Client Alert: 2012 OPDP Warning and Untitled Letters

Warning Letters indicated with * by the Date
Bad Ad Program enforcement indicated with † by the Form of Communication
2012 OPDP Warning and Untitled Letters
Date with
Hyperlink Drug and Indications Referenced
to Letter
in Letter
01-09-2012 Gleevec®
For treatment of patients with Kit
(CD117) positive (KIT+)
unresectable and/or metastatic
malignant gastrointestinal stromal
tumors (GIST).
Boxed Form of
Warning Communication
Summary of Alleged Violations
No Case Highlights Overstatement of Efficacy:
o Claims imply that Gleevec 400 mg once daily has been shown to provide
all patients with metastatic KIT+ GIST with progression free survival
lasting 5 years, but the claims are not sufficiently supported because a case
study of one patient’s treatment response does not constitute substantial
evidence.
o Claim implies that only 13% of patients with unresectable or metastatic
GIST treated with Gleevec 400 mg/day experience progressive disease,
which greatly underestimates the number of observed disease progression
events and grossly overstates the efficacy of Gleevec because a combined
analysis of two clinical studies showed that 75% of 818 patients progressed
during the studies.
o Claim implies a clinical benefit that was derived by combining the
percentage of patients achieving a partial response with patients who had
stable disease in a retrospective subgroup analysis, but stable disease is not
considered to be an accurate or valid indicator of therapeutic effect due to
drug therapy in GIST patients.
o Promotional case study is an accurate summary of a patient’s treatment,
but implies that a complete response to therapy is representative of the
typical response that patients may expect, but a selected case study of one
patient’s experience does not constitute substantial evidence and data do
not support the claim.
o Claim is an accurate summary of a patient’s treatment experience, but
implies that Gleevec has been shown to provide all patients with metastatic
KIT+ GIST with disease free survival lasting 3.5 years, but the claim is not
supported by substantial evidence and FDA is unaware of substantial
evidence that Gleevec is effective at controlling other supervening medical
problems.

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
o Disclaimers stating that case study results “are not necessarily
representative and may vary by patient” do not mitigate the misleading
impression of the claims and presentations.
Unsubstantiated Efficacy Claims:
o Claim is an accurate summary of a patient’s experience, but implies that
Gleevec is effective at treating melana without support by substantial
evidence.
02-28-2012 Saphris®
As a monotherapy, for the acute
treatment of manic or mixed
episodes associated with bipolar I
disorder; as an adjunctive therapy
with lithium or valproate, for the
acute treatment of manic or mixed
episodes associated with bipolar I
disorder.
Yes Oral Statements † Promotion of Unapproved Uses:
o Statement made during an oral presentation to a group of healthcare
professionals implies that Saphris is safe and effective for use as an
adjunctive treatment for major depressive disorder when Saphris is not
indicated for this use. The statements suggest a new intended use for
Saphris for which the Product Labeling (PI) lacks adequate directions for
use.
03-06-2012 Atralin
For topical treatment of acne
vulgaris.
No
Direct-to-
Consumer
Website,
Professional
Detail Aid
Unsubstantiated Superiority Claims/Unsubstantiated Claims:
o Claims and presentations in the aid suggest that Atralin’s formulation and
purported greater delivery to the dermis result in superior safety and
efficacy compared to other tretinoin products and that Atralin is more
tolerable than products of similar strength, but FDA is unaware of
substantial evidence for the claims.
o FDA is unaware of evidence demonstrating that Atralin gel has
pharmacological activity in the dermis, and there are no data to support the
notion that in vitro percutaneous absorption data predict or correlate with
comparative clinical efficacy because disease state might affect drug
penetration and bioavailability and the in vitro percutaneous absorption
method is not adequate for assessing comparative in vivo levels clinically
at the dermis for different formulations.
o A small footnote indicating that the clinical significance of in vitro data is
unknown and that differences were not statistically significant does not
correct the misleading impression.
o Claims in the website and aid suggest that Atralin is clinically superior to
other tretinoin formulations because individual ingredients in Atralin’s
vehicle are purported to provide specific clinical benefits such as
moisturizing skin, but this has not been demonstrated in adequate and wellcontrolled
head-to-head clinical trials comparing appropriate doses and
2

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
dose regimens of the subject drugs, and the PI includes statements about
dry skin in patients.
o A statement that the contribution of the individual components of the
vehicle have not been evaluated does not mitigate the misleading
impression.
Overstatement of Efficacy:
o Website claim suggesting that Atralin has specific demonstrated efficacy in
treating “rough” or severe acne is not supported by substantial evidence.
o Aid selectively presents more favorable lesion reduction data from
registration trials while failing to include less favorable Global Severity
Score Success Data, which was also a primary endpoint in trials.
Omission and Minimization of Risk Information:
o Website implies that patients are likely to “stick” with their treatment
because there is a “low potential of skin irritation” associated with use
when this is not the case. Website omits material facts about the possible
duration and/or severity of skin-related adverse reactions and the potential
need for discontinuation of the drug, and the PI warns about skin irritation
and lists skin-related reactions as the most common adverse reactions.
o Characterizing skin-related reactions as “mild to moderate irritation of the
skin” fails to adequately communicate the specific types of skin irritation
associated with use of Atralin.
o Website and detail aid completely omit warning regarding fish allergies.
Unsubstantiated Claims:
o
o
o
Claims and schematic in the aid suggest that Atralin’s micronized
formulation confers a beneficial effect on product safety and/or efficacy by
enabling the majority of tretinoin particles to enter follicles when this has
not been demonstrated. The cited reference does not provide evidence that
tretinoin enters the follicles and provides information on healthy skin.
Disclaimer that the clinical significance of micronization is unknown is
insufficient to correct the misleading impression.
Claim suggesting that patients will experience improvement in satisfaction
with self-appearance after using Atralin is not supported by the cited
analysis because the analysis did not reveal any statistically significant
differences between treatments groups in relevant domains and the study
was not adequately designed to evaluate individual components of the
overall composite score.
03-14-2012* Copaxone®
For reduction of the frequency of
No
Professional
Exhibit Panels,
3
Overstatement of Efficacy/Unsubstantiated Claims:
o Panel presentations imply that the drug has proven long term safety and

