FDA Warns Glaxo on Altabax Promotion
ROCKVILLE, Md., May 4, 2010 - The FDA today posted on its website a warning letter sent to GlaxoSmithKline regarding a professional slim jim with pull out tab for iimpetigo treatment Altabax. The letter is below.
TRANSMITTED BY
FACSIMILE 04/19/2010
Andrew Witty, Chief Executive Officer
GlaxoSmithKline
One Franklin Plaza
P.O. Box 7929
Philadelphia, PA 19101
RE: NDA 22-055
Altabax® (retapamulin
ointment), 1%
MACMIS# 18333
WARNING LETTER
Dear Mr. Witty:
The Division of Drug Marketing, Advertising, and Communications
(DDMAC) has reviewed a professional slim jim with pull out tab
(ABX307R0) (slim jim) for Altabax® (retapamulin ointment), 1%
(Altabax) submitted by GlaxoSmithKline (GSK) under cover of Form
FDA-2253. The slim jim is false or misleading because it broadens
the indication of Altabax, makes unsubstantiated superiority
claims, and omits and minimizes important risk information
associated with Altabax. Thus, the slim jim misbrands the drug in
violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21
U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(3)(i), (ii);
(e)(5); (e)(6)(i), (ii), (vii), & (xviii); (e)(7)(viii). These
violations are concerning from a public health perspective because
they suggest that Altabax is safer or more effective than has been
demonstrated by substantial evidence or substantial clinical
experience.
Background
According to the FDA-approved product labeling (PI) (in pertinent part, emphasis original): ALTABAX is indicated for use in adults and pediatric patients aged 9 months and older for the topical treatment of impetigo (up to 100 cm2 in total area in adults or 2% total body surface area in pediatric patients aged 9 months or older) due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes. To reduce the development of drug-resistant bacteria and maintain the effectiveness of ALTABAX and other antibacterial drugs, ALTABAX should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
WARNINGS AND PRECAUTIONS
Local Irritation
In the event of sensitization or
severe local irritation from ALTABAX, usage should be discontinued,
the ointment wiped off, and appropriate alternative therapy for the
infection instituted.
Not for Systemic or Mucosal
Use
ALTABAX is not
intended for ingestion or for oral, intranasal, ophthalmic, or
intravaginal use. ALTABAX has not been evaluated for use on mucosal
surfaces.
Potential for Microbial
Overgrowth
The use of
antibiotics may promote the selection of nonsusceptible organisms.
Should superinfection occur during therapy, appropriate measures
should be taken.
Prescribing ALTABAX in the absence of
a proven or strongly suspected bacterial infection is unlikely to
provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Broadening of Indication
The slim jim is misleading because it suggests that Altabax is
effective in a broader range of conditions than has been
demonstrated by substantial evidence or substantial clinical
experience.
The slim jim includes the following claims and presentations
(footnotes omitted)1:
• Bar graph entitled,
“ALTABAX is more potent in vitro than mupirocin . .
.All S. aureus isolates studied (n=1975),” which
compares the MIC90 (μg/mL) of Altabax to mupirocin
(page 2)
• “32x more potent in vitro. . .and ALTABAX was
just as active in vitro against S. aureus
resistant to mupirocin (ALTABAX MIC90 remained at 0.12
μg/mL)” (page 2)
• Bar graph entitled, “ALTABAX has a low propensity to
develop resistance in an in vitro multipassage study . . .
All S. aureus isolates studied (n=12),” which
compares the percentage of S. aureus isolates with a MIC
of ≤ 2 μg/mL after ≤ 20 days between Altabax and mupirocin
(page 2)
• “TARGET PATHOGENS
• ALTABAX is 32x more potent
in vitro than mupirocin against S.
aureus….
• ALTABAX is the only prescription topical antibacterial for
impetigo with simple 5-day b.i.d. dosing” (pages 3 and 5)
• “ALTABAX has superior
efficacy vs. vehicle in the treatment of impetigo due to
Staphylococcus aureus and Streptococcus
pyogenes” (page 4)
These claims are misleading because they create the overall
impression that Altabax is approved to treat all strains of
Staphylococcus aureus, when this is not the case. For
example, the graphs on page 2 suggest, among other things, that
Altabax is active against all S. aureus isolates studied.
This implication of broad efficacy against S. aureus is
exacerbated by the footnote associated with the potency graph on
page 2, which states:
A multicenter, global surveillance
program tested clinical isolates including pathogens resistant to
other commonly used antibiotics. Isolates were collected between
March 2004 and March 2005 in countries including the US. Isolates
were collected from adults and children who had hospital- or
community-associated uncomplicated SSSIs, including impetigo, with
only one isolate taken from each
subject2.
