Medication Guide App

FDA Sends Letter to GlaxoSmithKline Regarding Flonase Aid

ROCKVILLE, Md., May 9, 2007-The Food and Drug Administration today posted a letter on its website sent to GlaxoSmithKline regarding a professional detail aid for Flonase. The letter is below.

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Food and Drug Administration
Rockville, MD 20857
TRANSMITTED BY FACSIMILE
Munir Abdullah, Ph.D.
Director, U.S. Regulatory Affairs
GlaxoSmithKline
One Franklin Plaza
P.O. Box 7929
Philadelphia, PA 19101

Re: NDA # 20-121
Flonase® (fluticasone propionate) Nasal Spray, 50 mcg
MACMIS # 13807

Dear Dr. Abdullah:
The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a
professional detail aid (detail aid) (MH2026R0) for Flonase® (fluticasone propionate) Nasal Spray, 50
mcg (Flonase) submitted by GlaxoSmithKline (GSK) under cover of Form FDA-2253. This detail aid
is misleading because it makes unsubstantiated superiority claims for Flonase, omits material facts
about Flonase, and claims that Flonase is more effective than has been demonstrated by substantial
evidence or substantial clinical experience. The detail aid therefore misbrands the drug in violation of
the Federal Food, Drug and Cosmetic Act (Act). 21 U.S.C. 352(a) and 321(n); cf. 21 CFR
202.1(e)(6)(ii).

Background
According to the FDA-approved product labeling (PI), Flonase “is indicated for the management of the
nasal symptoms of seasonal and perennial allergic and nonallergic rhinitis in adults and pediatric
patients 4 years of age and older. Safety and effectiveness of FLONASE Nasal Spray in children
below 4 years of age have not been adequately established.”

As set forth in the Clinical Trials section of the PI,
A total of 13 randomized, double-blind, parallel-group, multicenter,
vehicle placebo-controlled clinical trials were conducted in the United
States in adults and pediatric patients (4 years of age and older) to
investigate regular use of FLONASE Nasal Spray in patients with
seasonal or perennial allergic rhinitis …. These trials evaluated the total
nasal symptom scores (TNSS) that included rhinorrhea, nasal
obstruction, sneezing, and nasal itching in known allergic patients who
were treated for 2 to 24 weeks.

According to the PI, subjects treated with Flonase exhibited significantly greater decreases in TNSS
than vehicle placebo-treated patients.

Unsubstantiated Superiority Claims
The first page of the detail aid presents the following misleading claims regarding the superiority of
Flonase over Nasonex® (mometasone furoate – Schering Corporation) (Nasonex):
• “Choose greater EFFICACY for your patients with SEASONAL ALLERGIC RHINITIS…”
(original emphasis) above a chart titled, “SUPERIOR REDUCTION in Patient-Rated TOTAL
NASAL SYMPTOM SCORES (TNSS) vs NASONEX1” (original emphasis) which in turn
presents data that Flonase patients experienced a superior reduction of 25% (P=0.03) in TNSS
versus Nasonex patients.

• “Patients given FLONASE experienced GREATER RELIEF of NASAL SYMPTOMS in a
head-to-head clinical study of seasonal allergic rhinitis (SAR) sponsored by Schering
Corporation, the maker of Nasonex®” (original emphasis).

These claims and presentations are misleading because they suggest that Flonase is superior to
Nasonex for the treatment of seasonal allergic rhinitis symptoms, when this has not been demonstrated
by substantial evidence or substantial clinical experience. The reference cited1 to support this claim
does not provide substantial evidence for the following reasons. First, the study design raises
multiplicity issues. It was designed as a placebo-controlled trial comparing Nasonex to placebo; the
active comparison was not clearly planned. It is therefore difficult to determine exactly what
significance level should be attached to that comparison. Second, the study was not replicated. In
general, a claim of superiority, like other claims under the Act, should be based on comparisons of the
two drug products in two adequate, well-designed, head-to-head clinical trials. FDA is not aware of
substantial evidence or substantial clinical experience demonstrating that Flonase is superior to
Nasonex. If you have additional data to support such claims, please submit them to FDA for review.
Omission of Material Fact

