NDA 21-515 Approval Letter 4
nelfinavir.
Based on these literature results, an in vivo drug interaction study may
be necessary.
In
addition, we have made specific changes in the revised labeling appended to
this letter. Please address these
changes in your complete response.
Clinical/Clinical Safety
We
have completed our review of the clinical safety information and proposed
package insert as provided in your NDA.
Our comments are incorporated into the revised labeling appended to this
letter, as bracketed comments, text insertions [underlined], or deletions
[strikethrough]. Please address these
changes specifically in your complete response.
Request
for Safety Update
In
your complete response to this letter, please include a safety update as
described in 21 CFR 314.50(d)(5)(vi)(b).
1.
The
safety update should include data from all non-clinical and clinical studies of
the drug under consideration, regardless of indication, dosage form, or dose
level.
2.
Please
describe in detail any significant changes or findings in the safety profile.
3.
When
assembling the sections describing discontinuations due to adverse events,
serious adverse events, and common adverse events, please incorporate new safety
data as follows:
·
Present
new safety data from the studies for the proposed indication using the same
format as the original NDA submission.
·
Include
tables that compare frequencies of adverse events in the original NDA with the
retabulated frequencies described in the preceding bullet point.
4.
For
indications other than the proposed indication, provide separate tables for the
frequencies of adverse events occurring in clinical trials.
5.
Please
present a retabulation of the reasons for premature study discontinuation by
incorporating the dropouts from the newly completed studies. Describe any new trends or patterns
identified.
6.
Please
provide case report forms and narrative summaries for each patient who died
during a clinical study or who did not complete a study because of an adverse
event. In addition, please provide
narrative summaries for serious adverse events.
7.
Please
describe any information that suggests a substantial change in the incidence of
common, but less serious, adverse events between the new data and the original
NDA data.
8.
Prior
to an approval action, we require an updated report on the world’s archival
literature pertaining to the safety of Wellbutrin XL. Please provide a summary of worldwide experience on the safety of
this drug. Include an updated estimate
of use for drug marketed in other countries.
This report should include only literature not covered in your previous
submissions. We will need your warrant
that you have reviewed this literature systematically, and in detail, and that
you have discovered no finding that would adversely affect conclusion about the
safety of Wellbutrin XL. The report
should also detail how the literature search was conducted, by whom (their
credentials) and whether it relied on abstracts or full texts (including
translations) of articles. The report
should emphasize clinical data, but new findings in preclinical reports of
potential significance should also be
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