Released by FDA: 8/5/02.  Posted by FDA:  9/4/02

Louise C. Johnson
Director, Regulatory Affairs
Elan Pharmaceuticals
800 Gateway Blvd.
South San Francisco, CA 94080

Re:   NDA # 20-397
        Zanaflex (tizanidine HCl) Tablets
        MACMIS # 10596

Dear Ms. Johnson:

This letter concerns the dissemination of promotional materials for Zanaflex (tizanidine HCl) Tablets.  As part of its routine monitoring and surveillance program, the Division of Drug Marketing, Advertising,. and Communications (DDMAC) has reviewed a visual aid (#ZFX-10730102) and a jar (#ZFX-1041.1001) submitted undercover of  Form FDA 2253 by Elan Pharmaceuticals (Elan).  These materials are misleading and, therefore, promote Zanaflex in violation of the Federal Food, Drug, and Cosmetic Act and applicable regulations.

Specifically, DDMAC has the following objections:

Unsubstantiated Efficacy Claims

The claim "Get Life Moving Again" (jar) and the graphic entitled "Complications associated with spasticity affect daily life" (page 3 of the visual aid) are misleading overstatements of efficacy because they imply that Zanaflex will improve general activities of daily living when this has not been demonstrated by adequate and well-controlled clinical studies.  Similarly, the graphic of the woman walking away from her shackles (on every page of the visual aid) implies a much broader freedom of movement than can be achieved by short-term alleviation of spasticity.  Finally, the tagline "Restore and Relieve" is a misleading overstatement of efficacy because the term "restore" implies, without substantiation, that Zanaflex treatment will provide symptomatic relief that brings an individual back to fully normal functioning for an indefinite period of time.

The above mentioned claims and presentations are also misleading because they are directly inconsistent with the approved product labeling (PI) for Zanaflex.  Specifically, the Clinical Studies section of the PI states that the reduction in muscle tone with Zanaflex compared to placebo "did not lead to any consistent advantage of tizanidine treated patients on measures of activities of daily living." (Emphasis added)  Moreover, the Indications and Usage section of the PI states that Zanaflex "is a short acting drug for the management of spasticity.  Because of the short duration of effect, treatment with tizanidine should be reserved for those daily activities and times when relief of spasticity is most important."

DDMAC finds these new claims particularly troublesome because, on January 16, 2002, we sent you an untitled letter objecting to the same or similar issues in promotional materials for Zanaflex.  Your response, dated January 25, 2002, assured us that Elan Pharmaceuticals (Elan) intended to comply with DDMAC's recommendations to discontinue the use of promotional materials and activities that conveyed the violative information.  Notwithstanding these commitments and assurances, Elan is continuing to make violative, unsubstantiated claims suggesting an impact on daily activities. We are concerned that the presentations described above demonstrate a continuing pattern and practice of violative behavior, in disregard of our previous comments and your representations to us.  Consequently, we request that you provide a detailed response to this issue.

Other Misleading Claims

1. The presentation on page 11 of the visual aid (e.g., "Few known interactions with Rx medications" and "Not likely to affect the metabolism of other drugs...") is misleading because it implies that Zanaflex has no problematic drug interactions when, in fact, Zanaflex interacts substantially with alcohol, oral contraceptives, and acetaminophen (see Drug Interactions section of the PI).
    
2. The claim that Zanaflex has a "unique dual CNS action" (jar and pages 4-5 of the visual aid) is misleading because the mechanism of action has not been fully elucidated.  Furthermore, the term "unique" implies that Zanaflex is distinct in its properties from other anti-spasmodic agents when, in fact, others may have the same mechanisms of action.

Fair Balance

The visual aid is lacking fair balance because it fails to provide sufficient emphasis regarding the warnings of Zanaflex.  For example, the warnings regarding risk of liver injury (associated with at least one death), sedation, and hallucinations, are minimized by listing them as "other adverse events" in a paragraph pertaining to common adverse events (see pages 7, 9, and 10).  Furthermore, the warning regarding hypotension is not addressed in the visual aid.

DDMAC requests that you immediately discontinue the use of the jar, the visual aid, and any other promotional material and practices with the same or similar messages, and that you submit a written response to this letter within ten days.  Your response should include a statement of your intent to comply with the above, a list of all promotional materials with the same or similar issues, and your methods for discontinuing these promotional materials.

If you have any questions or comments, please contact me by facsimile at (301) 594-6771, or at the Food and Drug Administration, Division of Drug Marketing, Advertising and Communications, HFD-42, rm. 17B-20, 5600 Fishers Lane, Rockville, MD 20857.  DDMAC reminds you that only written communications are considered official.  In all future correspondence regarding this particular matter, please refer to MACMIS ID # 10596 in addition to the NDA number.

Sincerely,


Lisa L. Stockbridge, Ph.D.
Regulatory Reviewer
Division of Drug Marketing,
  Advertising and Communications