In addition to implying that Altabax is effective against all
S. aureus strains, this description implies that Altabax
is effective at treating uncomplicated SSSIs other than impetigo.
This presentation is particularly concerning considering that
Altabax is not approved for any other uncomplicated SSSIs and
received a non-approval for the uncomplicated SSSIs indications of
secondarily infected traumatic lesions (SITL) and secondarily
infected dermatoses (SID). Furthermore, in clinical trials for
SITL, Altabax in vitro susceptibility did not correlate
with clinical success rates in patients with methicillin-resistant
S. aureus (MRSA).
Similarly, the other presentations cited above in the slim jim
contain prominent claims about the drug’s efficacy in
targeting S. aureus and suggest the drug is effective at
treating all strains of S. aureus. However, Altabax is
only approved to treat impetigo due to methicillin
susceptible isolates of Staphylococcus aureus.
(emphasis added) Any implication that Altabax could be effective
against other organisms, such as MRSA, is extremely concerning from
a public health perspective as it could lead to irreparable harm in
patients denied effective therapy.
We note that the approved indication for Altabax and the
footnote, “Methicillin-susceptible isolates only,” are
presented at the bottom of pages one and four of the slim jim in
small font in single-spaced block paragraph format. However, these
disclosures are not sufficient to overcome the misleading
impression created by the totality of the prominent claims and
presentations in the piece that suggest that Altabax is effective
against any strain of S. aureus.
Furthermore, especially when viewed in the context of the
numerous other claims in the slim jim that otherwise broaden
Altabax’s indication, the claim cited above that Altabax
“was just as active in vitro against S.
aureus resistant to mupirocin” misleadingly suggests
that Altabax is effective in treating infections caused by strains
of S. aureus that are resistant to mupirocin, when this
has not been demonstrated by substantial evidence or substantial
clinical experience. The reference2 cited
in support of this claim only presents comparisons of in
vitro data. As the slim jim itself notes at the bottom of page
two, in vitro data do not necessarily predict or correlate
with clinical efficacy. Accordingly, in vitro data, which
have limited, if any, utility for healthcare practitioners with
respect to their clinical experience with a drug, is insufficient
to support such a claim. However, the presentation of this in
vitro data to practicing clinicians (the ad’s intended
audience), particularly in the context of the overall impression
created by the ad, misleadingly implies that the cited in
vitro data are clinically relevant. That is, the presentation
of this in vitro data in the slim jim to practicing
clinicians misleadingly implies that Altabax is clinically
effective in treating infections caused by mupirocin-resistant
S. aureus. We are not aware of substantial evidence or
substantial clinical experience to support the implication that
Altabax is effective against strains of S. aureus that are
resistant to mupirocin. We note the inclusion of the statement,
“In vitro results do not necessarily correlate with
clinical efficacy,” at the bottom of page two. However, this
inclusion does not mitigate the misleading suggestion conveyed by
the above claim, by itself and in the context of the other claims
in the slim jim, that Altabax will be clinically effective against
infections caused by S. aureus strains that are resistant
to mupirocin.
The slim jim also includes the following claims and
presentations, which compare Altabax to mupirocin (footnotes
omitted):
• Table comparing the mechanism
of action of Altabax against that of Bactroban Ointment (mupirocin)
(page 2)
• “…and ALTABAX has a longer postantibiotic
effect than mupirocin in vitro” (page 2)
• Table comparing the number of applications per course of
therapy for Altabax against that of Bactroban Ointment (pages 3 and
5)
These claims and presentations are misleading because they imply
that Altabax is a safe and effective alternative to Bactroban
Ointment (mupirocin) for the conditions and causative pathogens
that mupirocin is indicated to treat, when this is not the case.
Mupirocin ointment is indicated for the topical treatment of
impetigo due to: S. aureus and S. pyogenes.
However, unlike Altabax’s impetigo indication, the indication
for mupirocin does not include limitations on specific
microorganisms. Altabax is only indicated to treat “impetigo
due to Staphylococcus aureus (methicillin-susceptible
isolates only) or Streptococcus pyogenes.”
(emphasis added) Therefore, these claims misleadingly broaden the
indication of Altabax.
Unsubstantiated Superiority Claims
The slim jim contains multiple claims regarding the superior
potency of Altabax over mupirocin. These claims include the
following (footnotes omitted):
• Bar graph entitled,
“ALTABAX is more potent in vitro than mupirocin. . .