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
relapses in patients with Relapsing-
Remitting Multiple Sclerosis
(RRMS), including patients who
have experienced a first clinical
episode and have PRI features
consistent with multiple sclerosis.
Boxed
Warning
Form of
Communication
Webpages
Summary of Alleged Violations
efficacy, but the PI only includes data for up to three years in duration.
The exhibit panels refer to open-label extension studies that do not account
for self-selection among patients who chose to participate in the studies,
and it is unclear why certain patients dropped out or were lost to follow-up.
o Claim suggests that Copaxone is superior to other RRMS therapies when
FDA is unaware of support for the claim.
Overstatement of Efficacy/Broadening of Claims:
o Webpage claims imply that Copaxone reverses patients’ disability and
enables them to lead active and regular lifestyles, which may accurately
reflect patients’ experiences, but Copaxone is not indicated for slowing,
preventing, or reversing physical disability associated with RRMS and
FDA is not aware of substantial evidence or experience supporting the
implication that treatment will result in the magnitude of effects described
in the testimonials. Highlights of other MS patients treated with Copaxone
and their subsequent athletic accomplishments are similarly misleading.
o Statement that individual results may vary does not mitigate the misleading
impressions and personal experiences of patients.
o The totality of the presentation implies that Copaxone is approved to treat
all types of MS when this is not the case.
o Webpages suggest ongoing treatment and imply that Copaxone is effective
for reducing the frequency of relapses or exacerbations for a period of time
beyond the three years that data in the PI covers.
o Panels suggest that 82% of patients on Copaxone were able to walk
independently, but the open-label study cited for the claim does not
constitute substantial evidence and the claim misleadingly suggests that
Copaxone prevents the progression of disability.
o A statement on the exhibit panel that Copaxone does not include an
indication for slowing progression of disability is not sufficient to mitigate
the misleading representations.
Omission of Risk Information:
o Webpages and patient testimonials include numerous claims regarding the
benefits of Copaxone, but fail to include any risk information associated
with the drug in the body of the webpages and testimonials.
o Links to “Important Safety Information” and the full PI does not mitigate
the omission of risk information from the webpages.
Omission and Minimization of Risk Information/Unsubstantiated
Superiority Presentation:
o Table on panel listing only three risks of Copaxone, numerous risks not
associated with Copaxone, and a claim that Copaxone has no warnings or
4

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
o
o
Summary of Alleged Violations
precautions for the adverse events suggests that Copaxone is safer than has
been demonstrated and implies that it is safer than other treatments for
RRMS. The PI does not list the other risks, but that does not mean that
such risks are not associated with the drug.
Presentation omits material information about other attributes of Copaxone
therapy that are highly relevant to any decision about whether to prescribe
Copaxone, including contraindications, warnings, and other serious risks
such as injection site reactions.
Panel claim that no initial or routine monitoring is required or
recommended suggests that Copaxone is a better and safer treatment than
other options for RMMS because it is the only one not requiring initial or
routine monitoring, but a comparison of other attributes of the products and
other material facts may be necessary in the context of the comparative
presentation even though the monitoring recommendations are consistent
with the product PIs.
Omission of Material Facts:
o
Panel presentation of a relative risk reduction is misleading because it
omits material facts regarding actual relapse rates for Copaxone and
placebo.
5

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink Drug and Indications Referenced
to Letter
in Letter
03-14-2012 Avonex®
For the treatment of patients with
relapsing forms of multiple
sclerosis to slow the accumulation
of physical disability and decrease
the frequency of clinical
exacerbations.
Boxed
Warning
No
Form of
Communication
Direct-to-
Consumer
Webpages
Summary of Alleged Violations
Overstatement of Efficacy:
o Webpage implies that Avonex will enable 80% of patients with relapsing
forms of multiple sclerosis to stay active and able for 10 years when
clinical studies in the PI only support efficacy for up to 3 years. The openlabel
follow-up study cited on the webpage is not substantial support.
o Statement that FDA-approved labeling includes up to 3 years of clinical
data does not mitigate the misleading impression.
o Presentation implies that Avonex is effective for each of the individual
functional areas of the Expanded Disability Status Scale (EDSS) listed on
the webpage, but the study in the PI evaluated impact on total EDSS score,
not each individual functional area.
Omission of Material Information/Unsubstantiated Superiority
Presentation:
o Webpage implies that Avonex is superior to other multiple sclerosis drugs
based on the selected attributes presented in the webpage that are
consistent with the products’ PIs, but the page fails to present information
about other attributes associated with the drugs, such as contraindications,
serious warnings and precautions, and laboratory test monitoring.
o Some safety information for Avonex is presented on the webpage, but
inclusion of the information in small font at the bottom of the page does
not mitigate the misleading impression.
03-30-2012 Firmagon®
For treatment of patients with
advanced prostate cancer.
No iPad Sales Aid Unapproved New Use:
o Aid suggests new intended uses for Firmagon as a neojuvant therapy
before local treatment and as treatment for patients with a rising prostate
specific antigen (PSA). Firmagon has a general indication for treatment of
advanced prostate cancer, but it has not been approved or evaluated by
FDA as a neojuvant therapy or as a treatment for rising PSA.
Overstatement of Efficacy:
o Claims suggest that the velocity of PSA reduction is clinically meaningful
for patients with advanced prostate cancer, which is not supported by
substantial evidence or experience.
o Statement that PSA results should be interpreted with caution and that
there is no evidence to show that rapidity of PSA decline is related to
clinical benefit does not mitigate the misleading impression.
o Claims suggest that the reduction in risk of PSA recurrence is clinically
meaningful or associated with improved disease control or survival when
this has not been demonstrated. Also, PSA levels were monitored as a
secondary endpoint in the pivotal study and the referenced study was an
6

