FDA Sends Letter to Novalar Regarding Promotions for OraVerse
ROCKVILLE, Md., Feb. 2, 2010 - The FDA today posted on its website a letter sent to Novalar Pharmaceuticals regarding a patient brochure for OraVerse injection. The letter is below.
DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health
Service
Food and Drug Administration Silver Spring, MD 20993
TRANSMITTED BY FACSIMILE
Laura A. Navalta Senior Vice President, Clinical and Regulatory
Novalar Pharmaceuticals, Inc. 12555 High Bluff Drive, Suite 300 San
Diego, CA 92130
RE: NDA #22-159
OraVerse (phentolamine mesylate) Injection
MACMIS #18185
Dear Ms. Navalta:
As part of its monitoring and surveillance program, the Division of
Drug Marketing, Advertising, and Communications (DDMAC) of the U.S.
Food and Drug Administration (FDA) has reviewed a
direct-to-consumer (DTC) patient brochure (0128, Rev. 01/2009) for
OraVerse (phentolamine mesylate) Injection (OraVerse) submitted by
Novalar Pharmaceuticals, Inc. (Novalar) under cover of Form FDA
2253. The patient brochure is misleading because it omits and
minimizes risks associated with the use of OraVerse, broadens the
indication for OraVerse and overstates the efficacy of OraVerse.
Thus, the patient brochure misbrands the drug in violation of the
Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a)
and 321(n), and FDA implementing regulations. 21 CFR 1.21(a); cf.
202.1(e)(5); (e)(6)(i), (xviii), & (e)(7)(viii).
Background
According to the Indications and Usage section of the FDA-approved
product labeling (PI):
OraVerse is indicated for reversal of the soft-tissue anesthesia,
i.e., anesthesia of the lip and tongue, and the associated
functional deficits resulting from an intraoral submucosal
injection of a local anesthetic containing a vasoconstrictor.
OraVerse is not recommended for use in children less than 6 years
of age or weighing less than 15 kg (33 lbs).
OraVerse is associated with a warning and precaution regarding
cardiovascular events. The most common adverse reaction with
OraVerse that was greater than the control group was injection site
pain. Adverse reactions, where the frequency was greater than or
equal to 3% in any OraVerse dose group and was equal to or exceeded
that of the control group, were tachycardia, bradycardia, injection
site pain, post procedural pain, and headache.
The Pediatric Use section of the PI states that the safety, but not
the efficacy, of OraVerse has been evaluated in pediatric patients
under the age of 6 years old.
In clinical studies, the primary endpoint was time to normal lip
sensation as measured by patient reported responses to lip
palpation. The secondary endpoints included patients’
perception of altered function, sensation and appearance, and their
actual functional deficits in smiling, speaking, drinking and
drooling.
Omission and Minimization of Risk
Promotional materials are misleading if they fail to reveal
material facts in light of representations made by the materials or
with respect to consequences that may result from the use of the
drug as recommended or suggested by the materials. The patient
brochure presents various efficacy claims for OraVerse, but omits
material risks associated with OraVerse treatment. In particular,
while the “Important Safety Information” presentation
in the brochure discloses that tachycardia, bradycardia, and
cardiac arrhythmias may occur, it fails to disclose any other risk
information for OraVerse, including the other common adverse
reactions experienced with OraVerse treatment (see background
section).
In addition, promotional materials are misleading if they fail to
present information about risks associated with a drug with a
prominence and readability reasonably comparable with the
presentation of information relating to the effectiveness of the
drug. The patient brochure prominently presents efficacy claims in
large bolded font size and colorful text and graphics surrounded by
a significant amount of white space. In contrast, risk information
is presented in small black font, and in single-spaced paragraph
format on the last fold of the brochure. Furthermore, while the
patient brochure presents efficacy claims for OraVerse in language
that is easily understandable to consumers, it presents risk
information using complex medical terminology that is not likely to
be comprehended by the same audience.
Therefore, the overall effect of this presentation undermines the
communication of important risk information, minimizing the risks
associated with OraVerse and misleadingly suggesting that OraVerse
is safer than has been demonstrated.
Broadening of Indication
The patient brochure is misleading because it suggests that
OraVerse is useful in a broader range of conditions or patients
than has been demonstrated by substantial evidence or substantial
clinical experience. Specifically, the patient brochure contains
the claim, “And now the safety and effectiveness of OraVerse
have been successfully demonstrated through clinical trials
involving pediatric, adolescent and adult patients ages 4 through
92.” This claim misleadingly suggests that OraVerse is
approved for all patients ages 4 through 92, when this is not the
case. FDA is not aware of substantial evidence to support efficacy
claims in patients under the age of 6 years old. According to the
Indications and Usage section of the PI, OraVerse is not
recommended for use in children less than 6 years of age or
weighing less than 15 kg (33 lbs). Furthermore, the Pediatric Use
section of the PI states, “The safety, but not the efficacy,
of OraVerse has been evaluated in pediatric patients under the age
of 6 years old” (emphasis added).
Overstatement of Efficacy/Minimization of Risk
Promotional materials are misleading if they suggest that a drug is
more effective or safer than has been demonstrated by substantial
evidence or substantial clinical experience. The patient brochure
includes the following claims (bolded emphasis in original;
underlined emphasis added):
•
“A new direction in comfort”
•
“Your dental professionals want you to have the most
comfortable experience
possible.”
•
“This breakthrough changes your measure of comfort by
creating an easy and
expedient return to your normal activities.
These claims misleadingly overstate the efficacy of OraVerse by
implying that treatment with OraVerse will provide
“comfort” for dental patients. FDA is not aware of
substantial evidence to support claims made in the patient brochure
related to the “comfort” of patients treated with
OraVerse. Moreover, these claims also minimize the risks associated
with OraVerse that may prevent a patient from feeling comfortable.
As stated in the PI, the most common adverse reaction with OraVerse
that was greater than the control group was injection site pain.
The presentations related to comfort in the patient brochure
minimize this risk and misleadingly suggest that OraVerse is safer
than has been demonstrated by substantial evidence or substantial
clinical experience.
The patient brochure also contains the following claims (bolded
emphasis in original):
•
“From numb to normal . . . it’s about
time.”
•
“OraVerse™ brings you back”
•
“This breakthrough changes your measure of comfort by
creating an easy and
expedient return to your normal activities.”
•
“Your return to normal”
•
“And that’s time you can put back in your day . . .
doing what you want to do without limitations.”
The totality of this presentation is misleading because it
overstates the efficacy of OraVerse by implying that the drug has a
broad impact on a patient’s activities of daily living. While
OraVerse’s impact on time to normal lip sensation and on
patients’ perception of altered function, sensation and
appearance or their actual functional deficits in smiling,
speaking, drinking, or drooling, was assessed in OraVerse clinical
studies, we are not aware of substantial evidence to support the
broad suggestions conveyed by the above claims (i.e., that patients
will be able to return to “normal,” engage in
“normal” activities without limitations and have time
to “put back in [their] day” after treatment with
OraVerse). Moreover, the common adverse reactions patients may
experience with OraVerse could all impact a patient’s ability
to return to “normal” and engage in
“normal” activities without limitations. Additionally,
OraVerse is indicated only for the reversal of the soft-tissue
anesthesia and not relief of pain from the dental procedure itself,
which may also prevent a patient’s return to
“normal” or engagement in “normal”
activities without limitations.
The patient brochure also contains the claim, “And for
parents, there is added peace of mind in knowing children will
regain normal feeling more quickly with OraVerse.” This claim
is misleading because it overstates the treatment benefit of
OraVerse by implying that the drug will give parents “peace
of mind” regarding the effects of reversal of soft-tissue
anesthesia or other aspects related to treatment with OraVerse,
when this has not been demonstrated by substantial evidence.
Furthermore, this claim misleadingly suggests a safety benefit
associated with the reversal of the local anesthetic when no such
benefit has been evaluated or observed in clinical studies for
OraVerse. This claim is particularly troubling given the misleading
claim in the brochure (discussed above) that OraVerse has been
shown to be safe and effective for children as young as 4 years of
age.
Conclusion and Requested Action
For the reasons discussed above, the patient brochure misbrands
OraVerse in violation of the Federal Food, Drug, and Cosmetic Act
(the Act), 21 U.S.C. 352(a) and 321(n), and FDA implementing
regulations. 21 CFR 1.21(a); cf. 202.1(e)(5); (e)(6)(i), (xviii),
& (e)(7)(viii).
DDMAC requests that Novalar immediately cease the dissemination of
violative promotional materials for OraVerse such as those
described above. Please submit a written response to this letter on
or before February 5, 2010, stating whether you intend to comply
with this request, listing all promotional materials (with the 2253
submission date) for OraVerse that contain violations such as those
described above, and explaining your plan for discontinuing use of
such violative materials. Please direct your response to me at the
Food and Drug Administration, Center for Drug Evaluation and
Research, Division of Drug Marketing, Advertising, and
Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266,
facsimile at 301-847-8444. In all future correspondence regarding
this matter, please refer to MACMIS # 18185 in addition to the NDA
number. We remind you that only written communications are
considered official.
The violations discussed in this letter do not necessarily
constitute an exhaustive list. It is your responsibility to ensure
that your promotional materials for OraVerse comply with each
applicable requirement of the Act and FDA implementing
regulations.
Sincerely,
{See appended electronic signature page}
Twyla Thompson, Pharm.D. Regulatory Review Officer Division of Drug
Marketing, Advertising, and Communications
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Application Submission
Submitter Name Product Name
Type/Number Type/Number
NDA-22159 ORIG-1 NOVALAR PHENTOLAMINE MESYLATE
PHARMACEUTICA INJECTION
LS INC
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
TWYLA N THOMPSON 01/22/2010
Posted: February 2010
