2011 OPDP (formerly DDMAC) Warning and Untitled Letters
Warning Letters indicated with * by the Date
Bad Ad Program enforcement indicated with † by the Form of Communication
Date with
Hyperlink
to Letter
01-04-2011*
Drug and Indications Referenced
in Letter
Oraqix®
For adults who require localized
anesthesia in periodontal pockets
during scaling and/or root planing
(“SRP”).
Boxed
Warning
or REMS
None
Form of
Communication
Professional
Direct Mailers,
Professional
Journal Ad
Summary of Alleged Violations
 Omission/Minimization of Risk Information:
Direct mailers fail to communicate any risk information.
Journal ad presents only limited risk information and completely omits
important and serious precautions regarding anaphylaxis, severe hepatic
disease, and common adverse reactions.
o The statement, “Please refer to prescribing information and DFU
enclosed,” at the bottom of the direct mailers does not mitigate the
complete omission of risk information.
o The statement, “Please see the accompanying brief summary of the
prescribing information,” at the bottom of the ad in small type does not
mitigate the misleading omission of risk information from the main body
of the ad.
 Unsubstantiated Superiority Claims:
o Claims misleadingly imply that Oraqix is clinically superior to injectable
anesthetics because it has greater anesthetic effect and higher patient
comfort during SRP procedures, but the difference in route of
administration does not provide support for these implications.
o Use of the word “protocol” suggests that there is some formal clinical
guidance to dentists suggesting that Oraqix is more effective and safer than
injectable anesthetics for use during SRP and is more efficient based solely
on the absence of a needle and the existence of a blunt tip applicator, but
FDA is not aware of substantial evidence or clinical experience supporting
these implications.
 Overstatement of Efficacy:
o Claims imply that the administration of Oraqix ensures patient comfort,
changes every aspect of the dental experience, decreases or eliminates the
need to periodically reassess the patient, and shortens the overall procedure
o
o
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
01-07-2011
Drug and Indications Referenced
in Letter
Boniva®
For the treatment and prevention of
osteoporosis in postmenopausal
women.
Boxed
Warning
or REMS
None
Form of
Communication
Summary of Alleged Violations
time, but FDA is not aware of substantial evidence or clinical experience to
support these claims.
 Broadening of Indication:
o Direct mailer suggests that Oraqix is safe and effective for use in any
patient undergoing routine dental cleaning when this is not the case.
o Direct mailer suggests that Oraqix is safe and effective for use in all
patients undergoing SRP procedures, which is a broader range of
conditions and patients than has been demonstrated by substantial evidence
or clinical experience.
o Misleading presentations are exacerbated by the failure to provide the
complete limitations to the approved indication.
 Overstatement of Efficacy:
Direct-toConsumer
(“DTC”) Print
Ad
o
o
02-17-2011
Feraheme®
For the treatment of iron
deficiency anemia in adult patients
with chronic kidney disease.
None
 Overstatement of Efficacy:
Professional
Direct Mailer
o
o
o
03-11-2011
Ovide®
For patients infected with
Pediculus humanus capitis (head
lice and their ova) of the scalp hair.
None
Claim suggests that treatment with Boniva will result in 9 out of 10 women
stopping or reversing their bone loss when this is not supported by
substantial evidence or clinical experience.
Claim was based on a per-protocol post-hoc analysis of a secondary
efficacy endpoint that the clinical study, which served as the basis for
approval, was not adequately designed to evaluate.
Claims suggest that increases in hemoglobin levels have been
demonstrated specifically in patients without concomitant erythropoiesisstimulating agent (“ESA”) use when this finding has not been
demonstrated by substantial evidence or clinical experience.
None of the three pivotal trials used to evaluate the clinical efficacy of
Feraheme were designed to evaluate efficacy based on ESA use and
patients were not stratified by ESA use at randomization, so the
conclusions based on sub-group analysis are considered exploratory and
are not substantial evidence.
The misleading impression is exacerbated by the complete omission of the
results of the actual primary analyses from the studies.
 Omission of Risk Information:
Book
o
2
Book entirely omits all risk information associated with the product and
misleadingly suggests that Ovide is safer than has been demonstrated.
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
03-21-2011*
Drug and Indications Referenced
in Letter
Infergen®
For treatment of chronic hepatitis
C in patients 18 years of age or
older with compensated liver
disease.
Boxed
Warning
or REMS
Boxed
Warning
Form of
Communication
STATgram†




3
Summary of Alleged Violations
Omission/Minimization of Risk Information:
o STATgram does not present all Boxed Warnings, contraindications to use
of Infergen and ribavirin, most warnings and precautions, or common
adverse events.
o STATgram minimizes Boxed Warnings regarding neuropsychiatric,
autoimmune, ischemic, and infectious disorders by failing to reveal that the
reactions can be fatal or life-threatening and that patients should be
monitored closely and withdrawn from therapy if they have persistently
severe or worsening symptoms of the adverse events.
o STATgram omits specific information from the Warnings and Precautions
section of the Prescribing Information (“PI”) related to the risk of severe
psychiatric adverse events.
o Referring readers to the product website for safety information is
insufficient to balance the efficacy claims in the STATgram.
Broadening of Indication/Omission of Material Facts:
o Claim implies that Infergen plus ribavirin is approved for retreating all
patients infected with hepatitis C virus when this is not the case.
o STATgram omits the material fact that the safety and efficacy of Infergen
in combination with ribavirin have not been evaluated in treatment-naive
patients or patients who are co-infected with hepatitis B virus or human
immunodeficiency virus type 1.
o STATgram omits material information that patients are less likely to
benefit from retreatment with combination therapy if they have certain
specific characteristics.
o STATgram omits the fact that no safety and efficacy data are available for
treatment with Infergen longer than one year.
o Omission of material facts about limitations in Infergen’s indication is
even more problematic given the serious safety risks associated with the
product and the serious deficiencies in the safety information presented.