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
exploratory subgroup analysis of the pivotal study that does not constitute
substantial evidence.
04-13-2012 Angiomax®
For use with aspirin: as an
anticoagulant in patients with
unstable angina undergoing
percutaneous transluminal
coronary angioplasty (PTCA); with
provisional use of glycoprotein
IIb/IIIa inhibitor (GPI) as listed in
the REPLACE-2 trial as an
anticoagulant in patients
undergoing percutaneous coronary
intervention (PCI); for patients
with, or at risk of, heparin induced
thrombocytopenia or heparin
induced thrombocytopenia and
thrombosis syndrome undergoing
PCI.
No Booth Panel Omission of Risk Information:
o Panel completely omits the warning and precaution regarding coronary
artery brachytherapy and fails to include important material information
regarding the risk of bleeding events.
o Panel fails to convey that the most common adverse event associated with
Angiomax is bleeding.
o Statement directing viewers to the exhibit representative for full
prescribing information does not mitigate the omission of risk information.
Unsubstantiated Superiority Claims:
o Totality of claims and presentations misleadingly implies that Angiomax is
more effective than heparin with or without GPI for patients with stable
angina, unstable angina, NSTEM, and STEMI who are undergoing PCI,
when this has not been demonstrated.
o A study cited by the panel contains ex vivo findings, which do not correlate
with claims of clinical benefit, so the study is not substantial evidence.
o Panel cites a non-inferiority trial, which is not designed to demonstrate
superiority over other agents, and in fact, the study failed to show noninferiority
when analyzed for the endpoint of death or myocardial
infarction at 30 days.
o Two studies cited by the panel were confounded by the administration of
other anti-thrombin agents prior to the randomized study drugs. One cited
study is a reanalysis of a trial that only included patients undergoing PTCA
and does not constitute substantial evidence, while two other studies are
review articles that do not mention Angiomax.
o Panel cites a clinical study included in the PI that was a non-inferiority
trial, so it was not designed to demonstrate superiority over other agents.
04-26-2012 Astepro®
For the relief of the symptoms of
seasonal and perennial allergic
rhinitis in patients 12 years of age
and older.
No
Professional
Telephone Script
7
Omission of Risk Information:
o Script includes efficacy claims, but entirely omits all risk information
associated with use of Astepro.
o Script indicates that the purpose of the call is to share the benefits of and
important safety information for Astepro and that sales representatives
should follow the appropriate procedures for adverse events, but these
statements do not mitigate the misleading presentation.
Overstatement of Efficacy:
o Script implies that Astepro is effective in the treatment of the specific

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
symptom of nasal congestion when that has not been demonstrated because
clinical studies assessed a composite measure of nasal symptoms and not
individual symptoms.
o Script implies that the clinical symptom of allergic rhinitis will be relieved
“rapidly” and “within 30 to 45 minutes” of the administration of the drug,
but FDA is not aware of substantial evidence and clinical experience to
support the claim.
Failure to Fulfill “Adequate Provision” Requirement:
o Script fails to either present a brief summary of required information or
make adequate provision for dissemination of the PI.
05-24-2012* EpiPen® and EpiPen® Jr.
For the emergency treatment of
allergic reactions (Type I)
including anaphylaxis to…
allergens, as well as idiopathic
anaphylaxis and exercise-induced
anaphylaxis.
No
Direct-to-
Consumer
Broadcast
Television
Advertisement †
Overstatement of Efficacy:
o The overwhelming impression of the presentation in the ad implies that
EpiPen alone obviates the need for taking precautionary measures and
provides protection against any potential risks due to exposure to an
allergen when this has not been demonstrated and the PI states that the
EpiPen is emergency supportive therapy.
o Statement that EpiPen cannot eliminate the risk of anaphylaxis does not
mitigate the overall misleading impression.
8

