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


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