Overstatement of Efficacy:
o Claims regarding patient response are based on open-label studies that
were not adequately powered to draw valid statistical conclusions about the
efficacy of Infergen/ribavarin in particular subgroups in the overall study
population.
Unsubstantiated Claim:
o Claim that patients maintaining full doses of Infergen/ribavarin therapy had
a sustained virologic response of 17% is not supported by substantial
evidence or clinical experience.
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
04-14-2011
04-26-2011
Drug and Indications Referenced
in Letter
Boxed
Warning
or REMS
AzaSite®
For the treatment of bacterial
conjunctivitis caused by
susceptible isolates of CDC
coryneform group G, Haemophilus
influenzae, Staphylococcus aureus,
Streptococcus mitis group, and
Streptococcus pneumoniae.
None
Nitrolingual®
For acute relief of an attack or
prophylaxis of angina pectoris due
to coronary artery disease.
None
Form of
Communication
Summary of Alleged Violations
 Failure to Provide Adequate Directions for Use:
o STATgram does not appear to have been disseminated with the full FDAapproved product labeling for Infergen.
 Broadening of Indication:
Professional
Journal Ad
Totality of the presentation suggests that AzaSite is indicated to treat any
condition that causes ocular surface damage, which has not been
demonstrated by substantial evidence or clinical experience.
o Presentation of the indication in small font on the bottom of the third page
does not mitigate the overwhelming impression that AzaSite is useful in a
much broader range of conditions or patients than has been demonstrated.
 Unsubstantiated Claims:
o Claim implies that AzaSite delivers anti-inflammatory effects, which has
not been demonstrated because the cited poster presentation does not
provide adequate descriptions of the study materials, methods, or results,
and the studies describe in vitro work on human cells and pre-clinical
animal work, the clinical relevance of which is not known.
o Other trials evaluated treatment efficacy based on clinical resolution and
bacterial eradication and do not constitute substantial evidence to support
claims regarding anti-inflammatory effects.
o Claim implies that AzaSite has been shown to maintain therapeutic
concentrations in ocular surface tissues for at least five days after the last
dose, which has not been demonstrated because the cited poster
presentation does not provide adequate descriptions of the study material,
methods, or results. The study assessed pharmacokinetic parameters only
and did not assess clinical efficacy, and the maintenance of therapeutic
concentrations in ocular surface tissues was not a pre-specified endpoint in
the trials.
 Omission/Minimization of Risk Information:
o Ad omits warnings and precautions regarding the risk of anaphylaxis and
hypersensitivity with systemic use of azithromycin.
o Ad fails to present risk information with prominence and readability
reasonably comparable to the presentation of efficacy claims.
o
 Unsubstantiated Superiority Claims/Unsubstantiated Claims:
Professional
Sales Aid, Patient
Brochure, Patient
Brochure Holder
o
4
Claims and presentations imply that Nitrolingual Pumpspray is more potent
and provides faster pain relief from acute angina pectoris with fewer or no
headaches compared to the nitroglycerin tablet formulation and is therefore
clinically superior when this has not been demonstrated.
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
or REMS
Form of
Communication
Summary of Alleged Violations
A study cited in support of the claims is not substantial evidence or clinical
experience because it used subjective questionnaires to assess the efficacy
and safety of nitroglycerin lingual spray and nitroglycerin tablets.
o Another study cited, an open-label trial of 20 healthy volunteers that
compared the vasodilatory effects of the spray and tablet, does not
constitute substantial evidence or clinical experience because it was not
adequately powered, used an open-label design, and evaluated an endpoint
that has unknown clinical relevance.
o Claims that patients prescribed nitroglycerin tablets frequently carry
subpotent tablets is not supported by substantial evidence or clinical
experience because the cited patient survey did not provide information
confirming that nitroglycerin tablets were in fact post-expiration or
subpotent, as reported by patients.
o Totality of claims implies that Nitrolingual Pumpspray is “patient-friendly”
and that overall treatment is “convenient” when compared to tablets when
this is not the case. Cited studies did not specifically assess patientfriendliness and overall convenience, both of which are broad terms that
include many factors, and the PI describes multiple considerations for use
and detailed instructions on administration.
o Claim that Nitrolingual Pumpspray is not affected by dry mouth or
diminished salivary secretions is not supported.
o Claim implying that patients using Nitrolingual Pumpspray will not be
“slow[ed] down” at all is not supported.
 Omission/Minimization of Risk Information:
o Direction to use Nitrolingual Pumpspray “with caution” in patients who
show hypersensitivity to it minimizes the contraindication in patient who
are allergic to it.
o Claim that Nitrolingual Pumpspray should be used with caution if patients
have low systemic blood pressure minimizes the risk of severe hypotension
in patients with low systolic blood pressure.
o Sales aid omits the warning regarding use after an acute myocardial
infarction and precautions regarding hypertrophic cardiomyopathy and
tolerance associated with use of Nitrolingual Pumpspray.
o Brochure and brochure holder completely omit important information such
as a precaution regarding tolerance associated with use of Nitrolingual
Pumpspray.
o Brochure and brochure holder fail to present risk information with a
prominence and readability comparable with the presentation of efficacy
information.
o
5
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
04-28-2011
04-28-2011
Drug and Indications Referenced
in Letter
Savella®
For the management of
fibromyalgia.
Omapro™
(Investigational New Drug)
Boxed
Warning
or REMS
Boxed
Warning
None
Form of
Communication
Oral Statements
by Sales
Representative†
Summary of Alleged Violations
 Promotion of Unapproved Uses:
o Sales representative made an unsolicited sales call to a physician office and
stated that Savella is useful in back pain and mood disorder and approved
for depression in Europe, but FDA is not aware of substantial evidence or
clinical experience supporting use for back pain, mood disorder, or
depression.