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink Drug and Indications Referenced
to Letter
in Letter
05-25-2012 Incivek
For the treatment of genotype 1
chronic hepatitis C in adult patients
with compensated liver disease,
including cirrhosis, who are
treatment-naïve or who have
previously been treated with
interferon-based treatment,
including prior null responders,
partial responders, and relapsers.
06-07-2012 Sodium Ferric Gluconate
Complex in Sucrose
For treatment of iron deficiency
anemia in adult patients and in
pediatric patients aged 6 years and
older undergoing chronic
hemodialysis who are receiving
supplemental epoetin therapy.
Boxed Form of
Warning Communication
Summary of Alleged Violations
No Branded Story Overstatement of Efficacy:
o Claims may be an accurate reflection of the patient’s own experience, but
story implies that most or all cirrhotic prior null responders infected with
hepatitis C will successfully achieve Sustained Virologic Response (SVR)
on Incivek combination therapy, but one patient’s treatment response does
not constitute substantial evidence for this claim, clinical trials do not
support this misleading impression, and the PI states that a high proportion
of previous null responders with cirrhosis did not achieve SVR.
o Claims overstate efficacy by suggesting that the usual outcome of
treatment is a positive effect on the patient’s interpersonal relationships,
physical functioning, work productivity, and overall quality of life, but
FDA is not aware of substantial evidence or clinical experience to support
these claims.
Omission of Material Fact:
o Claims of patients “clear[ing]” the virus implies removal of the hepatitis C
virus (HCV) from the body when this is not the case because patients with
undetectable HC-RNA levels after therapy may still have replication
competent virus.
Minimization of Risk Information:
o Story minimizes the risk of rash and alopecia associated with Incivek
combination therapy because it suggests that a rash is not a serious side
effect when this is not the case and serious skin reactions have been
reported in patients.
o Accompanying the story with a slide deck of important safety information
does not mitigate the misleading minimization of risk information
regarding rash.
o The PI warns that Incivek must not be administered as a monotherapy and
must only be prescribed with both peginterferon alfa and ribavirin, for
which alopecia is a common adverse reaction, so implication that the side
effect is “nothing” minimizes the risk.
No Journal Ad Unsubstantiated Claims:
o Claims suggest that sodium ferric gluconate has been proven to reduce the
need for erythropoiesis-stimulating agents (ESA) during treatment, but
reduced ESA dose requirements can be due to multiple confounding
factors, making it difficult to identify the specific cause for any reductions
in ESA dosing, so epoetin dose reduction is not a valid or appropriate
endpoint for assessing the truth efficacy of sodium ferric gluconate.
o The cited reference is not sufficient support because it discusses a
9

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
o
o
o
o
o
Summary of Alleged Violations
nonrandomized, uncontrolled clinical trial performed in hemodialysis
patients, and it is unclear how the study defined endpoints or assessed
efficacy parameters.
Claims suggest the addition of sodium ferric gluconate to ESA therapy will
result in a significant cost savings compared to ESA therapy alone due to
the ability of sodium ferric gluconate to improve patients’ response to ESA
therapy over 12 weeks compared to ESA therapy alone, but the claims are
not supported by substantial evidence. One cited study was an open-label,
randomized, controlled trial that primarily assessed the change in Hb level
from baseline and cannot support the 12 week endpoint, and the other
study was a 6-week observational extension of the first study designed to
investigate the extended effects of intravenous ferric gluconate on ESA
dosage under usual clinical management, so adjustments to ESA and
intravenous iron therapy were unrestricted and left to the discretion of the
individual clinicians or study sites.
Statements imply that treatment plus ESAs will have a positive impact on
all aspects of treatment costs compared to treatment with ESAs alone, but
the cited reference does not support these global conclusions because the
studies were not designed to demonstrate the underlying clinical efficacy
premise necessary to support the claim, and the study describes an
economic model that only evaluated drug acquisition costs and costs
associated with hospitalizations.
Disclaimer that the economic model only included drugs and
hospitalizations due to serious adverse events does not correct the overall
misleading impression.
Ad suggests that cost savings is applicable to the general patient population
for which sodium ferric gluconate is indicated when the referenced
economic model was based on a specific subgroup of hemodialysis patients
with iron deficiency anemia undergoing chronic hemodialysis who receive
supplemental ESA therapy.
Footnote describing patients in the model is not adequate to mitigate the
overall misleading impression.
06-07-2012 Kepivance®
To decrease the incidence and
duration of severe oral mucositis in
patients with hematologic
malignancies receiving myelotoxic
therapy requiring hematopoietic
No Webpage Omission of Risk Information:
o Webpage contains claims regarding reduction in the direction of severe
oral mucositis, reduction in the incidence of severe grades of oral
mucositis, and positive impact on patient reported outcomes and associated
measures, but omits important risk information about the drug regarding
the potential for stimulation of tumor growth and drug interactions.
10

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
stem cell support. o Links to the PI and Kepivance Safety & Tolerability section of the website
are not sufficient to overcome the misleading impression of the omissions.
o Webpage omits the incidences of the most common adverse reactions.
Misleading Efficacy Claims:
o Claims and presentations imply that treatment in patients with severe oral
mucositis will improve a patient’s ability to eat, drink, swallow, and talk,
but the studies cited to support the claim do not constitute substantial
evidence because the questionnaire in the studies has not been established
for assessing the underlying concepts.
o FDA is not aware of substantial evidence supporting Kepivance’s impact
on all sequelae of oral mucositis.
o Claim implies that treatment with Kepivance will result in decreases in
duration of opioid use and reduction in the need for total parenteral
nutrition (TPN), but the study cited did not examine the duration of opioid
use and the incidence of TPN use as pre-specified endpoints.
06-19-2012 Zmax®
For the treatment of mild to
moderate infections caused by
susceptible isolates of the
designated microorganisms in the
specific conditions listed below:
(1) Acute bacterial sinusitis in
adults due to Haemophilus
influenzae, Moraxella catarrhalis,
or Streptococcus pneumoniae; (2)
Community-acquired pneumonia
in adults and pediatric patients six
months of age or older due to
Chlamydiphila, Haemophilus
influenzae, Mycoplasma
pneumoniae, or Streptococcus
pneumoniae, in patients
appropriate for oral therapy.
No Brochure Omission/Minimization of Risk Information:
o Brochure contains information regarding most commonly reported adverse
events, but fails to include information regarding the important risk of QT
prolongation associated with Zmax use.
o Brochure fails to disclose that severe and fatal allergic and skin reactions
have been observed with azithromycin.
o The brochure advises patients to seek emergency help if certain symptoms
develop, but fails to disclose the severity of potentially fatal allergic
reactions, including recurrence of allergic symptoms even when the drug is
discontinued, which misleadingly minimizes the risks of Zmax.
o Brochure presents efficacy claims in large, bolded, colorful font and
graphics surrounded by significant white space, while risk information is
minimized by being placed in block format in obscure locations without
headers or signals.
o Statement advising readers to see the full attached PI does not mitigate the
misleading risk presentation.
Unsubstantiated Safety Superiority Claim/Minimization of Risk
Information:
o Claims imply that Zmax demonstrates a superior safety profile when
compared to other antibiotics due to the supposed superior tolerability of
the drug, but FDA is not aware of adequate support for the claim.
o Suggestion that pediatric patients will necessarily tolerate Zmax minimizes
the risk of gastrointestinal adverse events that may occur while using the
11