,” which compares the MIC90 (μg/mL) of Altabax to
mupirocin (page 2)
• “32x more potent in vitro. . .and ALTABAX was
just as active in vitro against S. aureus
resistant to mupirocin (ALTABAX MIC90 remained at 0.12
μg/mL)” (page 2)
• “ALTABAX is 32x more potent in vitro than
mupirocin against S. aureus” (pages 3 and 5)
Taken together, the totality of these presentations implies that
Altabax is a more effective agent for treating impetigo than
mupirocin. However, the reference2 cited
in support of these presentations does not present a head-to-head
clinical comparison of Altabax to mupirocin. The reference presents
comparisons of in vitro data only. As noted above, in
vitro data do not necessarily predict clinical efficacy.
Additionally, the cited study2 tested
isolates obtained from multiple countries. These data are not
sufficient to predict and compare in vitro activity of
topical antibacterials against isolates solely encountered in U.S.
environments. Furthermore, the cited study2 tested
isolates obtained between March 2004 and March 2005. Because there
is a correlation between increases in exposure to antibiotics and
resistance patterns, these data may not reflect the current in
vitro resistance profile of Altabax. We are not aware of
substantial evidence or substantial clinical experience to support
the implication created by this slim jim that Altabax is superior
to mupirocin for the treatment of impetigo.
In addition, the slim jim includes the following claims and
presentations, which suggest that Altabax is clinically superior to
mupirocin in terms of resistance (footnotes omitted):
• “ALTABAX has a low propensity to develop resistance in an in vitro multipassage study” (pages 2, 3, and 5)
o Bar graph which compares the percentage of S. aureus isolates with a MIC of ≤ 2 μg/mL after ≤ 20 days between Altabax and mupirocin. The graph shows that Altabax has 100% of isolates with a MIC of ≤ 2 μg/mL after ≤ 20 days and mupirocin has 0% of isolates with a MIC of ≤ 2 μg/mL after ≤ 20 days (page 2)
• “ALTABAX demonstrated a
lower potential to develop resistance” (page 2)
• “Mupirocin demonstrated a higher potential to develop
resistance” (page 2)
• “Resistance to mupirocin occurred as early as Day
4” (page 2)
The above claims create an overall impression that Altabax is
associated with less resistance than mupirocin in clinical
practice. The FDA is not aware of substantial evidence or
substantial clinical experience to support claims that Altabax has
(or will have) a lower propensity to develop resistance than
mupirocin. These claims rely on in vitro
data3 for support. However, in
vitro data are not substantial evidence to support a claim of
less resistance for Altabax. Furthermore, the PI for Altabax
includes a Warning and Precaution regarding the potential
development of drug resistance. The PI states, “Prescribing
ALTABAX in the absence of a proven or strongly suspected bacterial
infection is unlikely to provide benefit to the patient and
increases the risk of development of drug-resistant
bacteria.” The implication that Altabax has less resistance
is especially concerning in light of the slim jim’s
suggestion that Altabax is safe and effective for the treatment of
all strains of S. aureus, when this is not the case.
Finally, the slim jim includes the following claims and
presentations, which suggest that Altabax has a superior mechanism
of action to other antibacterials, including Bactroban (footnotes
omitted):
• “Not all topical
antibiotics agents are the same. . .” (page 2)
• “ALTABAX is the first in a new and different class of
prescription antibacterials – the
pleuromutilins” (page 2)
• Table comparing the mechanism of action of Altabax to
Bactroban Ointment (mupirocin) (page 2)
These claims misleadingly imply that Altabax is clinically
superior to mupirocin because Altabax affects three aspects of
protein synthesis while Bactroban Ointment (mupirocin) affects only
one aspect of protein synthesis. However, there is no evidence that
interference with more than one aspect of protein synthesis results
in greater clinical efficacy. Furthermore, the FDA is not aware of
adequate and well-controlled head-to-head clinical trials that
compare the clinical efficacy of Altabax and Bactroban Ointment
and/or any other mupirocin products. Altabax was only shown to be
superior to placebo (vehicle) in a clinical efficacy study in
patients with impetigo due to Staphylococcus aureus
(methicillin-susceptible isolates only) or Streptococcus
pyogenes in patients aged 9 months or older.
