• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Drugs

  • Print
  • Share
  • E-mail

DENTSPLY Pharmaceutical 1/4/11

  

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 

Silver Spring, MD 20993 


 

TRANSMITTED BY FACSIMILE

Bret W. Wise
Chairman and Chief Executive Officer
DENTSPLY Pharmaceutical
221 W. Philadelphia Street
York, PA 17405-0872

RE: NDA 021451
Oraqix ® (lidocaine and prilocaine periodontal gel) 2.5% / 2.5%
MACMIS # 18658

WARNING LETTER

Dear Mr. Wise:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed two professional direct mailers (PHA01-0509-1; PHA01-0509-2) (direct mailers), and a professional journal advertisement (PHA01-0509-3) (journal ad) for Oraqix® (lidocaine and prilocaine periodontal gel) 2.5%/2.5% (Oraqix) submitted by DENTSPLY Pharmaceutical (Dentsply) under cover of Form FDA 2253. The direct mailers and journal ad are false or misleading because they omit and minimize risk information associated with Oraqix, make unsubstantiated superiority claims, overstate the efficacy, and broaden the indication of the drug. The direct mailers and journal ad therefore misbrand the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1(e)(5); (e)(6)(i) & (ii); and (e)(7)(viii).

Background

According to its FDA approved product labeling (PI):

Oraqix® is indicated for adults who require localized anesthesia in periodontal pockets during scaling and/or root planing.

Oraqix is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type or to any other component of the product. Oraqix is associated with a number of important warnings and precautions. For example, the PI includes warnings relating to elevated methemoglobin levels and states that Oraqix should not be used in patients with congenital or idiopathic methemoglobinemia. The PI states that pediatric patients are more susceptible to methemoglobinemia. The PI further includes multiple precautions including: directions to not inject Oraqix and to use it with Oraqix® Dispenser only; anaphylactic reactions; and caution in patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally and the greater risk of developing toxic plasma concentrations of lidocaine and prilocaine. The PI also presents information pertaining to the common adverse reactions associated with the drug. Specifically, the PI states, “Following SRP [Scaling and Root Planing] treatment with Oraqix in 391 patients, the most frequent adverse events were local reactions in the oral cavity. . . . These events, which occurred in approximately 15% of patients, included pain, soreness, irritation, numbness, vesicles, ulcerations, edema and/or redness in the treated area.”

According to the CLINICAL STUDIES section of the PI, the percent of patients treated with Oraqix versus placebo reporting “no pain” or “mild pain” during SRP were as follows: 90% versus 64%; 78% versus 76%; and 70% versus 48% in studies B1, B2, and B3 respectively.

Furthermore, the DOSAGE AND ADMINISTRATION section of the PI states, “Apply Oraqix® on the gingival margin around the selected teeth using the blunt-tipped applicator included in the package . . . . If the anesthesia starts to wear off, Oraqix® may be re-applied if needed.”

Selected Prior Communication with DDMAC

(b)(4)

Omission/Minimization of Risk Information

Promotional materials are misleading if they fail to reveal facts that are material in light of the 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 direct mailers and the journal ad present multiple efficacy claims for Oraqix. However, the direct mailers fail to communicate any of the risk information associated with Oraqix. While we note that the statement, “Please refer to prescribing information and DFU enclosed,” appears at the bottom of the direct mailers, this statement does not mitigate the complete omission of risk information from the direct mailers themselves. The journal ad presents only limited risk information associated with Oraqix, and completely omits important and serious precautions regarding anaphylaxis and severe hepatic disease, as well as the common adverse reactions associated with Oraqix (see background section). We note that the statement, “Please see the accompanying brief summary of the prescribing information,” appears at the bottom of the journal ad in small type print. However, this statement does not mitigate the misleading omission of risk information from the main body of the journal ad.