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
12
Summary of Alleged Violations
drug product, especially because the PI contains a Warning and Precaution
regarding gastrointestinal disturbances.
Omission of Material Facts:
o Brochure omits important information regarding the required course of
action in the event that a patient vomits after administration of the drug.
o Brochure suggests that Zmax demonstrates similar efficacy when
compared to a wide array of antibiotics when this is not supported by
substantial evidence or experience.
Broadening of Indication:
o
Brochure implies that Zmax is indicated to treat types of infections other
than acute bacterial sinusitis and community-acquired pneumonia by using
the word, “including,” after “certain infections” when Zmax is indicated to
treat specific conditions.
o Totality of brochure presentation suggests that Zmax is approved to treat
any conditions associated with a list of symptoms, including viral
infections that cause influenza or the common cold, when this has not been
demonstrated and the PI states that Zmax only works against bacteria.
Unsubstantiated Superiority Claim:
o
Claims suggest that Zmax is clinically superior to other antibiotics because
of its “1 day, 1 dose” dosage regimen, but clinical studies only
demonstrated that Zmax was non-inferior to other dosage regimens for
other antibiotics, so the claim is not supported by substantial evidence.
Misleading Efficacy Claims:
o
Brochure presentation misleadingly suggests that Zmax demonstrates
clinically significant efficacy for a period of time not demonstrated in
clinical trials. Clinical trials included evaluations 7 to 14 days post
treatment, but because Zmax is only administered one time as a single
dose, it is unclear exactly how long the extent of the therapeutic benefit is
maintained, so suggestion that the clinical effect lasts for 10 days following
administration is misleading.
Unsubstantiated Claims:
o
o
Claims suggest that adult patients and parents of pediatric patients would
take Zmax again if they were to have the same infection, but the telephone
survey responses used to support the claim are not sufficient support for
the outcomes claimed because the survey cannot adequately assess all
factors that may influence decisions to take any particular treatment again.
Claim suggests that treatment is “much easier” to complete as compared to
other antibiotic products, but the question used to support this claim is not
sufficient because it does not assess whether the effects of the drug,

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
combined with its risks, translate into an overall “easier” treatment
compared to other options.
06-21-2012 Xenazine®
For the treatment of chorea
associated with Huntington’s
disease (HD).
Yes
Patient
Assessment
Video, Webpage
Overstatement of Efficacy:
o Video before and after presentations suggest that treatment with Xenazine
will lead to significant improvements in balance, walking, and postural
stability in patients with HD, but Xenazine has only been demonstrated to
improve the Total Chorea Score in studies and not other symptoms such as
balance, walking, or postural stability.
o Statement that Xenazine does not cure the cause of HD chorea or treat
other symptoms of HD and that individual results may vary does not
mitigate the misleading presentation.
Omission of Material Facts:
o Video fails to communicate the recommended starting and maximum dose
of Xenazine, the frequency of administration, dosing recommendations for
extensive, intermediate, and poor metabolizers of CYP2D6, and dosing
considerations for those who take strong CYP2D6 inhibitors.
o Inclusion of limited dosing information and a link to dosing information
does not correct the misleading omission of material information.
Omission and Minimization of Risk Information:
o Video fails to convey any risks associated with Xenazine during the audiovideo
presentation.
o The webpage containing the video presents some risk information, but the
information is at the bottom of the webpage below the video in read-only
text format, where it is unlikely to draw attention, so the presentation fails
to convey important risk information with a prominence and readability
reasonably comparable to the claims of effectiveness.
o Webpage where the video is located completely omits the risk of clinical
worsening and adverse effects associated with Xenazine and the increased
risk of somnolence and sedation with concomitant use of alcohol or other
sedating drugs.
o Webpage minimizes the risks of Neuroleptic Malignant Syndrome,
akathisia, agitation, parkinsonism, and dysphagia associated with Xenazine
by failing to include important material information about these Warnings
and Precautions.
06-21-2012 Ampyra®
For treatment to improve walking
in patients with multiple sclerosis
No Video Segment Overstatement of Efficacy:
o Video statements may be accurate reflections of a patient’s own
experience, but they imply that Ampyra treatment results in patients being
13

