit of 8%. A total of 8% represents 32 mg/day at the maximum recommended dose (400 mg) in humans. We thus requested that the sponsor perform bridging studies with drug containing the maximum allowable amounts of impurities in the new formulation, also to include a group receiving drug containing the impurity profile which was present in the original toxicity testing of the currently marketed drug substance. (My memo of 5/24/93), Dr. Fitzgerald’s memo of 6/7/93, and letter to sponsor of 6/8/93). The sponsor’s summary of the levels of impurities in the various studies performed are as follows:
|
% |
|||||||
|
|
3 Chloro- benzoic Acid |
268W93 |
3134W92 |
269W93 |
852U77 |
20U78 |
827U76 |
|
14
Day Toxicity Study in Rats |
- |
- |
- |
- |
- |
- |
- |
|
90
Day Toxicity Study in Rats |
0.7 |
2.7 |
0.8 |
1.8 |
6.2 |
2.4 |
1.3 |
|
Ames
Mutagenicity Assay |
1.1 |
1.7 |
0.7 |
2.1 |
5.9 |
2.4 |
1.7 |
|
Cytogenicity
Study in Rats |
0.7 |
3.1 |
0.8 |
2.1 |
6.5 |
2.5 |
1.2 |
|
Teratogenicity
Study in Rats |
0.7 |
2.6 |
0.7 |
1.4 |
6.3 |
2.3 |
1.2 |
In the 90 day rat study (75, 100, 150, 300 mg/kg/day, plus 300 mg/kg/day of original formulation, by gavage), drug effects included salivation (all doses), increased liver weights (all doses), minimal centrilobular hepatocellular hypertrophy (see at HD; lower doses not examined), and increased incidence of very minimal-to-mild chronic progressive nephrosis in HD M (lower doses not examined). Thyroid and adrenal weights were slightly increased in HD M without histological correlates. There were no clear differences between the old and new formulations. (Plasma level data obtained in this study indicated that levels of bupropion, but not metabolite 306U73, were greater on day 82 than on day 10 of treatment. This is in disagreement with previous data suggesting that B can induce its own metabolism, as well as the sponsor’s contention that the histological effects of B on the liver (also seen in previous studies) are secondary to enzyme induction. However, it is noted that the plasma level data are not definitive in view of the small N and large inter-animal variations noted. It was also seen that levels of bupropion in F were several fold higher than in M, in agreement with other studies).
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