 Unsubstantiated Superiority Claims/Minimization of Risk:
o Sales representative stated that Savella has a 3:1 affinity for norepinephrine
reuptake inhibition, which makes it a better analgesic than Cymbalta, but
pre-clinical data demonstrating Savella’s increased affinity for
norepinephrine reuptake inhibition does not constitute substantial evidence
of superiority.
o Sales representative stated that Savella is less sedating and does not result
in peripheral edema and/or as much weight gain compared to Lyrica, but
FDA is not aware of any adequate and well-controlled head-to-head trials
comparing these effects of Savella versus Lyrica.
o Statements comparing the safety of Savella versus Lyrica and failure to
mention any of the most serious and common risks associated with use of
Savella suggest that the drug is safer than has been demonstrated.
 Unsubstantiated Mechanism of Action Claim:
o Statement that the increase in spinal cord norepinephrine provides
analgesia for Savella and is the mechanism of action that should be
targeted as the goal for use of centrally acting analgesics implies a greater
deal of certainty about the mechanism of action of Savella than is
supported by substantial evidence or clinical experience. The exact
mechanism of the central pain inhibitory action of Savella and its ability to
improve symptoms of fibromyalgia in humans is unknown.
 Promotion of an Investigational New Drug:
Brochure
Claims promote Omapro for treatment of chronic myelogenous leukemia
and other hematologic malignancies, but Omapro has not yet been
demonstrated to be safe and effective for treatment of these conditions in
patients.
 False or Misleading Statements:
o Statements touting positive clinical trial data are false or misleading.
o FDA is not aware of the establishment of expanded compassionate use
access for Omapro, as claimed in the brochure.
o
6
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
05-05-2011
05-06-2011*
Drug and Indications Referenced
in Letter
Atelvia™
For the treatment of osteoporosis
in postmenopausal women.
Vyvanse®
For the treatment of Attention
Deficit Hyperactivity Disorder
(“ADHD”) in children.
Boxed
Warning
or REMS
None
Boxed
Warning
Form of
Communication
YouTube Video†
Summary of Alleged Violations
 Omission of Indication and Risk Information:
o Video fails to communicate any of the risks associated with use of Atelvia,
including contraindications, warnings and precautions, and adverse
reactions.
o Video fails to communicate Atelvia’s indication.
 Omission of Material Facts/Misleading Claims Regarding Dosing:
o Video omits material facts about dosing.
o Video implies that patients have a choice to eat and drink when taking
Atelvia when the Dosage and Administration section of the PI states that
Atelvia should be taken immediately following breakfast.
 Failure to Submit Under Form FDA-2253:
o Video was not submitted to FDA at the time of initial dissemination or
publication.
 Omission of Indication and Risk Information:
Magnet†
o
o
o
05-24-2011
Pexeva®
For the treatment of Major
Depressive Disorder (“MDD”),
obsessions and compulsions in
patients with Obsessive
Compulsive Disorder (“OCD”) as
defined in the DSM-IV, Panic
Disorder (“PD”), with or without
agoraphobia, as defined in DSMIV, and Generalized Anxiety
Disorder (“GAD”), as defined in
DSM-IV.
Boxed
Warning
Magnet fails to adequately communicate the full indication for Vyvanse,
including important information on special diagnostic considerations, the
need for comprehensive treatment, and long-term use.
Magnet fails to adequately disclose risk information associated with the
use of Vyvanse because a majority of the risk information is covered by a
sales representative business card.
The statement, “Please see full accompanying Prescribing Information,
including Boxed Warning,” at the bottom of the magnet does not mitigate
the omission of indication and risk information.
 Broadening of Indication/Unsubstantiated Claims:
Flashcard
o
o
7
Flashcard presentation implies that Pexeva is effective in treating patients
with co-morbid MDD and GAD when no clinical studies demonstrate
efficacy of Pexeva in treating patients experiencing the two conditions
concurrently, and co-morbid MDD and GAD is not recognized as a distinct
clinical entity in the DSM-IV-TR or in the academic or clinical
community.
Study cited to support a claim that anxiety symptoms are associated with
MDD is not substantial evidence or clinical experience because the study
was a cross-sectional study that only evaluated efficacy endpoints related
to depression scales. No scales for GAD were included, nor were any
corrections for multiple statistical comparisons performed, and the purpose
of the study was to directly compare the clinical features of depression for
patients entering clinical trials at primary and specialty care settings, not to
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
or REMS
Form of
Communication
Summary of Alleged Violations
identify anxiety disorders distinct from MDD.
o Inclusion of the statement, “Pexeva is indicated for the treatment of MDD,
GAD, Panic Disorder, and OCD,” in the bottom corner of the flashcard
does not mitigate the misleading impression.
 Overstatement of Efficacy:
o Flashcard presentation implies that Pexeva is efficacious in treating certain
individual symptoms, but FDA is not aware of any substantial evidence or
clinical experience to support the claim that patients will experience
improvement in individual symptoms because clinical trials showed that
Pexeva was effective based on the total scores of scales evaluating mood
disorder.
o The statement, “These selected symptoms of GAD, MDD, OCD, and PD
are used here only as examples,” does not mitigate the misleading
presentation.
 Omission/Minimization of Risk Information:
o Flashcard entirely omits the warning regarding potentially fatal serotonin
syndrome and neroleptic malignant syndrome-like reactions, as well as
precautions related to the activation of certain adverse events upon
discontinuation of treatment with Pexeva, akathisia, hyponatremia, and
abnormal bleeding.
o Flashcard fails to include important material facts from the Warnings
section that the contraindication in patients taking monoamine oxidase
inhibitors and thioridazine is due to serious, potentially fatal interactions
that may result from concomitant use of Perexa and the drug products.
o Disclosures about suicidality and antidepressant drugs in the Boxed
Warning fail to include the material fact that families and caregivers should
be advised of the need for close observation and communication with the
prescriber, and that Pexeva is not approved for pediatric patients.
o Flashcard fails to include important information from the Warnings section
that all patients being treated with antidepressants for any indication should
be monitored appropriately and observed closely for clinical worsening,
suicidality, and unusual changes in behavior, especially during the initial
few months of a course of drug therapy or at times of dose changes.
o The statement, “Please see accompanying full Prescribing Information
including WARNING – Clinical Worsening and Suicide Risk,” does not
mitigate the misleading impression.
o Claim of “[s]ignificant improvements in associated sleep disturbances” is
misleading because it fails to include the material fact that Perexa is
associated with a 13% incidence of insomnia in MDD patients.