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
(MS).
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
able to walk longer distances with decreased use of assistive devices, but
clinical studies do not indicate whether the observed change in walking
speed in patients supports this claim.
o Claims and images suggest that treatment can have a positive impact on the
disability caused by MS such that patients can carry out daily activities that
they may have stopped due to difficulty walking, but poll results do not
constitute substantial evidence supporting this claim.
Minimization of Risk Information:
o Video minimizes the risks of Ampyra by failing to convey significant risk
information during the patient interview and presenting the majority of risk
information to a running telescript format with rapidly scrolling, small text.
o Video statement implies that patients who experience adverse events such
as paresthesia and insomnia “will get used to it” and such events will
disappear within a month, but FDA is not aware of substantial evidence or
experience supporting this claim.
06-25-2012 Equetro®
For treatment of acute manic and
mixed episodes associated with
Bipolar I Disorder.
Yes
Professional
Webpages
Omission/Minimization of Risk Information:
o Webpages entirely omit all risk information from the Contraindications and
Precautions section of the PI, as well as certain warning information.
o Statement referring readers to the full PI does not mitigate the omission of
important risk information.
o Webpages fail to include important material facts regarding the increased
risk of suicidal behaviors and ideation associated with use of the drug.
o Webpages misleadingly claim that anti-epileptic drugs “may increase” the
risk of suicidal thoughts or behaviors when the PI indicates that a direct
relationship between such drugs and suicidal behavior and ideation has
been determined.
Unsubstantiated Claims:
o Claims suggest that patients treated with Equetro will experience no weight
gain when this has not been demonstrated and data from pivotal trials
clearly demonstrate a weight increase in patients during Equetro treatment.
o Webpage presents an open-label extension study in support of no weight
gain claims, but safety data derived from the study do not constitute
substantial evidence and there was a significant drop-out rate in the study.
o Claims and presentations suggest that patients with Bipolar I Disorder
treated with Equetro experience no worsening of depression or depression
symptoms when this has not been demonstrated. The cited study is not
substantial evidence because the depression score used in the study was not
a pre-specified measure and the study itself calls for larger controlled
14

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
studies to assess efficacy.
06-29-2012 Ixempra®
In combination with capecitabine,
for the treatment of metastatic or
locally advanced breast cancer in
patients after failure of an
anthracycline and a taxane; as a
monotherapy, for the treatment of
metastatic or locally advanced
breast cancer in patients after
failure of anthracycline, a taxane,
and capecitabine.
07-18-2012 Zovirax®
For the treatment of recurrent
herpes labialis (cold sores) in
adults and adolescents (12 years of
age and older).
Yes Sales Aid Unsubstantiated Efficacy Claims:
o Sales aid makes claims regarding stable disease, stable disease ≥ 6 months,
and progressive disease, but these claims are not supported by substantial
evidence or experience because these were not pre-specified endpoints in
the pivotal studies.
o Statement that stable disease was a pre-specified analysis and not a prespecified
endpoint is not sufficient to mitigate the misleading implications,
and FDA does not consider stable disease to be a valid endpoint for
measurement of response in these patients because it may reflect in part the
natural history of the disease rather than an effect of the drug.
o Sales aid presents the results of retrospective subgroup analyses performed
using pooled sets of clinical data collected from multiple trials with
differing clinical endpoints. Subgroup analyses of secondary endpoints
from combined clinical studies do not constitute substantial evidence.
Broadening of Indication:
o Claim suggests that prior therapy with capecitabine is optional for all of the
indicated uses, when this is not the case.
o Presentation of Ixempra’s full indication at the bottom of the cover of the
sales aid does not mitigate the misleading impression that Ixempra can be
given as a monotherapy without first having failed treatment with
capecitabine.
No Webpage Overstatement of Efficacy:
o Webpage suggests that Zovirax is proven effective when initiated during
the ulcer or weeping, crust or scabbing, or healing stages of a herpes lesion
when the PI states that therapy should be initiated as soon as possible or
within 1 hour following onset of signs or symptoms.
o Clinical trials in the PI were not designed to evaluate the effectiveness of
Zovirax when treatment is initiated late, and the cited review article does
not constitute substantial evidence.
o Footnote stating that therapy should be initiated as soon as possible and
defining late stages does not mitigate the misleading impression.
Unsubstantiated Superiority Claims:
o Chart and effectiveness claim above imply that Zovirax is clinically
superior to Valtrex due to an extended timeframe of treatment initiation,
but FDA is not aware of substantial evidence or experience to support this
claim.
15

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
08-01-2012 Daliresp®
For treatment to reduce the risk of
Chronic Obstructive Pulmonary
Disease (COPD) exacerbations in
patients with severe COPD
associated with chronic bronchitis
and a history of exacerbations.
No Oral Statements † Broadening of Indication:
o Sales representatives stated in a sales call to a physician’s office that
Daliresp was effective for COPD exacerbations without presenting the
appropriate patient population for the drug. Nor did the representatives
state the limitations of use that Daliresp is not a bronchodilator and is not
indicated for the relief of acute bronchospasms.
Minimization of Risk:
o Sales representatives responded to direct questions regarding the risks of
weight loss and psychiatric events including suicidality in a manner
consistent with the PI, but immediately downplayed the risks with
anecdotal claims regarding other physicians’ experience with the drug and
their lack of reports on any adverse events.
o Sales representative minimized the risk of weight loss by saying it may
actually be beneficial in overweight COPD patients.
08-10-2012 Amyvid®
For Positron Emission
Tomography (PET) imaging of the
brain to estimate β-amyloid
neuritic plaque density in adult
patients with cognitive impairment
who are being evaluated for
Alzheimer’s Disease (AD) and
other causes of cognitive decline.
No
Webpage,
Commercial
Exhibit Image
Misleading Presentation:
o Image presentation suggests that Amyvid PET images can be displayed
and therefore interpreted in color in patients, but the PI states that images
should be displayed and reviewed using a black-white scale.
o The PI does not provide instructions for estimating β-amyloid neuritic
plaque density using a color scale with Amylid, so use of a color PET scan
image is misleading, particularly considering a warning regarding the risk
of image misinterpretation and other errors.
09-18-2012* FazaClo®
For the management of severely ill
schizophrenic patients who fail to
respond adequately to standard
drug treatment for schizophrenia;
for reducing the risk of recurrent
suicidal behavior in patients with
schizophrenia or schizoaffective
disorder who are judged to be at
chronic risk for re-experiencing
suicidal behavior, based on history
and recent clinical state.
Yes
Direct-to-
Consumer Patient
Brochure
16
Omission/Minimization of Risk Information:
o Brochure fails to state that agranulocytosis is a potentially life-threatening
adverse reaction and that patients must have a baseline white blood cell
count and absolute neutrophil count before initiation of treatment, as well
as weekly for 4 weeks following drug discontinuation.
o Brochure fails to state that only after acceptable white blood cell counts
and absolute neutrophil counts have been maintained during the first 6
months of treatment can a patient be monitored every 2 weeks for the next
6 months.
o Statement advises patients to see the enclosed PI and Boxed Warning, but
fails to include material facts about significant risks, such as the fact that
elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk for death and that FazaClo is not approved