Furthermore, page two of the slim jim contains the claim,
“. . . and ALTABAX has a longer postantibiotic effect than
mupirocin in vitro.” This claim is misleading
because it implies that Altabax is clinically superior to mupirocin
because of a longer post-antibiotic effect, when this has not been
demonstrated by substantial evidence or substantial clinical
experience. As discussed above, in vitro data do not
necessarily correlate to clinical efficacy, and it is misleading to
use such data to imply any clinical effect. Post-antibiotic effect
(PAE) is typically defined as the continued suppression of
bacterial growth after administration of a systemic antibiotic has
ceased and the serum concentration of the drug has fallen below the
MIC. It is a characteristic of the metabolism of systemic
antibiotics. The clinical significance of PAE for topical
antibiotics, such as Altabax, is unclear.
The misleading nature of these claims is amplified by the
overall impression created by the slim jim that Altabax is superior
to mupirocin. We note that the footnotes, “In vitro
results do not necessarily correlate with clinical efficacy,”
and “The effectiveness of ALTABAX versus mupirocin has not
been studied in a clinical trial,” are presented at the
bottom of pages two, three, and five of the slim jim. However,
these footnotes are not sufficient to mitigate the misleading
impression created by the totality of the prominent claims and
presentations in the piece, which convey that Altabax has a
superior resistance profile, greater potency, and superior
mechanism of action to mupirocin, and suggest it is therefore
clinically superior to mupirocin.
In summary, the FDA is unaware of any data demonstrating the
superior efficacy of Altabax to mupirocin for the treatment of
impetigo, such as data showing Altabax to (1) be more potent; (2)
have less resistance; (3) have a superior mechanism of action; or
(4) have a longer post-antibiotic effect than mupirocin. In the
absence of adequate and well-controlled head-to-head clinical
studies of Altabax versus mupirocin demonstrating the superiority
of Altabax, these claims and presentations are misleading.
Omission and Minimization of Risk
Promotional materials are misleading if they fail to reveal
facts that are material in light of the representations made or
with respect to the consequences that may result from the use of
the drug as recommended or suggested in the materials. The only
risk disclosure presented for Altabax in the slim jim is the most
common drug-related adverse reaction, which is found at the bottom
of page three written in small font size in single-spaced block
paragraph format and on page four. However, the slim jim
misleadingly fails to communicate any of the Warnings and
Precautions for Altabax. The omission of the Warning and Precaution
information regarding the potential development of drug resistance
is particularly concerning given the numerous misleading claims in
the piece implying Altabax is effective against strains of S.
aureus it is not indicated to treat and implying Altabax is
associated with very low resistance.
Conclusion and Requested Action
For the reasons discussed above, the slim jim misbrands Altabax
in violation of the Act, 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR
202.1(e)(3)(i), (ii); (e)(5); (e)(6)(i), (ii), (vii), &
(xviii); (e)(7)(viii).
DDMAC requests that GSK immediately cease the dissemination of
violative promotional materials for Altabax such as those described
above. Please submit a written response to this letter on or before
May 3, 2010, stating whether you intend to comply with this
request, listing all promotional materials (with the 2253
submission date) for Altabax that contain violations such as those
described above, and explaining your plan for discontinuing use of
such violative materials. Because the violations described above
are serious, we request, further, that your submission include a
comprehensive plan of action to disseminate truthful,
non-misleading, and complete corrective messages about the issues
discussed in this letter to the audience(s) that received the
violative promotional 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 facsimile at 301-847-8444. In all future correspondence
regarding this matter, please refer to MACMIS ID #18333, in
addition to the NDA number. We remind you that only written
communications are considered official. If you choose to revise
your promotional materials, DDMAC is willing to assist you with
your revised materials by commenting on your revisions before you
use them in promotion.
The violations discussed in this letter do not necessarily
constitute an exhaustive list. It is your responsibility to ensure
that your promotional materials for Altabax comply with each
applicable requirement of the Act and FDA implementing
regulations.
Failure to correct the violations discussed above may result in
FDA regulatory action, including seizure or injunction, without
further notice.
Sincerely
/S/
Thomas W. Abrams, RPh, MBA
Director
Division of Drug Marketing,
Advertising, and Communications
_________________________________________________
1 Please note that for the purpose of this letter, page one represents the front cover of the slim jim, page two represents the inside spread of the slim jim, page three represents the back cover of the slim jim, and pages four and five represent a tabbed pull-out card that is inserted in a pocket inside the slim jim.
2 Data on file ABX107-01, GlaxoSmithKline.
3 Kosowska-Shick K, Clark C, Credito K, et al. Single- and multistep resistance selection studies on the activity of retapamulin compared to other agents against Staphylococcus aureus and Streptococus pyogenes. Antimicrob Agents Chemother. 2006;50:765-769.
Posted: May 2010