8
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
or REMS
Form of
Communication
o
05-31-2011
Focalin XR®
For the treatment of ADHD in
patients aged 6 years and older.
Boxed
Warning
 Unsubstantiated Superiority Claims:
Professional One
Point Leave
Behind Detail
Aid
o
o
06-16-2011
Acanya®
For the topical treatment of acne
vulgaris in patients 12 years and
older.
None
Summary of Alleged Violations
Presentation of insomnia as an adverse event somewhere else on the
flashcard is too far removed from the claims and presented at the bottom of
the page with other risk information.
Claims imply that Focalin XR is superior to Concerta because of a benefit
demonstrated at 2 hours post-dose. However, the referenced clinical
studies do not constitute substantial evidence or clinical experience to
support the claims because the studies only focused on one specific time
point as the primary efficacy measure and did not account for the different
pharmacokinetic profiles and subsequent efficacy profiles associated with
Focalin XR and Concerta over the entire treatment course.
Detail aid implies that Focalin XR is better or more effective than other
ADHD medications and should be the “first” choice when considering
treatment options, but this claim is not supported by substantial evidence or
clinical experience.
 Overstatement of Efficacy:
Website
Claims and presentations imply a substantial effect of Acanya at 2 weeks
and continued improvement throughout a 12-week treatment period, but
the clinical study cited does not constitute substantial evidence or clinical
experience to support the claim because the study had co-primary efficacy
variables measured at week 12. Patients were evaluated at weeks 4 and 8,
but the earlier timepoints were not pre-specified endpoints in the clinical
studies.
o The “Acanya Gel: Consumer Home Page” and subsequent pages include
large images of faces depicting completely clear, acne-free skin that
conveys the impression that treatment with Acanya will result in complete
clearing of acne when this has not been demonstrated by substantial
evidence or clinical experience.
o Presentation of before and after photos followed by the statements, “These
unretouched photos represent actual clinical trial experience. As with all
treatments, results may vary from person to person,” does not mitigate the
misleading impression.
 Omission of Material Facts/Minimization of Risk Information:
o Website communicates that patients with a history of colitis should not use
Acanya, but fails to communicate that use of the drug is contraindicated in
patients with a history of Crohn’s disease.
o Website indicates that the drug “may cause diarrhea” and that patients who
o
9
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
or REMS
Form of
Communication
o
o
o
o
o
06-17-2011
Solaraze®
For the topical treatment of actinic
keratoses (“AKs”).
None
Summary of Alleged Violations
experience diarrhea should stop using Acanya immediately and call their
doctor, but fails to convey that severe abdominal cramps are another
symptom of colitis.
Website fails to convey that Acanya may cause serious allergic reactions
and that patients who experience allergic reactions should stop using
Acanya and call their doctor right away.
Website does not present risks in order of severity.
Inclusion of a link to the full PI does not mitigate the misleading
impression.
Claim implies that Acanya is gentle to the skin when clinical trials showed
up to 8% and 2% of patients experienced mild and moderate burning,
respectively, up to 6% and 1% experienced mild and moderate stinging,
respectively, and mild and moderate erythema, scaling, and itching were
common local side effects.
The statement, “Side effects may include redness, scaling, itching, burning,
and stinging,” presented at the bottom of the webpage does not mitigate the
misleading impression of the claim.
 Overstatement of Efficacy:
Flashcard
Flashcard overstates the efficacy of Solaraze in clearing target lesions and
is inconsistent with the efficacy results demonstrated in the Clinical
Studies section of the PI.
o Claims regarding the efficacy of Solaraze 1 year post-treatment are not
supported by the approved PI, which specifically states that “No long-term
patient follow-ups, after the 30-day assessments, were performed for the
detection of recurrence,” and FDA is not aware of substantial evidence to
support claims that Solaraze has a long-lasting treatment effect after use
has been discontinued.
o Claims that Solaraze is effective in treating subclinical lesions are
misleading because the efficacy of Solaraze in treating subclinical lesions
was not studied.
o Claim that Solaraze has been demonstrated to prevent recurrence of AKs is
not supported by substantial evidence or clinical experience and is
inconsistent with the PI, which states that no long-term follow-ups were
performed after 30-day assessments.
 Minimization of Risk:
o Claim that Solaraze is “well-tolerated” minimizes the adverse events
associated with Solaraze use and is not supported by the PI, which
describes adverse events involving skin and the application site in 83% of
o
10
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
06-21-2011
Drug and Indications Referenced
in Letter
Trisenox®
For induction of remission and
consolidation in patients with acute
promyelocytic leukemia (“APL”)
who are refractory to, or have
relapsed from, retinoid and
anthracycline chemotherapy, and
whose APL is characterized by the
presence of the t(15;17)
translocation or PML/RAR-alpha
[promyelocytic leukemia/retinoic
acid receptor-alpha] gene
expression.
Boxed
Warning
or REMS
Form of
Communication
Boxed
Warning
Professional
Website
Summary of Alleged Violations
treated patients and discontinued participation in clinical trials mainly due
to skin irritation of cutaneous adverse reactions.
 Misleading Patient Compliance Claim:
o Claim that a “[m]ajority of patients were compliant with treatment” is not
supported by the cited reference, which was an open-label study designed
to assess the efficacy of Solaraze for treatment of AKs and not patient
compliance with Solaraze.
 Broadening of Indication:
Prominent, bolded headers at the top of the webpages suggest that Trisenox
is approved to treat patients with any kind of relapsed or refractory APL
when this is not the case.
o Inclusion of the full indication statement in small type on the bottom of
each webpage beneath the list of references does not mitigate the
misleading impression created by the bolded headers.
