Food and Drug
Administration
Center for Drug Evaluation and Research
Holiday Inn, The
Ballroom,
Michael
Camilleri, M.D., Chair Joel
Richter, M.D.
David Colin
Metz, M.D. Byron Cryer, M.D.
Robert Alan
Levine, M.D. John
Thomas LaMont, M.D.
Ronald Fogel, M.D. Susan Cohen,
Consumer Rep.
David Kelsen, M.D. Otis Brawley, M.D.
Howard McLeod,
Pharm.D. Michael Prochan,
Ph.D.
Zeruesenay Desta,
Ph.D. Ruth Hoffman,
Patient Rep.
FDA
Participants
Gary
Della’Zanna, D.O., M.Sc., Venkat
Jarugula, M.D.
These summary minutes for the
I
certify that I attended the
_______________________________ _______________________________
Thomas H. Perez, M.P.H., R.Ph. Michael Camilleri, M.D.
Executive
Secretary Chair
The Gastrointestinal Drugs Advisory Committee of the Food and Drug
Administration, Center for Drug Evaluation and Research met
The Committee discussed new drug application (NDA) 21-549, EMENDÔ (aprepitant) Capsules, Merck & Co., Inc., for the following indication: “EMEND, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.”
The Committee had received a briefing document from
the FDA, and a background package from Merck in
preparation for this meeting.
There were approximately 170 persons present in the
meeting. The meeting was called to order
at
Merck
representatives began their presentations at
Introduction Dennis
M. Erb, Ph.D.
Background and Rationale &
Clinical Pharmacology Kevin J.
Petty, M.D., Ph.D.
Clinical Efficacy Kevin
J. Horgan, M.D.
Clinical Safety Scott
A. Reines, M.D., Ph.D.
Summary and Conclusions Scott
A. Reines, M.D., Ph.D.
The Merck
presentations were followed by a 25-minute question and answer period.
FDA
representatives began their presentations at
Clinical Summary Gary
Della'Zanna, D.O., M.Sc.,
Division of
Gastrointestinal and Coagulation Drug Products
Biopharmacology Summary Venkat
Jarugula, Ph.D.,
Clinical Pharmacology and Biopharmaceuticcs Reveiwer
The FDA
presentations were followed by a 25-minute question and answer period.
The meeting had a lunch break at
There were no participants for the Open Public
Hearing and the Committee began to discuss the meeting questions presented by
the FDA. A thorough discussion of the
questions followed, and the open public meeting was adjourned at
The meeting transcript will be made available on the
web in approximately three weeks. Transcripts
may be accessed at the following web address www.fda.gov/ohrms/dockets/ac/acmenu.htm.
The Committee discussed the following questions.
Questions for
the Committee
1. Has the aprepitant regimen
been demonstrated to be effective in the prevention of nausea and vomiting in
the acute phase? In the delayed phase?
Committee’s Vote
In the Acute Phase: 13
Yes 0 No
In the Delayed Phase: 13 Yes 0 No
2. Is the designation of “highly emetogenic chemotherapy” appropriate
given the regimens used in the clinical studies?
Committee’s Vote: 12
Yes 0 No 1 Abstain
3. Can the recommended regimen
be expanded beyond that used in the clinical studies to include the use of any
5-HT3 antagonist as part of the aprepitant regimen? If not, what additional studies would you
recommend?
Committee’s Vote: 9
Yes 3 No 1 Abstain
Several members of the committee added that postmarketing studies are
needed.
4. Aprepitant is an inhibitor
of the CYP3A4 metabolic pathway. For
chemotherapeutic drugs that are metabolized by this pathway, moderate
inhibition of their metabolism could result in serious or life-threatening
toxicity.
a) The applicant has analyzed
the safety data by chemotherapy regimen and a significant number of patients
received etoposide, vinorelbine, or paclitaxel (substrates for CYP 3A4) in
combination with cisplatin and the aprepitant regimen. Is this data sufficient to support the safety
of aprepitant in combination with these drugs?
If not, what additional studies would you recommend and should these be
done pre-approval or post-approval?
Committee’s Vote: 9
Yes 3 No 1 Abstain
Several members of the committee added that
postmarketing studies are needed; including evaluating the outcome of the
cancer, further studies of pulmonary function when used in combination with
vinorelbine, studies to evaluate pharmacokinetics particularly for drugs that
are metablolized by CYP 3A4 and drug interactions with warfarin.
b) Few or no patients received
docetaxel, vinblastine, vincristine, ifosfamide, irinotecan, or imatinib
(substrates of CYP 3A4) in combination with cisplatin and the aprepitant
regimen. The docetaxel drug-drug
interaction study has accrued only five patients. Is there sufficient data to support the safety
of aprepitant in combination with these drugs?
If not, what additional studies would you recommend and should these
studies be done pre-approval or post-approval?
Committee’s Vote: 0
Yes 13 No
The Committee recommended that labeling should list
the drugs where there is sufficient safety information and the drugs where the
safety data is insuficient. Stated
limitations included the prophylactic use of aprepitant for 5 days to treat
chemotherapy induced nausea and vomiting.
Also it was recommended that postmarketing studies be performed to
determine effects of drugs most likely to be used in combination with
aprepitant.
5. Does the Committee have
specific concerns regarding potential drug-drug interactions with other
chemotherapeutic agents or other drug classes?
If yes, please discuss them and whether any additional studies are
recommended.
The Committee consensus was Yes. One example provided was the need to study
warfarin, particularly in elderly patients.
It was stated that answers to this question had been provided during
earlier discussions of previous questions.