NDA 20-358

Page 7

 

 

Item 7. Fate of Emitted Substances in the Environment:

 

a.        It should be confirmed that the unidentified polar metabolites are more polar than the parent compound and contain the same backbone chemical structure.

 

b.       A literature reference to the publication of the water solubility of the drug substances should be provided, together with any supportive data obtained or appearing since 1976.

 

c.        A reference for the method used to measure hydrolysis should be provided, together with a discussion of any significant deviations from the EATAD 3.09 of the FDA’s Environmental Assessment Technical Assistance Handbook.

 

d.       For the measurement of dissociation constant, a discussion of any significant deviation from ETAD 3.04 Assistance Handbook should be provided.

 

e.        A literature reference to the publication of the log Kow of the drug substance should be provided together with any supportive data obtained or appearing since 1976.

 

f.         For aqueous photodegradation:  The half-lives presented are experimental values in the presence of xenon arc lamp.  Considerably longer half-lives for aqueous photodegradation were obtained from calculation which normalized these results to flat bodies of water at various seasons and latitudes (see page 177).  Since many of these half-lives exceed the threshold of 5 days, the statement that the drug substance is subject to rapid photodegradation in aqueous media (page 14) is misleading.  Photodegradation cannot be considered a primary depletion mechanism unless the longer half-lives can be shown to be irrelevant to the locations or seasons where the substances may be released.

 

Item 8. Environmental Effects of Released Substances:

 

Please search the literature and report available test data and also report any mammalian toxicity information.  A computerized structure activity relationship modeling program could be used to supplement the literature information

 

In accordance with the policy described in 21 CFR 314.102(d) and in the Center for Drug Evaluation and Research Staff Manual Guide CDB 4820.6, you may request an informal conference with the Division to discuss what further steps you need to secure approval.  The meeting is to be requested at least 15 days in advance.  Alternatively, you may choose to receive such a report via a telephone call.  Should you wish this conference of a telephone report, or should any questions arise concerning this NDA, please contact Mr. Paul David, Regulatory Management Officer, at (301) 594-2777.

 

 

 

 

 

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