 Minimization of Risk:
o Information about serious and potentially fatal risks associated with
Trisenox, including the Boxed Warning, are relegated to the bottom of the
pages after the list of references and written in small single-spaced font,
which is not with a prominence or readability reasonably comparable to
effectiveness claims.
o Website understates several risk-related statements by listing below the
headline, “Safety Profile for Trisenox,” claims that emphasize the absence
or low incidence of selected side effects instead of the most serious and
common risks.
o Information from the Boxed Warning and that fact that serious adverse
events were common are relegated to the bottom of the page after a list of
references.
o Characterization of the serious and significant risks associated with
Trisenox as “manageable” and “generally well tolerated” minimizes the
risks and contributes to the overall suggestion that Triselox is safer than
has been demonstrated.
o Statement misleadingly suggests that Trisenox is safer than chemotherapy
by implying that Trisenox does not expose patients to cytotoxic adverse
effects and is not associated with potentially fatal side effects when the
Boxed Warning and Warning and Precautions section of the PI describes
severe side effects, some of which may be fatal, and states that serious
adverse reactions were common in patients taking Trisenox.
o Suggestions that Trisenox should be considered before chemotherapy for
o
11
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
or REMS
Form of
Communication
12
Summary of Alleged Violations
young patients on the basis of the implied lower toxicity is unsubstantiated,
and the PI explicitly states that there is “limited data about the pediatric use
of Trisenox” and that “the safety and efficacy of Trisenox has not been
studied in patients younger than four years of age.”
 Overstatement of Efficacy:
o Website misleadingly overstates the efficacy of Trisenox because it is
based on a retrospective recalculation of the original efficacy results using
new, less stringent criteria that make the response rates appear more
favorable than those reported in the PI.
o While calculation criteria may have been revised since the time of the
pivotal study, approval of Trisonex was based on earlier-established
criteria. It is misleading to promote inflated response rates that are
inconsistent with the efficacy findings from pivotal clinical studies for the
drug, as reflected in the PI.
o Claims related to overall survival and relapse-free survival are not
supported by substantial evidence or clinical experience because pivotal
studies did not measure either as endpoints and time-to-event analyses are
not interpretable in a single-arm clinical trial. Furthermore, median
follow-up times was 16, not 18, months as claimed.
o Statements reference clinical studies performed in patients with APL who
were treated with all-trans retinoic acid or various chemotherapy agents
during induction, consolidation, or salvage therapy, and suggest that
patients treated with Trisenox will experience similar survival outcomes
based on their molecular response status, but the correlation between levels
of PML/RAR-alpha transcript and the probability of relapse or relapse-free
survival were not pre-defined endpoints in the Trisenox pivotal trial.
 Unsubstantiated Claims:
o Several claims in an animated video relate to the mechanism of action of
Trisenox, but according to the PI, the mechanism of action is not
completely understood; the PI does not indicate that Trisenox selectively
targets and degrades the PML/RAR-alpha protein in vivo or that these
functions confer a clinical benefit to patients with APL.
o Cited references describe in vitro studies performed in cell culture with
different concentrations of arsenic trioxide, but these finds do not
necessarily correlate to in vivo activity or support any claim of clinical
benefit.
o Inclusion in the animated video of the statement, “[t]he mechanisms of
action of Trisenox are not completely understood and are actively studied,”
is insufficient to mitigate the misleading implications in the video.
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
Drug and Indications Referenced
in Letter
Boxed
Warning
or REMS
Form of
Communication
Summary of Alleged Violations
 Misleading Claims:
Claims that dosing or administration of Trisenox is “manageable” are
misleading given the fact that patients may be spending four hours a day,
every day, for two months being infused with the medication.
o Given the extent to which patients must be monitored and the potential for
serious adverse effects if they are not carefully monitored, it is misleading
to characterize the complex regimen as “manageable” for patients and their
providers.
 Omission of Risk:
o Website fails to include important risk concepts from the Warnings and
Precautions sections of the PI, including warnings that Trisenox is a human
carcinogen and may cause fetal harm when administered to pregnant
women and the precaution against using Trisenox when nursing.
o
06-30-2011
KRX-0401 (Perifosine)
(Investigational New Drug)
None
 Promotion of an Investigational Drug:
Website
o
o
o
07-13-2011*
Bromday™
For the treatment of postoperative
inflammation and reduction of
ocular pain in patients who have
undergone cataract surgery.
None
Website makes numerous statements that promote KRX-0401 as safe
and/or effective for treatment of various types of tumors, both as a single
agent and in combination with other therapies when it has not been
approved for these uses.
The totality of claims makes the conclusions that the drug is well-tolerated,
can be safely given to humans with a manageable toxicity profile, and has
a safety profile that is “distinctly different from that of most cytotoxic
agents” when the safety and effectiveness of KRX-0401 have not been
established yet.
A disclaimer stating, “This investigational drug product has not been
approved by the US Food and Drug Administration for safety and
effectiveness. This investigational drug product is still undergoing clinical
study to verify its safety and effectiveness” is not sufficient to mitigate the
misleading impression conveyed by claims on the website.
 Omission of Risk Information:
Flyer
o
o
o
13
Flyer discloses the most common adverse reactions associated with use of
Bromday, but fails to reveal any of the warnings and precautions for the
drug, including serious and important warnings and precautions regarding
the potential for anaphylactic and life-threatening allergic reactions to
sodium sulfite and other adverse reactions.
Flyer fails to communicate the warning and precaution that Bromday
should not be administered while wearing contact lenses.
Inclusion of the statement, “Please see full prescribing information on
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
08-02-2011
08-05-2011*
Drug and Indications Referenced
in Letter
Boxed
Warning
or REMS
Mephyton®
For the treatment of certain
coagulation disorders that are due
to faulty formation of factors II,
VII, IX, and X when caused by
Vitamin K deficiency or
interference with Vitamin K
activity.