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
for use in these patients, among other risks.
o Brochure completely omits other important risks, including all
contraindications, certain warnings, and common adverse reactions.
o Brochure fails to present risk information in a manner reasonably
comparable with the presentation of claims of effectiveness because risk
information is not presented until late in the brochure in a brief, incomplete
disclosure.
o Statements referring patients to the risk disclosure and the full PI are not
sufficient to mitigate the misleading omission.
Broadening of Indication:
o Claim suggests that FazaClo is indicated for the overall treatment of
schizoaffective disorder and its symptoms generally when the PI states that
it is only indicated for reducing the risk of recurrent suicidal behavior in
patients with schizoaffective disorder, not for overall treatment of the
disorder itself.
o Claim fails to adequately define the severely ill patient population for
which FazaClo is approved in the management of treatment-resistant
schizophrenia.
Unsubstantiated Superiority Claims:
o Claim suggests that clozapine is more effective than all other schizophrenia
treatments, but FDA is not aware of substantial evidence supporting this
claim, although FDA acknowledges that clozapine has been demonstrated
to be more effective than chlorpromazine and is the only product currently
approved to treat severely ill schizophrenic patients who fail to respond
adequately to standard drug treatment for schizophrenia.
o Claim suggests that FazaClo is superior to other available treatments for
schizophrenia based on its risk profile, but FDA is not aware of substantial
evidence supporting this claim.
Overstatement of Efficacy:
o Claims imply treatment will improve the specific individual symptoms of
agitation, unusual thoughts, hearing voices, lack of motivation, and lack of
interest in social activities, but a clinical study only demonstrated the
drug’s effect on the composite total scores on psychiatric and global
impression scales, not the individual components of the scales.
o Claim implies that FazaClo will improve a patient’s academic, work, or
social functioning when the clinical study did not measure the effect of the
drug on these areas.
o Claims suggest that treatment will cause symptoms to “disappear” and that
the outcome of treatment is the complete resolution of symptoms in
17

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
patients with treatment-resistant schizophrenia, but the clinical trial used to
demonstrate efficacy of the drug does not support these claims and did not
evaluate the long-term effect of clozapine in patients with treatmentresistant
schizophrenia to determine if patients experienced improvement
with no relapses or tolerability issues that would cause discontinuation of
the drug, or that treatment had a sustained effect or response.
09-25-2012 Vantas®
For the palliative treatment of
advanced prostate cancer.
No
Caregiver
Brochure
Omission of Risk Information:
o Brochure fails to state that paralysis may result from the risk of spinal cord
compression and that patients are at an increased risk of developing
hyperglycemia, diabetes mellitus, myocardial infarction, sudden cardiac
death, and stroke.
10-03-2012 Tarceva®
For the maintenance treatment of
patients with locally advanced or
metastatic non-small cell lung
cancer whose disease has not
progressed after four cycles of
platinum-based first-line
chemotherapy; for the treatment of
patients with locally advanced or
metastatic non-small cell lung
cancer after failure of at least one
prior chemotherapy regimen.
No Visual Aids Misleading Efficacy Claims/Minimization of Risk:
o Presentation drastically overstates efficacy by suggesting that in patients
who develop grade 2+ rash, the addition of Tarceva to gemcitabine
provides an additional 3.7 month overall survival (OS) benefit and that
these patients may have a median OS of 10.7 months when the PI states
that the addition of Tarceva increased survival by approximately 12 days.
o The development of rash and its correlation with OS were not pre-specified
endpoints in the pivotal study and were derived from a retrospective,
exploratory subgroup analysis.
o Presentation portrays the adverse reaction of “rash” as an efficacy predictor
and therefore, a potential benefit to patients, when the PI states that grade
3/4 rash was reported in 5% of patients and resulted in dose reductions and
study discontinuation for some patients.
o Statement that data do not support increasing dosage to cause rash does not
mitigate the misleading impression.
o Claims based on retrospective exploratory analyses of a subgroup of
patients with adenocarcinoma and squamous cell carcinoma do not support
claims about reduction in risk of death because although tumor histology
was collected along with other demographic characteristics during
enrollment, there was a lack of adequate prospective statistical design.
Overstatement of Efficacy:
o Presentation strongly suggests that time is standing still for the cancer
patient because of Tarceva therapy, which drastically overstates the OS
benefit for patients because studies do not support the implication that
Tarceva can slow disease progression and greatly improve survival.
o Claim about extending survival “for moments that matter” suggests a
18

