Released by FDA: 6/27/00.  Posted by FDA:  7/17/00

Kevin Dransfield 
Manager, Drug Regulatory Affairs 
Boehringer Ingeiheim Pharmaceuticals, Inc. 
900 Ridgebury Road 
P.O. Box 368 
Ridgefteld, CT 06877

RE:    NDA 20-636 / 20-933 
         Viramune (nevirapine) Tablets and Oral Suspension 
         MACMIS ID #9064

Dear Mr. Dransfield:

This letter is to inform the Regulatory Affairs Department of Boehringer lngelheim Pharmaceuticals, inc. (BIPI) that the current web site for Viramune is in violation of the Federal Food, Drug and Cosmetic Act (the Act) and its applicable regulations.  As part of our monitoring and surveillance program, the Division of Drug Marketing, Advertising and Communications (DDMAC) reviewed the web site on June 23, 2000. The web site is violative for the reasons cited below.

Use of Outdated Product Labeling 
The Viramune web site violates the Act because an outdated version of the approved product labeling (P1) is linked to the promotional messages on your www.viramune.com web site.  The failure of providing the current Pl results in the omission of important safety information as described below.

The Food and Drug Administration (FDA) approved revisions to the Viramune Pl in October 1999.  These revisions included adding risk information to the boxed warning and other sections of the Pl regarding potentially fatal hypersensitivity reactions, as well as adding new drug interaction information.  Although the main web page states that the Viramune web site was updated on April 13, 2000, the “Product Information” is linked to a September 10, 1998 version of the l.  The September 1998 version of the Pl fails to include, among other things, information about fatal hypersensitivity reactions that have occurred in patients treated with Viramune, characteristics of these reactions and that Viramune must be discontinued as soon as possible if hypersensitivity is suspected. Your failure to provide the most current Pl misbrands Viramune.  DDMAC is especially concerned with this violation since the omission of complete information about this potentially fatal adverse reaction associated with Viramune raises significant safety concerns.

“Product Information” Web Page 
Although DDMAC did not object to a detail aid that contains the same or similar claims as those presented on the Viramune “Product Information” web page, the review was done in 1996 and based on the original Pl.  Since that review in 1996, the Viramune Pl has been revised a number of times, several antiviral agents for HIV have been approved by FDA and the issues surrounding the care of patients with HIV have evolved.  Despite the changes cited above, the information on the Viramune “Product Information” web page has not been revised. Important risk information from the current Pl is not included on this web page and numerous claims on this web page are misleading.

Omission of important Risk information 
The risk information listed under the heading “Generally well tolerated” is misleading because the information is not complete and the selective presentation of data suggests Viramune is safer than clinical evidence demonstrates.  Information regarding the potentially fatal hypersensitivity reaction is not listed.  In addition, the risk for potentially fatal hepatotoxicity is minimized by the statement “Because hepatitis has occasionally been reported, liver function tests should be monitored.”  Finally, adverse reaction data from Trial Bl 1046 are not included.   The data from this trial are included in the current Pl and reflect a higher incidence rate for adverse reactions than currently presented in the table on the web page.  

Misleading Claims 
The claim of “no clinically significant drug interactions” with Viramune is misleading because it minimizes the risk of potentially significant drug interactions.  Currently, information in the Precautions/Drug Interactions section states that:

• Rifampin/rifabutin should only be used concomitantly with Viramune if clearly indicated and with careful monitoring. 

• Oral contraceptives should not be administered concomitantly with Viramune. 

• Viramune and ketoconazole should not be administered concomitantly. 

• Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

Your claim of “no significant drug interactions” is misleading because it implies that Viramune is not associated with drug interactions and it fails to describe important information about the concomitant use of specific drugs with Viramune.

The claim that Viramune possesses “Unique features for patient compliance” is misleading because the features touted as unique to Viramune are no longer unique.  For example, Viramune’s dosing interval is not unique.  A number of antiretroviral drugs, including a non-nucleoside reverse transcriptase inhibitor (NNRTI) like Viramune, are approved for once daily or twice daily dosing.  Although more than one tablet or capsule may be required, there is a lack of evidence documenting that patients taking fewer pills at the same dosing interval are more compliant.  Thus, these dosing characteristics are inadequate to support your patient compliance claim.

Patient Information Web Page 
The information found on the “Patient Information” web page contains the same or similar claims from a patient brochure reviewed by DOMAC in 1996.  Revisions to the Viramune Pl and changes in the standard of care for patients with HIV render much of the information on the web page misleading.  The web page contains several statements that imply that monotherapy is an option for patients with HIV.  For example, statements such as “Combination class therapy rnay be more effective against H IV” (emphasis added) are misleading.  The current standard of care for patients with HIV is combination therapy.  In addition, important risk information is not included in the section titled “Potential Side Effects Associated With Viramune (rievirapine).”  For example, information regarding hepatotoxicity and hypersensitivity reactions, both potentially life-threatening adverse reactions, is not included.  The combination of out- of-date information regarding HIV therapy and the omission of important risk information poses a significant safety risk to patients accessing the Viramune “Patient Information” web page for information on HIV therapy and Viramune.

BlPl should immediately cease using the Viramune web pages and all other promotional materials for Viramune that fail to provide the current Pl or that contain the same or similar claims or presentations.  BIPI should submit a written response to DDMAC on or before July 12, 2000 describing its intent and plans to comply with the above.  Your response should list similarly violative materials that were discontinued and the discontinuation date.

The violations discussed in this letter do not necessarily constitute an exhaustive list. We are continuing to evaluate other aspects of your web site and may determine that additional remedial measures will be necessary.

If you have any questions, please contact the undersigned by facsimile at (301) 594- 6771 or by written communication at the Division of Drug Marketing, Advertising and Communications, HFD-42, Room 17B-20, 5600 Fishers Lane, Rockville, MD 20857. In all future correspondence regarding this matter, please refer to MACMIS ID #9064 and the NDA number.  DDMAC reminds BIPI that only written communications are considered official.

Sincerely.

Rebecca Redman, Pharrn.D.
Regulatory Review Officer 
Division of Drug Marketing, Advertising and 
   Communications