None
Multikine®
(Investigational New Drug)
None
Form of
Communication
Booklet
Containing Slide
Presentation
Summary of Alleged Violations
reverse,” at the bottom of the flyer does not mitigate the omission of risk
information.
 Omission of Material Facts:
o Flyer fails to reveal important dosing limitations that are material to the
safe use of the drug.
o The omission is particularly concerning in light of the claim that Bromday
is the replacement for Xibrom, which suggests that Bromday has the same
dosing regimen that was previously approved for Xibrom when this is not
the case.
o Omission of dosing information is concerning because the Warnings and
Precautions section of the PI states that use of topical non-steroidal antiinflammatory drugs more than 24 hours prior to surgery or use beyond 14
days post-surgery may increase patient risk for the occurrence and severity
of corneal adverse events.
 Broadening of Indication:
Booklet presentation creates the impression that Mephyton is indicated for
all patients with Vitamin K deficiency when this has not been
demonstrated.
o Presentation of Mephyton’s indication on other slides does not mitigate the
misleading impression of the presentation.
 Unsubstantiated Claims:
o Booklet suggests that at 24 hours post-administration, Mephyton is as
clinically effective as intravenously administered phytonadione when this
has not been demonstrated by substantial evidence or clinical experience
because the cited study is a retrospective review of multiple clinical studies
that were performed in diverse patient populations with different doses and
dosage forms of phytonadione under varying clinical protocols.
o
 Promotion of Investigational New Drug:
Webpages
o
o
14
Claims suggest that Multikine is safe and/or effective for the treatment of
various kinds of cancers, including those of the head and neck, when it has
not been approved for such uses.
Totality of claims suggest that the drug is “non-toxic” and has
demonstrated “impressive” and “extraordinary” improvements in overall
survival “over what can be expected from the current therapy,” but the
indications, warning, precautions, adverse reactions, dosage, and
administration have not been established yet and are currently unknown.
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
08-26-2011
Drug and Indications Referenced
in Letter
Nucynta®
For the relief of moderate to severe
acute pain in patients 18 years of
age or older.
Boxed
Warning
or REMS
None
Form of
Communication
Oral Statements
Made by
Representative
15
Summary of Alleged Violations
 Promotion of Unapproved Uses:
o Sales representative indicated that Nucynta is useful in the treatment of
Diabetic Peripheral Neuropathic Pain (“DPNP”) when Nucynta is only
indicated generally for relief of moderate to severe pain in patients 18
years of age or older and not specifically for the treatment of DPNP, a
chronic pain condition.
 Unsubstantiated Superiority Claims/Minimization of Risk:
o Sales representative indicated that Nucynta is clinically superior (i.e.,
safer) compared to oxycodone and tramadol for DPNP patients, and that
Nucynta has been shown to have fewer gastrointestinal adverse reactions in
comparison to oxycodone and/or tramadol when FDA determined that
clinical studies for Nucynta were not adequately powered for analysis of
multiple safety endpoints and that doses of oxycodone used as a
comparator were not demonstrated to be equianalgesic to the doses of
Nucynta studied, so safety comparative data were not considered clinically
meaningful or included in the approved PI for Nucynta.
o FDA is not aware of any adequate and well-controlled head-to-head
clinical trials comparing the incidence of constipation, nausea, or vomiting
for Nucynta versus tramadol.
o Claim that Nucynta results in less constipation, nausea, and vomiting
minimizes the risks associated with use because nausea and vomiting were
the most common adverse reactions associated with use of Nucynta in
clinical trials and among the most common reasons for discontinuation of
treatment.
o Sales representative implied that treatment with Nucynta has been shown
to reduce length of hospital stay in comparison to oxycodone and tramadol
and that Nucynta-treated patients will have a bowel movement without use
of docusate or senna, but 8% of Nucynta-treated patients reported
constipation as an adverse event in clinical studies versus 3% in the
placebo arm. The lack of support comparing the safety and efficacy of
Nucynta to oxycodone and tramadol makes it impossible to make a
treatment cost comparison based on the length of hospital stay.
 Unsubstantiated Efficacy Claim:
o Sales representative implied that Nucynta has been shown to be noninferior to oxycodone, tramadol, or other opiods and that Nucynta has been
shown to provide equivalent “pain control” (equianalgesia) when
compared to other opiods, but FDA determined that analyses used to obtain
non-inferiority claims regarding the efficacy of Nucynta compared to
oxycodone were inadequate, so the results of those analyses were excluded
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
08-31-2011
Drug and Indications Referenced
in Letter
Chantix®
For use as an aid to smoking
cessation treatment.
Boxed
Warning
or REMS
Both
(Chantix)
Form of
Communication
Summary of Alleged Violations
from the approved PI. FDA is not aware of any well-controlled head-tohead clinical trials comparing the efficacy of Nucynta to tramadol or any
other opioids.
 Omission of Risk Information:
Webpage†
o
o
Caduet®
For the treatment of patients for
whom treatment with both
amlodipine and atorvastatin is
appropriate.
“Online Resources” webpage for Lipitor fails to communicate any risk
information about the products.
Inclusion of links that lead to the Lipitor site, which contains a link to the
individual product websites for Caduet and Chantix and the PI for Norvasc
is insufficient to mitigate the omission of risk information in the “Online
Resources” webpage.
Norvasc®
For the treatment of hypertension
and vasospastic angina [Prinzmetal
or variant angina] and the
symptomatic treatment of chronic
stable angina.
10-14-2011
Pataday™
For the treatment of ocular itching
associated with allergic
conjunctivitis.
