Mary Carpenter
Director, Regulatory Affairs
Adolor Corporation
700 Pennsylvania Drive
Exton, PA 19341

RE:  NDA 021775
       ENTEREG® (alvimopan) Capsules
       MACMIS #18496


Dear Ms. Carpenter:

As part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has become aware of oral statements made by an Adolor Corporation (Adolor) representative on December 8, 2009, regarding its drug ENTEREG® (alvimopan) Capsules (Entereg).  The representative’s statements minimize the serious risks associated with Entereg and overstate the product’s efficacy.  Thus, this promotional activity misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(n) & (f)(1), and FDA implementing regulations.  21 CFR 202.1(e)(5)(i) & (e)(6)(i). 

Background

According to its FDA-approved product labeling (PI):

Entereg was approved with a risk evaluation and mitigation strategy (REMS) with elements to assure safe use to mitigate a specific serious risk, myocardial infarction, listed in the labeling of the drug.  The REMS includes a special restricted distribution program, the Entereg Access Support and Education (E.A.S.E.™) program.  The PI for Entereg includes a Boxed Warning regarding short-term hospital use only and regarding use only by hospitals which have registered in and met the requirements for the E.A.S.E.  program.  Entereg is contraindicated in patients who have taken therapeutic doses of opioids for more than seven consecutive days immediately prior to taking Entereg.  The PI contains Warnings and Precautions regarding myocardial infarction in a 12 month study in patients treated with opioids for chronic pain, the distribution program for Entereg, opioid tolerance and gastrointestinal-related adverse effects, severe hepatic impairment, end-stage renal disease, and bowel obstruction.  The most common adverse reactions (incidence >3% and >1% placebo) in patients undergoing bowel resection were anemia, dyspepsia, hypokalemia, back pain, and urinary retention. 

False or Misleading Statements/Minimization of Risk Information

On Tuesday, December 8, 2009, at the Entereg exhibit hall booth during the 2009 American Society of Health-System Pharmacists Midyear Clinical Meeting and Exhibition in Las Vegas, Nevada, an Adolor representative stated in word or substance to a DDMAC representative that:

This statement minimizes the serious risks associated with Entereg by misleadingly suggesting that the REMS program is not risk-related.  Contrary to the representative’s statement, the REMS program was implemented to mitigate a serious risk, myocardial infarction, by limiting Entereg’s duration of therapy and use to the appropriate environment— the very subject of the boxed warning.  Adolor was specifically informed of this fact in the May 20, 2008, approval letter for Entereg, which stated that “Entereg can be approved only if the elements necessary to assure safe use are required as part of a REMS to mitigate a specific serious risk, myocardial infarction, listed in the labeling of the drug.” As provided in the Act, risk evaluation and mitigation strategies are required where they are necessary to ensure the benefits of a drug outweigh its risks; such strategies are never “due to logistics.” See 21 U.S.C. 355-1.  The representative’s statement minimizes the REMS and the serious risks associated with the drug, thereby misleadingly suggesting that Entereg is safer than has been demonstrated by substantial evidence or substantial clinical experience.

False or Misleading Statements/Overstatement of Efficacy

On Tuesday, December 8, 2009, the same Adolor representative stated in word or substance to a DDMAC representative that the use of Entereg:

These statements misleadingly overstate the efficacy of Entereg by implying that the use of Entereg will result in a decrease in the incidence of deep vein thromboses or hospital-acquired infections, when such has not been demonstrated by substantial evidence.  We note that the PI states, “Across studies 1-4, patients receiving ENTERG had their discharge order written approximately 13 to 21 hours sooner compared to patients receiving placebo.” However, while the endpoint of hospital discharge may be regarded as potentially clinically meaningful to some healthcare practitioners, endpoints such as reduction of the occurrence of nosocomial infections (e.g. pneumonia, sepsis) and reduction of post-operative complications (e.g. pulmonary embolism, atelectasis, deep vein thrombosis) were not evaluated as prespecified co-primary or secondary endpoints.  FDA is not aware of any substantial evidence or substantial clinical experience to support these claims.  If you have any evidence to support these claims, please submit them to FDA for review. 

Conclusion and Requested Action

The oral statements made by your representative minimize the serious risks associated with Entereg and overstate the efficacy of Entereg, and thus misbrand Entereg in violation of the Act, 21 U.S.C. 352(n) & (f)(1), and FDA implementing regulations.  21 CFR 202.1(e)(5)(i) & (e)(6)(i). 

DDMAC requests that Adolor immediately cease the dissemination of violative promotional materials for Entereg such as those described above.  Please submit a written response to this letter on or before May 5, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Entereg 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 #18496 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 Entereg comply with each applicable requirement of the Act and FDA implementing regulations.

Sincerely,


Kathleen Klemm, Pharm.D. 
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications