Bala Venkataraman, CEO
Alaven Pharmaceutical LLC
200 North Cobb Parkway, Suite 428
Marietta, GA 30062

RE:  NDA #19-618
       Rowasa^® (mesalamine) Rectal Suspension Enema
       MACMIS #17336

Dear Mr. Venkataraman:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a Holiday Promotion Postcard 2008 (postcard) for Rowasa^® (mesalamine) Rectal Suspension Enema (Rowasa) submitted by Alaven Pharmaceutical LLC (Alaven) under cover of Form FDA-2253.  The postcard is misleading because it omits important risk information associated with the use of Rowasa, overstates the efficacy of the drug, and broadens the indication of Rowasa.  Thus, the postcard misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) and 321(n).  Cf. 21 CFR 202.1(e)(5) & (e)(6)(i).  In addition, it appears that the postcard was not accompanied by the FDA-approved product labeling (PI) for Rowasa in violation of 21 CFR 201.100(d).  These violations are a concern from a public health perspective because they suggest that the product is safer and more effective than has been demonstrated. 

Background

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

ROWASA^® (mesalamine) Rectal Suspension Enema is indicated for the treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis or proctitis. 

Rowasa is also associated with several risks, including the following Warnings and Precautions:

ROWASA^® (mesalamine) Rectal Suspension Enema contains potassium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.  .  . 

Mesalamine has been implicated in the production of an acute intolerance syndrome characterized by cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache and a rash; in such cases prompt withdrawal is required.  . 

Patients on ROWASA® (mesalamine) Rectal Suspension Enema, especially those on concurrent oral products which liberate mesalamine and those with preexisting renal disease, should be carefully monitored with urinalysis, BUN (blood urea nitrogen), and creatinine studies.  . 

[C]aution should be exercised when mesalamine is initially used in patients known to be allergic to sulfasalazine.  These patients should be instructed to discontinue therapy if signs of rash or fever become apparent. 

While using ROWASA® (mesalamine) Rectal Suspension Enema, some patients have developed pancolitis.  . 

Worsening of colitis or symptoms of inflammatory bowel disease, including melena and hematochezia, may occur after commencing mesalamine. 

Rare instances of pericarditis have been reported with mesalamine containing products including sulfasalazine. 

Additionally, the PI includes the following adverse reactions that occurred at an incidence of >2% and greater than placebo: Abdominal Pain/Cramps/Discomfort (8.10% versus 7.81 % for placebo), Gas/Flatulence (6.13% versus 3.91 % for placebo), Flu (5.28% versus 0.78% for placebo), Fever (3.19% versus 0.00% for placebo) and Leg/Joint Pain (2.09% versus 0.78% for placebo). 

Omission of Risk Information

Promotional materials are misleading if they fail to reveal facts that are material 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 postcard presents various efficacy claims for Rowasa, but entirely omits risk information for Rowasa, including the warnings, precautions, and common adverse events associated with the drug.  We acknowledge that the statement, “For Full Prescribing Information visit www.rowasakit.com” is written in small type font at the bottom of the postcard.  However, this does not mitigate the misleading omission of risk information.  By omitting the most serious and frequently occurring risks associated with the drug, the postcard misleadingly suggests that Rowasa is safer than has been demonstrated. 

Overstatement of Efficacy

Promotional materials are misleading if they suggest that a drug product is more effective than has been demonstrated by substantial evidence or substantial clinical experience.   Specifically, the postcard states the following:

. . . Unwanted UC flares can make a surprise visit during the holidays.  A change in diet and erratic stress levels may make flare symptoms worse.  Make sure your patients are armed and ready with flare relief.  Give them the gift of ROWASA Kit now.  With a sample and a prescription of ROWASA Kit on hand, your patients are flare ready.  They can enjoy the holidays (and so can you!) (underlined emphasis in original; bolded emphasis added; footnote omitted). 

The above claims overstate the efficacy of Rowasa by implying that treatment with Rowasa will allow patients and their healthcare providers to “enjoy the holidays” by successfully treating all the various symptoms of flares from ulcerative colitis despite changes in stress and diet.  We are not aware of substantial evidence or substantial clinical experience to support this implication.  While Rowasa has been shown to reduce patients’ disease activity index (DAI) over several weeks (according to the Clinical Pharmacology section of the PI, Rowasa reduced overall DAI by 55.07% versus 21.58% reduction for placebo (change from baseline to endpoint)), this does not in any way support the implication that Rowasa will keep all symptoms under control during time periods like the holidays where flares are particularly likely to occur.  We also note that Rowasa therapy is associated with numerous adverse events, as described in the Background section above, any of which can impair patient enjoyment of the holidays. 

Broadening of Indication

The postcard is misleading because it suggests that Rowasa is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience.  Specifically, the postcard presents the following claims:

‘tis the Season for UC [ulcerative colitis] Flares
Unwanted UC flares can make a surprise visit during the holidays.  .  .  .Make sure your patients are armed and ready with flare relief .  .  .  .  With a sample and a prescription of ROWASA Kit on hand, your patients are flare ready (bolded and italicized emphasis in original; underlined emphasis added; footnote omitted). 

These claims misleadingly suggest that Rowasa is approved to treat any patient with ulcerative colitis.  However, Rowasa is indicated, among other conditions, for the treatment of active mild to moderate distal ulcerative colitis.  The postcard fails to present this material limitation, thereby broadening the indication of Rowasa. 

Failure to Provide Adequate Directions for Use

We note that the postcard does not appear to have been disseminated with the full FDA- approved product labeling (PI) for Rowasa, in violation of 21 CFR 201.100(d). 

Conclusion and Requested Action

For the reasons discussed above, the postcard misbrands Rowasa in violation of the Act, 21 U.S.C. 352(a) and 321(n).  Cf. 21 CFR 202.1(e)(5) & (e)(6)(i).  In addition, it appears that the postcard was not accompanied by the FDA-approved product labeling (PI) for Rowasa in violation of 21 CFR 201.100(d). 

DDMAC requests that Alaven immediately cease the dissemination of violative promotional materials for Rowasa such as those described above.  Please submit a written response to this letter on or before July 27, 2009, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) in use for Rowasa as of the date of this letter, identifying which of these materials 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 #17336 in addition to the NDA number.  We remind you that only written communications are considered official.  If you choose to revise your promotional materials, DDMAC is willing to assist you with your revised materials by commenting on your revisions before you use them in promotion. 

The violations discussed in this letter do not necessarily constitute an exhaustive list.  It is your responsibility to ensure that your promotional materials for Rowasa 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,

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