None
 Inappropriate Reminder Labeling/Omission of Indication and Risk
Rebate Card
Information:
o Rebate card makes a representation regarding the use of Pataday for the
“relief” of symptoms of allergic conjunctivitis caused by plant allergens
and presentation of the Pataday logo in conjunction with the words “Once
Daily” makes a dosage recommendation for the drug product, so the card is
not considered reminder labeling and needs to include appropriate risk
information and full indication information.
o Rebate card fails to include the fact that Pataday is only indicated for the
treatment of ocular itching associated with allergic conjunctivitis.
o Inclusion of the statement, “For prescribing information visit
pataday.com,” is not sufficient to mitigate the rebate card’s omission of
risk and indication information.
 Unsubstantiated Superiority Claim:
o Image of the eye with a superimposed plant allergen accompanied by the
claim of “Most Relief” suggests that Pataday provides superior relief as
compared to other available therapies approved for the same indication, but
OPDP is not aware of substantial evidence or clinical experience
16
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
10-17-2011
Drug and Indications Referenced
in Letter
Busulfex®
For use in combination with
cyclophosphamide as a
conditioning regimen prior to
allogeneic hematopoietic
progenitor cell transplantation for
chronic myelogenous leukemia.
Boxed
Warning
or REMS
Boxed
Warning
Form of
Communication
Summary of Alleged Violations
supporting the claim.
 Omission of Material Facts:
Website
Website omits risks associated with use of Busulfex in pediatric patient
populations, such as the risk of cardiac tamponade in pediatric patients
receiving high doses of oral busulfan and other adverse events.
o The “Important Safety Information” section of the website omits material
facts regarding hepatic veno-occlusive disease (“HVOD”) and
hepatotoxicity.
o The “Dosing and Straightforward Administration” webpage omits material
facts regarding the need to pre-medicate patients with antiemetics prior to
the first dose of Busulfex therapy and on a fixed schedule for the duration
of Busulfex treatment.
 Minimization of Risk/Unsubstantiated Claims:
o Website claims that Busulfex has a “[l]ow incidence of severe toxicities,”
but the Boxed Warning indicates that Busulfex is a cytotoxic drug
associated with profound myelosuppression that occurs in all patients and
includes other significant warnings and precautions.
o Website presentation suggests that the use of lorazepam for seizure
prophylaxis eliminates the risk of seizures with Busulfex therapy when this
is not demonstrated by substantial evidence or clinical experience because
the referenced study is a retrospective analysis in a limited pediatric
population. This suggestion is also contrary to a recommendation in the
Dosage and Administration section of the PI that phenoytoin be used
because busulfan is known to induce seizures, and a statement that use of
other anticonvulsants may result in increased risk of HVOD or seizures.
o Totality of presentation is concerning due to a warning in the Busulfex PI
regarding the risk of seizures.
 Unsubstantiated Claims:
o Claims and presentations imply that Busulfex has a “predictable
pharmacokinetic profile,” “predictable and consistent” area under the curve
(“AUC”) values, and “excellent interdose reproducibility” when the
referenced study used a sampling schedule that caused invalid comparisons
of AUC values and dose values that differed significantly and prevented
accurate Cmax predictions.
o Totality of the presentation misleadingly implies that there is a direct
correlation between a “predictable pharmacokinetic profile” and the ability
to induce myeloablation in an “accurate,” “controlled,” and “optimal” way
when OPDP is not aware of any substantial evidence supporting such a
o
17
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
10-25-2011
Drug and Indications Referenced
in Letter
TechneLite®
For use in adults for brain imaging,
thyroid imaging, salivary gland
imaging, placenta localization,
blood pool imaging, urinary
bladder imaging, and nasolacrimal
drainage system imaging, and for
use in children as an agent for
brain imaging, thyroid imaging,
blood pool imaging, and urinary
bladder imaging.
Boxed
Warning
or REMS
Form of
Communication
None
Exhibit Panel
Summary of Alleged Violations
correlative relationship.
 Overstatement of Efficacy:
o Kaplan-Meier graph titled, “Overall Survival and Disease-Free Survival,”
makes efficacy claims regarding the probability of overall survival (“OS”)
and disease-free survival (“DFS”) following Busulfex therapy, but the
referenced publication calculates probability estimates for these endpoints
in a way that does not accurately reflect the number of patients still at risk
for the events, which results in an overestimate of the probability of OS
and DFS. The graph is not supported by the Busulfex PI either because the
single-arm open-label pivotal study does not adequately characterize timeto-event endpoints and did not calculate OS and DFS probability estimates.
 Misleading Claim:
o Claim regarding straightforward IV administration is misleading because
there are several instructions required for proper administration of
Busulfex.
o Presentation of administration information in the website is not sufficient
to mitigate the misleading impression of the claim.
 Omission of Risk Information:
Exhibit panel fails to include any of the warnings and precautions
associated with use of the drug, though the “Important Safety Information”
section of the panel includes a statement about allergic reactions.
o The statement, “Please see a representative in this booth for full
Prescribing Information,” does not mitigate the omission of information.
 Unsubstantiated Superiority Claim:
o Exhibit panel suggests that TechneLite is favored over other available
generators for the indicated uses, which has not been demonstrated by
adequate and well-controlled head-to-head studies.
 Unsubstantiated Claims:
o Statement regarding simple, hassle-free use is misleading because the
TechneLite PI describes a complex series of steps that are required for
proper preparation and administration of TechneLite and safe use and
disposal of radioactive material.
 Inadequate Presentation of Established Name:
o Exhibit panel fails to present the established name of the product
(Technetium Tc 99m Generator) in conjunction with the proprietary name
(TechneLite).
o
18
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
12-13-2011
12-13-2011
12-14-2011
Boxed
Warning
or REMS
None
Form of
Communication
Fact Sheet
Qutenza®
For the management of
neuropathic pain associated with
postherpetic neuralgia.
None
Exhibit Booth
Latuda®
For the treatment of patients with
schizophrenia.