Promotional materials are also misleading if they represent or suggest a drug is safer than has been demonstrated by substantial evidence or substantial clinical experience. The direct mailer (PHA01-0509-1) claims Oraqix “Avoids lingering numbness in the lip and the tongue.”
This and similar claims in the piece minimize the risks associated with Oraqix by implying that patients treated with Oraqix will not experience numbness in the lips and tongue following SRP treatment, when this is not the case. Specifically, as noted in the Background section above, the most frequent adverse events following SRP treatment with Oraqix were local reactions in the oral cavity, including numbness in the treated area, which occurred in approximately 15% of patients. Furthermore, DDMAC notes that in the clinical studies used to assess the safety of Oraqix, numbness in the lips and the tongue were reported as an adverse event with duration ranging from 71 to 252 minutes.

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 journal ad prominently presents efficacy claims with colorful pictures and bolded headlines. In contrast, the limited risk information is presented at the bottom of the page in small font type without any header. As such, the journal ad fails to present the risk information with a prominence and readability reasonably comparable with the presentation of information relating to the effectiveness of the drug.

By omitting and minimizing important risk information, the direct mailers and journal ad misleadingly suggest that Oraqix is safer than has been demonstrated by substantial evidence or substantial clinical experience.

Unsubstantiated Superiority Claims

Promotional materials are misleading if they represent or suggest that a drug is safer or more effective than another drug, when this has not been demonstrated by substantial evidence or substantial clinical experience.

The journal ad and direct mailers present claims such as the following (underlined emphasis added):

• “If you think of injectable anesthesia as standard procedure, think again. Needle-free Oraqix is the fast, effective anesthetic that more clinicians are turning to everyday. . . . There’s a new protocol in patient comfort, and only one name that can deliver it: Needle-free Oraqix.” (journal ad)

• “No needle means greater patient comfort, giving you greater confidence and control.” (journal ad)

• “Greater Patient Comfort. . .Greater Confidence and Control” (direct mailer PHA010509-1) (ellipsis in original)

• “I guess after so many years of scaling and root planing with the needle and then going to [Oraqix], I was a little leery patients would be comfortable. . . Now I’m using it for every patient for scaling and root planing. . . I haven’t needed to give patients the other type of anesthesia.” (direct mailer PHA01-0509-2) (ellipses and brackets in original)

We acknowledge that Oraqix is applied using a blunt-tipped applicator rather than a needle and that this application of the anesthesia may result in more patient comfort initially. However, the absence of a needle stick does not mean that there is greater patient comfort during the SRP procedure itself. These claims above misleadingly imply that Oraqix is clinically superior to injectable anesthetics. For example, the claims imply that Oraqix has a greater anesthetic effect than injectable anesthetics used for SRP, and that patients will be more comfortable during SRP procedures compared with injectable anesthetics (i.e., gives greater patient comfort during these dental procedures and greater healthcare provider confidence and control). The difference in route of administration between Oraqix and injectable anesthetics does not provide support for such implications. In addition, the use of the word “protocol” in the first claim suggests that there is some formal clinical guidance to dentists explaining that Oraqix is superior to injectable anesthetics. FDA is unaware of any such information. The totality of these claims and presentations suggests that Oraqix is more effective and safer than injectable anesthetics for use during scaling and root planing, and is more efficient than such anesthetics based solely on the absence of a needle and the existence of a blunt tip applicator. FDA is not aware of substantial evidence or substantial clinical experience to support these implications. If you have data to support these claims,
please submit them to FDA for review.