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
quality of life benefit for patients, which was not demonstrated in studies.
o Claims about stable disease and disease control rate imply a clinical benefit
of disease control that has not been demonstrated because the studies in the
PI did not examine these two elements as pre-specified endpoints, and
duration of response was not examined.
Minimization of Risk:
o Aids minimize risks by including important risk information underneath an
efficacy header, and risks are difficult to distinguish from efficacy claims
due to a lack of white space.
o Risk information is presented on the back page in what appears to be a
summary of promotional materials for Tarceva, is limited to five common
adverse reactions, and does not mention any of the serious, potentially fatal
risks associated with use of the drug.
o Footnotes referring the reader to the Important Safety Information do not
mitigate the misleading risk presentation.
10-18-2012 Antineoplastons A10 and AS2-1
Injections
Investigational New Drug with
proposed indication for treatment
of inoperable brainstem glioma.
N/A
Website Press
Releases,
Website Videos
Promotion of an Unapproved New Drug:
o Website press releases and embedded videos claiming that the drug is
“well tolerated,” “work[s] without causing side effects,” and has
demonstrated “remarkable” results suggest that Antineoplastons are safe
and/or effective for the treatment of various types of brain tumors when
they have not been approved for these uses.
10-31-2012 Infasurf®
For the prevention of Respiratory
Distress Syndrome (RDS) in
premature infants at high risk for
RDS and for treatment (“rescue”)
of premature infants who develop
RDS.
No
Professional
Website Video,
Professional
Webpages
19
Unsubstantiated Superiority Claims:
o Claims and presentations imply that Infasurf is clinically superior
compared to other available surfectants when the clinical study in the PI
compared Infasurf to Exosurf Neonatal, which is no longer marketed, and
did not demonstrate that Infasurf was clinically superior to Survanta for
treatment or prophylaxis of RDS.
o Claims and presentations imply that Infasurf is clinically superior to
Survanta and Curosurf due to a more rapid and sustained acute effect on
respiratory function, but the cited references do not support this claim
because the first study measures physiologic data that have not been
demonstrated to correlate with any clinically relevant variables, and the
second study did not include Infasurf as a comparator in the study.
Omission / Minimization of Risk Information:
o Claim completely omits significant common adverse reactions associated
with Infasurf dosing other than cyanosis, airway obstruction, bradycardia,
and ETT reflux.

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
o Links to the PI do not mitigate the misleading omission of important risk
information.
o Video fails to disclose during the audio presentation any risks associated
with use of Infasurf, and the presentation of risks is relegated to the last
seven seconds of the video in read-only text format.
o The webpage containing the video includes risk information, but the
information is relegated to the bottom portion of the webpage below the
video in read-only text format where it is unlikely to draw viewers’
attention.
o Claims that Infasurf is “well-tolerated” minimize serious risks associated
with use of Infasurf.
Unsubstantiated Claims:
o Claims implying that Infasurf has been demonstrated to be “equivalent” to
all other surfectants in terms of the clinical benefit of lowered mortality in
patients with RDS are not supported by substantial evidence or experience.
10-31-2012 Curosurf®
For the treatment (“rescue”) of
Respiratory Distress Syndrome
(RDS) in premature infants.
No
Professional
Pitch Letter with
Press Release
Omission of Risk Information:
o Letter fails to communicate any risk information associated with use of
Curosurf.
Unsubstantiated Superiority Claims:
o Letter and press release imply that Curosurf is superior to two other animal
derived surfactants for reducing the rate of mortality associated with RDS,
but the cited study was a retrospective, observational, cohort study
comparing all-cause, in-hospital mortality in preterm infants with RDS
treated with one of three marketed surfactants. The study is insufficient
support because it did not include a pre-specified efficacy analysis for
comparison of the three products. Database information relied upon for the
study analysis is inadequate because details are not available regarding
precise causes of death, the number of surfactant doses administered, or
concomitant treatment with antenatal steroids.
o The press release discloses the study design and some of its limitations, but
this does not mitigate the misleading implication of the presentation.
Inadequate Presentation of Established Name:
o Press release fails to present the established name (poractant alfa) in direct
conjunction with the propriety name (Curosurf) where the proprietary
name is featured in the headline.
11-13-2012 Patanase®
For the relief of the symptoms of
No
Professional
Sales Aid
20
Overstatement of Efficacy:
o Presentation implies that Patanase has been shown to be effective in the

2222012 OPDP Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
seasonal allergic rhinitis in adults
and children 6 years of age and
older.
Boxed
Warning
Form of
Communication
o
o
o
o
Summary of Alleged Violations
treatment of nasal congestion when the clinical studies used for approval of
Patanase evaluated a composite measure of symptoms and did not
specifically evaluate efficacy for the individual symptom of nasal
congestion.
Cited references were pharmacodynamic studies conducted in allergen
chamber environmental exposure units, which does not reflect real world
situations.
Claims suggest a guarantee of clinical symptom relief within 30 minutes of
administration based on dosing in the environmental exposure unit, but the
PI states that onset of action was seen after 1 day of dosing in seasonal
allergy trials.
Claims and presentation suggest that symptom relief is maintained beyond
14 days, but the cited studies were not designed to measure efficacy
beyond 14 days.
The claim of improvement through 2 weeks appears on a graph, but does
not mitigate the misleading impression, and the graph presents data as a
pooled average, which may overestimate the statistical significance of any
differences between the active and placebo treatment arms.
11-27-2012 Crofelemer Tablets
Investigational New Drug with
proposed indications for treatment
of HIV-indicated diarrhea,
pediatric diarrhea, and acute
infectious diarrhea.
N/A
Company
Website, Podcast
of Interview with
CEO
Omission/Minimization of Risk Information:
o Claims on website and podcast suggest that crofelemer is safe and/or
effective for the treatment of various types of diarrhea and for the
treatment of pediatric patients as young as three months, when it is still
under investigation for such uses.
21