Promotional materials are misleading if they fail to reveal facts that are material in light of the
representations made by the materials or with respect to consequences that may result from the use of
the drug as recommended or suggested by the materials. The detail aid fails to present the full
approved indication for Flonase (see Background section), including material limitations to the
indication. Specifically, although the detail aid presents claims about Flonase’s use in treating
seasonal allergic rhinitis and nasal allergies, it fails to reveal that Flonase is only indicated in “adults
and pediatric patients 4 years of age and older. Safety and effectiveness of FLONASE Nasal Spray in
children below 4 years of age have not been adequately established.” Your failure to disclose the
complete indication, including the material limitation that safety and effectiveness of Flonase in
children below 4 years of age have not been adequately established, renders your detail aid misleading.
This is especially concerning in light of the Precautions-Pediatric Use section of the Flonase PI which
states that "Controlled clinical studies have shown that intranasal corticosteroids may cause a reduction
in growth velocity in pediatric patients."
____________
1 Drouin MA. Trial I94-001. Efficacy and safety of mometasone furoate aqueous nasal spray vs placebo and vs fluticasone
propionate (Flonase) in seasonal allergic rhinitis (SAR) patients. FDA Web site. Summary Basis of Approval section of
the New Drug Application for Nasonex, NDA #20-762. Available at
http://www.fda.gov/cder/foi/nda/97/020762ap_Nasonex_medrP2.pdf. Accessed June 7, 2005.

Overstatement of Efficacy
The detail aid highlights “congestion” as a specific symptom for which Flonase should be prescribed,
and includes the claim, “WHEN NASAL CONGESTION IS CERTAIN, BUT THE TRIGGERS ARE
NOT PRESCRIBE FLONASE FIRxST” (original emphasis). This presentation is misleading because it
implies that Flonase is specifically indicated to treat nasal congestion. In fact, Flonase is not
specifically approved for treatment of nasal congestion. Rather, according to the PI, "FLONASE
Nasal Spray is indicated for the management of the nasal symptoms of seasonal and perennial allergic
and nonallergic rhinitis in adults and pediatric patients 4 years of age and older. Safety and
effectiveness of FLONASE Nasal Spray in children below 4 years of age have not been adequately
established." The Clinical Trials section of the Flonase PI indicates that Flonase was evaluated in
clinical trials that measured total nasal symptom scores (TNSS). That section variously indicates that
TNSS is a composite measure of symptoms including "rhinorrhea, nasal obstruction, sneezing, and
nasal itching” in patients with known seasonal and perennial allergic rhinitis and that patient-rated
TNSS is a composite measure of symptoms including "nasal obstruction, postnasal drip [and]
rhinorrhea” in patients with perennial nonallergic rhinitis. However, demonstrating an effect on
composite multiple symptom measures of the TNSS and patient-rated TNSS do not represent a clear
effect on any individual component of the TNSS or patient-rated TNSS, and in the absence of
substantial evidence or substantial clinical experience demonstrating Flonase's effect on the particular
component symptom, making a claim related only to the component symptom of the TNSS or patientrated
TNSS overstates Flonase's efficacy. FDA is not aware of any substantial evidence or substantial
clinical experience demonstrating that Flonase specifically treats nasal congestion. If you have
additional data to support such claims, please submit them to us for review.
Conclusion and Requested Action

The detail aid is misleading because it contains unsubstantiated superiority claims, omits material
facts, and overstates the effectiveness of Flonase. Therefore, it misbrands your drug in violation of the
Act, 21 U.S.C. 352(a) and 321(n); cf. 21 CFR 202.1(e)(6)(ii).

DDMAC requests that GSK immediately cease the dissemination of promotional materials for Flonase
that are the same as or similar to those described above. Please submit a written response to this letter
on or before May 18, 2007, describing whether you intend to comply with this request, listing all
promotional materials for Flonase that contain claims that are the same as or similar to those described
above, and explaining your plan for discontinuing use of these materials. Please direct your response
to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of
Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-
1266, or by facsimile at 301-796-9877. In all future correspondence regarding this matter, please refer
to MACMIS ID # 13807 in addition to the NDA number. We remind you that only written
communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your
responsibility to ensure that your promotional materials for Flonase comply with each applicable
requirement of the Act and FDA implementing regulations.

Sincerely,
{See appended electronic signature page}
Michelle Safarik, MSPAS, PA-C
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
Michelle Safarik
5/7/2007 07:36:05 AM

Posted: May 2007


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