Overstatement of Efficacy

Promotional materials are misleading if they suggest that a drug is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The journal ad and direct mailer make numerous claims that misleadingly overstate the efficacy of Oraqix.
These claims include the following (underline emphasis added):

• “Just apply Oraqix within the subgingival pocket for exceptional, clinically proven results.” (journal ad)

• “It’s nice to be able to tell them I’m going to give you anesthesia but it’s not going to be a shot. You can see their reaction… It’s amazing how it changes everything.” (direct mailer PHA01-0509-2) (ellipses in original)

• “A lot of people, if they see a hygienist they don’t usually see will ask for it because it’s been used before and they’re comfortable with it… [Using Oraqix saves time] because you can feel confident that the person is comfortable; You don’t have to keep stopping and reaffirming that. . . it makes them more relaxed” (direct mailer PHA01-0509-2) (ellipses and brackets in original)

These and similar claims misleadingly overstate the efficacy of Oraqix by implying that the administration of Oraqix ensures patient comfort, changes every aspect (“everything”) of the dental experience, decreases or eliminates the need for the clinician to periodically reassess the patient, and shortens the overall procedure time (“saves time”). FDA is not aware of substantial evidence or substantial clinical experience to support these implications. As noted in the background section above, Oraqix may wear off requiring the practitioner to stop the procedure and re-apply the drug. Additionally, 10% to 30% of the patients treated with Oraqix in the clinical studies failed to achieve “no pain” or even “mild pain.” Moreover, Oraqix is associated with numerous adverse reactions during and after the SRP procedure that may impact the dental experience, or prevent a patient from feeling comfortable, such as pain, soreness, irritation, numbness, vesicles, ulcerations, edema and/or redness in the treated area.

Broadening of Indication

Promotional materials are misleading if they suggest that a drug is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. The direct mailer presents the claim (underlined emphasis added):

• “A lot of people won’t even let me clean their teeth without Oraqix” (direct mailer PHA01-0509-2)

This claim is misleading because it suggests that Oraqix is safe and effective for use in any patient undergoing routine dental cleaning, when this is not the case. Rather, as stated in the PI, “Oraqix® is indicated for adults who require localized anesthesia in periodontal pockets during scaling and/or root planing.” (emphasis added).

The direct mailer, PHA01-0509-2 also presents the following claim: (emphasis added):

• “I guess after so many years of scaling and root planing with the needle and then going to [Oraqix], I was a little leery patients would be comfortable. . . Now I’m using it for every patient for scaling and root planing. . . .” (direct mailer PHA01-0509-2)

This claim and other similar claims are misleading because they suggest that Oraqix is safe and effective for use in all patients undergoing scaling and/or root planing procedures. Oraqix is not approved for this broad patient population. As noted above, Oraqix is indicated for use only in adult patients, not pediatric patients,1 and only in those adult patients who require localized anesthesia during scaling and/or root planing procedures.

This promotional piece thus misleadingly broadens the indication of Oraqix by suggesting that the drug is useful in a broader range of conditions and patients than has been demonstrated by substantial evidence or substantial clinical experience. These misleading presentations are exacerbated by the failure to provide the complete limitations to the approved indication in these promotional materials.

Conclusion and Requested Action

For the reasons discussed above, the direct mailers and journal ad misbrand Oraqix in violation of the Act, 21 U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1(e)(5); (e)(6)(i) & (ii); and (e)(7)(viii).

DDMAC requests that Dentsply immediately cease the dissemination of violative promotional materials for Oraqix such as those described above. Please submit a written response to this letter on or before January 19, 2011, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Oraqix that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials. Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, or facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS 18658 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 Oraqix comply with each applicable requirement of the Act and FDA implementing regulations.

Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.

 

Sincerely,
{See appended electronic signature page}

Thomas W. Abrams, RPh, MBA
Director
Division of Drug Marketing,
Advertising, and Communications
 


---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------

/s/
----------------------------------------------------

THOMAS W ABRAMS
01/04/2011
 

Reference ID: 2886305

 

 

1We note that the PI includes warnings relating to elevated methemoglobin levels and states that Oraqix should not be used in patients with congenital or idiopathic methemoglobinemia. Oraqix is not approved in pediatric patients. The Pediatric section of the PI for Oraqix states, “Safety and effectiveness in pediatric patients have not been established. Very young children are more susceptible to methemoglobinemia. . . .”