NDA
20-358 WELLBUTRIN® SR tablets
APPENDIX
II: Details
of Market Formulations
APPENDIX
III: Details
of Dissolution Data
APPENDIX
IV: Individual
Subject Plasma Concentration/Time Data For Each Study Report
(Note: The appendices contain more detailed data/information such as individual study reports, formulation of dosage forms, dissolution methodology and specification, assay methodology and validation, and individual plasma concentration/time data. This information is being retained in the Division of Biopharmaceutics and can be obtained upon request.)
BACKGROUND:
Bupropion
HCL (WELLBUTRIN®) is an antidepressant of the aminoketone class. It is chemically unrelated to the
tricyclic or tetracyclic antidepressant.
Bupropion
HCL was approved in December 1985 under NDA 18,644 for the treatment of
depression at doses of 300 to 450 mg per day given in divided doses not to
exceed 150 mg per dose with at least six hours separating successive doses. Bupropion HCL is currently marketed by
Burroughs Wellcome Co. as WELLBUTRIN® 75 mg and 100 mg immediate release (IR)
tablets. The IR formulation is
usually associated with the incidence (0.4%) of seizures at doses of 405
mg/day. Preclinical and clinical
evidence suggested that these seizures are related to peak plasma levels and
total daily dose. A sustained
release (SR) formulation has been developed in an effort to improve patient
compliance as well as the safety profile of bupropion over the IR product. This SR formulation should produce
lower bupropion plasma peak levels and hence, less incidence of peak-associated
seizures. In addition, it will
provide for twice daily (q12h) dosing which will lead to better compliance in
the patient population.
MECHANISM
OF ACTION: The neurochemical mechanism
of the antidepressant effect of bupropion is not known. In vitro, bupropion blocks the neuronal
re-uptake of dopamine to some extent.
It is a weak blocker of norepinephrine and serotonin neuronal re-uptake.
PHYSICOCHEMICAL
PROPERTIES: Bupropion HCL is a white
crystalline powder, highly soluble in water, and has a molecular weight of
276. The drug is a weak base with
a pKa value of 8.6.
STRUCTURAL
FORMULA: The structure of bupropion closely
resembles that of diethylpropion, it is related to phenylethylamines. The chemical name is: (±)
2-tert-butylamino-3’-chloropropiophenone hydrochloride. The empirical formula is C13H18CINO.HCL. The
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