Boxed
Warning
Drug and Indications Referenced
in Letter
ProstaScint®
For use as a diagnostic imaging
agent in newly diagnosed patients
with biopsy-proven prostate cancer
thought to be clinically localized
after standard diagnostic
evaluation and who are at high-risk
for pelvic lymph node metastases,
and for use as a diagnostic imaging
agent in post-prostatectomy
patients with a rising prostatespecific antigen and a negative or
equivocal standard metastatic
evaluation in whom there is a high
clinical suspicion of occult
metastatic disease.
Summary of Alleged Violations
 Omission of Risk Information:
o Fast sheet omits all contraindications, important warnings and precautions,
and the most commonly reported adverse reactions associated with the use
of ProstaScint.
 Overstatement of Efficacy:
o Claims suggest that ProstaScint is effective for confidently determining
specific treatment options (i.e., definitive and salvage) or as a prognostic
indicator for prostate cancer patients when this has not been demonstrated
by substantial evidence or clinical experience; two phase three trials found
overall accuracy of interpreted ProstaScint images to be 63% in patients
with high clinical suspicion for occult recurrent or residual prostate cancer
and 68% in patients with clinically localized prostate cancer who were at
high risk for metastases. The PI warns that patient management should not
be based on ProstaScint scan results without appropriate confirmatory
studies due to the high rate of false positive and false negative image
interpretations in pivotal trials, and that ProstaStint imaging should be
considered in conjunction with other diagnostic information.
 Inadequate Communication of Indication:
o Fact sheet fails to adequately communicate ProstaScint’s full approved
indication.
 De Facto Omission of Risk Information:
o
Risk information included in the exhibit booth was presented at the bottom
of the display panels and behind bags, boxes, and other materials, which
completely obscured the information from view.
 Promotion of Unapproved Uses:
Oral Statements
Made by a Sales
Representative
Sales representative indicated in a sales call that studies of Latuda use for
bipolar disorder are being done, that it is only a matter of time before
Latuda is approved for bipolar disorder, and that two area psychiatrists use
Latuda for bipolar disorder and are pleased with the results, but Latuda is
only indicated for treatment of schizophrenia.
o Statement that Latuda is only approved for schizophrenia and that use for
treatment of bipolar disorder is off-label does not mitigate the misleading
impression that Latuda is safe and effective for treatment of bipolar
disorder.
 Minimization of Risk Information/Unsubstantiated Claim:
o Sales representative minimized the risk of common adverse reactions and
stated that somnolence can occur during the beginning of treatment, but
o
19
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
12-22-2011
Drug and Indications Referenced
in Letter
Colcrys®
For prophylaxis and treatment of
acute gout flares.
Boxed
Warning
or REMS
None
Form of
Communication
Summary of Alleged Violations
usually goes away after a week when the PI does not include information
indicating a decreased risk of somnolence over time, includes a warning
and precaution regarding the potential for cognitive and motor impairment,
and reports somnolence as one of the most common adverse reactions
associated with use of Latuda.
 Omission and Minimization of Risk Information:
Pharmacy Sell
Sheet and
Professional
Video
Sell sheet and video omit material facts regarding the risk of
rhabdomyolysis.
o Sell sheet presentation implies that Colcrys is not risky or harmful (i.e.,
“gentle”) when this is not supported by substantial evidence or clinical
experience and the PI lists serious risks.
o Sell sheet and video imply that the safety profiles of Colcrys and placebo
are not different or that the difference is minimal when the adverse
reactions section of the PI states that 23% of patients in the recommended
low-dose group experienced diarrhea versus 14% of the placebo group.
o The main part of the video omits a discussion of the serious and significant
risks and the most commonly reported adverse reactions, and risk
information is not presented with a prominence and readability reasonably
comparable to the presentation of effectiveness information.
 Minimization of Risk Information/Unsubstantiated Safety Superiority
Claims:
o Video suggests that there are not significant safety concerns for Colcrys in
patients who have comorbid conditions and who are taking concomitant
medications, but this has not been demonstrated by substantial evidence or
clinical experience.
o Presentation misleadingly implies that Colcrys is clinically superior (i.e.,
safer) in patients with comorbid conditions and has fewer drug interactions
when taken with concomitant medications compared to non-steroidal antiinflammatory drugs, but OPDP is not aware of any adequate and wellcontrolled head-to-head studies supporting these claims, and the PI
includes warnings and precautions regarding fatal overdoses, blood
dyscrasias, life-threatening and fatal drug interactions, and neuromuscular
toxicity.
 Overstatement of Efficacy:
o Video implies that Colcrys effectively reduces pain associated with gout
flares within 16 hours when this has not been demonstrated by substantial
evidence or clinical experience because the clinical trial in the PI assessed
efficacy at 24 hours following the time of first dose, was not appropriately
o
20
2222011 OPDP (formerly DDMAC) Warning and Untitled Letters
Date with
Hyperlink
to Letter
12-22-2011
Drug and Indications Referenced
in Letter
Fondaparinux Sodium Solution
For the prophylaxis of deep vein
thrombosis that may lead to
pulmonary embolism in patients
undergoing hip fracture surgery,
hip replacement surgery, knee
replacement surgery, or abdominal
surgery who are at risk for
thromboembolic complications;
treatment of acute deep vein
thrombosis when administered in
conjunction with warfarin sodium;
or treatment of acute pulmonary
embolism when administered in
conjunction with warfarin sodium
when initial therapy is
administered in the hospital.
Boxed
Warning
or REMS
Form of
Communication
Boxed
Warning
Professional
Website
Summary of Alleged Violations
powered to evaluate outcomes at the 16-hour time point, and did not apply
appropriate pre-specified adjustments for multiple comparisons between
treatment groups during analysis of the study data.
 Minimization of Risk Information:
o
o
o
21
Website fails to prominently display the Boxed Warning for the drug,
which is not presented until the bottom of the webpage.
The website navigation tab appears to list all sections of the PI, but does
not include the Boxed Warning section.
Boxed Warning risks are conveyed as part of the patient video and text at
the very bottom of the website, but the overall effect of the presentation
undermines the communication of the Boxed Warning.