CENTER FOR DRUG EVALUATION AND
RESEARCH

APPLICATION NUMBER:

205641Orig1s000
RISK ASSESSMENT and RISK MITIGATION
REVIEW(S)

 Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research
Office of Surveillance and Epidemiology
Office of Medication Error Prevention and Risk Management
Final Risk Management Review
Date:

February 20, 2014

Reviewer(s):

Kendra Worthy, Pharm. D., Division of Risk Management
(DRISK)

Team Leader

Reema Mehta, Pharm. D., M.P.H.,
DRISK

Division Director

Claudia Manzo, Pharm. D.,
DRISK

Drug Name(s):

Asmanex HFA (mometasone furoate)

Therapeutic Class:

Corticosteroid

Dosage form:

metered dose inhaler

Application Type/Number:

NDA 205641

Applicant/sponsor:

Merck

OSE RCM #:

2013-1602

1
Reference ID: 3456909

 1

INTRODUCTION

This review documents the Division of Risk Management (DRISK) evaluation of the
need for a Risk Evaluation and Mitigation Strategy (REMS) for Asmanex HFA
[mometasone fuorate (MF)] metered dose inhaler (MDI), NDA 205641.
The application was initially considered a new molecular entity (NME) but was later
reclassified as a 505(b)(1) for a non-NME1.
2

BACKGROUND

Asmanex HFA MDI is a corticosteroid administered by oral inhalation at a dose of
2 inhalations of 100mcg or 200mcg twice daily. MF is considered to have potent antiinflammatory activity. The proposed indication is for maintenance treatment of asthma as
prophylactic therapy in patients 12 years of age and older.
MF has been approved as Asmanex Twisthaler dry powder inhaler (DPI), 110 and
220mcg, since 2005. In 2008, the DPI formulation was subsequently extended to include
patients aged 4 years and older.
Dulera HFA (mometasone furoate/ formoterol), a long-acting beta-agonist (LABA), was
approved in 2010. It is available as 200mcg/10mcg and 400mcg/10mcg strengths. Dulera
HFA was approved with a REMS that was required for the entire LABA class for the risk
of asthma-related deaths, intubations, and hospitalizations associated with the use of
LABAs. The originally approved REMS consisted of a Medication Guide, a
communication plan, and a timetable for submission of assessments. The Agency
internally agreed in June 2012 that the REMS for LABAs were no longer required2. In
2012, the Agency issued a complete response (CR) for this formulation for a COPD
indication.
Upon the approval of Dulera HFA, the Agency requested that the Sponsor consider
development of the HFA mometasone monotherapy- to which they agreed1; this NDA
application is the subject of this review.
3

4

MATERIALS REVIEWED


DPARP Clinical Midcycle slides dated November 25, 2013, Kim Witzmann,
Medical Officer.



DRISK REMS Elimination review of Dulera dated May 8, 2013, Yasmin
Choudhry, Medical Officer.

OVERVIEW OF CLINICAL PROGRAM

1

DPARP Clinical Midcycle slides dated November 25, 2013, Kim Witzmann, Medical Officer.

2

DRISK REMS Elimination review of Dulera dated May 8, 2013, Yasmin Choudhry, Medical Officer.

2
Reference ID: 3456909

 The DPARP medical officer noted that the sponsor identified eight studies in support for
the efficacy of Asmanex HFA. The pivotal studies for this application (P04334 and
P04431) were the same pivotal trials used for Dulera HFA. The remaining six studies
identified by the Sponsor are from the mometasone monotherapy program in the mid’90s, which utilized the older formulation. The Agency confirmed with the sponsor that
the sponsor would not need to submit additional studies for this NDA3.
4.1

SAFETY CONCERNS

At total of 4015 asthma patients (>12yo) have received doses of MF across the entire
program. There were five total deaths; two from pivotal studies already reviewed, one in
the bone mineral density study, and two others from a study in steroid-dependent
patients3. The medical officer notes that there do not appear to be any significant safety
differences between the older and newer formulations of MF. The most common adverse
events were influenza, nasopharyngitis, sinusitis, and headache.
5

RISK MANAGEMENT PROPOSED BY APPLICANT

The sponsor did not submit a proposed REMS or proposed risk management plan with
this application.
6

DISCUSSION

At the midcycle review, the safety profile of Asmanex HFA was considered acceptable
by the clinical reviewer; the clinical reviewer is not recommending a REMS at this time.
The safety profile is consistent with the known safety profile for Asmanex Twisthaler and
Dulera HFA and no new safety issues were identified.
MF was previously approved under a REMS as part of a combination product with a
LABA (Dulera); however, the Agency internally agreed in June 2012 that the REMS for
LABAs was no longer required. Furthermore, there are no REMS required for the single
entity of MF or any inhalation corticosteroids.
7

CONCLUSION AND RECOMMENDATIONS

In conclusion, at this time, risk mitigation measures beyond professional labeling are not
warranted for Asmanex HFA (MF). Asmanex HFA has proven efficacy for maintenance
treatment of asthma as demonstrated by the clinical program. The safety profile for
Asmanex HFA is consistent with the known safety profile for comparable approved
products. Thus, the benefit-risk profile for Asmanex HFA is favorable and the risks can
be mitigated through professional labeling.
Should the Division have any concerns or questions, or feel that a REMS may be
warranted for this product, please contact DRISK.

3

DPARP Clinical Midcycle slides dated November 25, 2013, Kim Witzmann, Medical Officer.

3
Reference ID: 3456909

 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
--------------------------------------------------------------------------------------------------------/s/
---------------------------------------------------KENDRA C WORTHY
02/19/2014
CLAUDIA B MANZO
02/19/2014
concur

Reference ID: 3456909