Graydon Elliott, Director DRA
Regulatory Advertising & Promotional Review
Novartis Pharmaceuticals Corporation
One Health Plaza
East Hanover, NJ 07936

RE: NDA No. 20-726 Femara® (letrozole tablets)
      NDA No. 21-283 Diovan® (valsartan) Tablets
      NDA No. 21-990 Exforge® (amlodipine and valsartan) Tablets
      NDA No. 21-882 EXJADE® (deferasirox) Tablets for Oral Suspension
      NDA No. 21-588 GLEEVEC® (imatinib mesylate) Tablets for Oral Use
      MACMIS ID #17313

Dear Mr. Elliott:

As part of its monitoring and surveillance program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U. S. Food and Drug Administration (FDA) has reviewed Novartis Pharmaceuticals Corporation’s (Novartis) sponsored links on internet search engines (e.g., Google.com) for the following products: Femara® (letrozole tablets) (Femara), Diovan® (valsartan) Tablets (Diovan), Exforge® (amlodipine and valsartan) Tablets (Exforge), EXJADE® (deferasirox) Tablets for Oral Suspension (Exjade), and GLEEVEC® (imatinib mesylate) (Gleevec).  The sponsored links cited in this letter are misleading because they make representations and/or suggestions about the efficacy of Femara, Diovan, Exforge, Exjade, and Gleevec, but fail to communicate any risk information associated with the use of these drugs.  In addition, the sponsored links for Femara and Exjade inadequately communicate the drugs’ indications.  Furthermore, all of the sponsored links fail to use the required established name.  Thus, the sponsored links misbrand the drugs in violation of the Federal Food, Drug, and Cosmetic Act (the Act) and FDA implementing regulations.  See 21 U. S.C. 352(a) & (n), 321(n); 21 CFR 201.10(g)(1), 202. 1(b)(1), (e)(3)(i), (ii) & (e)(6)(i).

Background

Femara
According to its FDA-approved product labeling (PI), Femara “is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer....

Femara is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy....

Femara is indicated for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer.  Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.”

The Indications and Usage section of the PI includes important limitations for Femara’s use in the adjuvant setting, including that the effectiveness of Femara in early breast cancer is based on an analysis of disease-free survival in patients treated for a median of 24 months and followed for a median of 26 months and follow up analyses will determine long-term outcomes for both safety and efficacy.  This section also includes important limitations for Femara’s use in the extended adjuvant setting, including that the effectiveness of Femara in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated for a median of 24 months and further data will be required to determine long-term outcome.

Femara is associated with a number of risks, as reflected in the Contraindications, Warnings, Precautions, and Adverse Reactions sections of its PI.

Diovan
According to its FDA-approved PI, Diovan is indicated, among other things, for the treatment of hypertension.  It may be used alone or in combination with other antihypertensive agents. 

Diovan is associated with a number of risks, as reflected in the Boxed Warning, Warnings and Precautions, and Adverse Reactions sections of its PI.

Exforge
According to its FDA-approved PI, Exforge “is indicated for the treatment of hypertension.

Exforge may be used in patients whose blood pressure is not adequately controlled on either [amlodipine or valsartan as] monotherapy.

Exforge may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. 

The choice of Exforge as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the lowest dose of Exforge….”

Exforge is associated with a number of risks, as reflected in the Boxed Warning, Warnings and Precautions, and Adverse Reactions sections of its PI. 

Exjade
According to its FDA-approved PI, Exjade “is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.”

Exjade is associated with a number of risks, as reflected in the Contraindications, Warnings and Precautions, and Adverse Reactions sections of its PI. 

Gleevec
According to its FDA-approved PI, Gleevec is indicated for the following:

•  Newly diagnosed adult patients with Philadelphia chromosome positive chronic
myeloid leukemia in chronic phase.  Follow-up is limited to 5 years. 
•  Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. 
•  Pediatric patients with Ph+ CML in chronic phase who are newly diagnosed or whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy.  There are no controlled trials in pediatric patients demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. 
•  Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia. 
•  Adult patients with myelodysplastic/myeloproliferative diseases associated with
PDGFR (platelet-derived growth factor receptor) gene re-arrangements. 
•  Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. 
•  Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. 
•  Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. 
•  Patients with Kit (CD117) positive unresectable and/or metastatic malignant
gastrointestinal stromal tumors. 
•  Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST. 

Gleevec is associated with a number of risks, as reflected in the Warnings and Precautions and Adverse Reactions sections of its PI.

Omission of Risk Information

Promotional materials, other than reminder pieces, which include the name of the drug product but do not include indications or other representations or suggestions relative to the drug product (see 21 CFR 200.200, 201.100(f), 202.1(e)(2)(i)), are required to disclose risk and other information about the drug.  Such 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 sponsored links present the following claims:

•  Breast Cancer Information
Online Resource for Women with
Breast Cancer.  Review Treatments. 
www.Femara.com

•  What is Hypertension?
www.DIOVAN.com Get The Facts & Effective Treatment Now - Receive Free Info At Home. 

•  High Blood Pressure?
Information About a Powerful
Combination Treatment To Lower BP. 
www.EXFORGE.com

•  EXJADE ® Treatment
www.US.EXJADE.com No more pumps or infusions for Iron Overload.  Learn More

•  GLEEVEC ® Official Site
www.Gleevec.com Find Out How GLEEVEC Helps Treat Certain Forms of Cancer.  Learn More

These sponsored links make representations and/or suggestions about the efficacy of Femara, Diovan, Exforge, Exjade, and Gleevec, respectively, but fail to communicate any risk information.  This omission of risk information is particularly concerning as two of these products, Diovan and Exforge, have Boxed Warnings.  For promotional materials to be truthful and non-misleading, they must contain risk information in each part as necessary to qualify any claims made about the drug.

By omitting the most serious and frequently occurring risks associated with the drugs promoted in the links above, the sponsored links misleadingly suggest that Femara, Diovan, Exforge, Exjade, and Gleevec are safer than has been demonstrated.  We note that these sponsored links contain a link to the products’ websites.  However, this is insufficient to mitigate the misleading omission of risk information from these promotional materials.

Inadequate Communication of Indication

The sponsored links for Femara and Exjade provide very brief statements about what the drugs are for; however, these statements are incomplete and misleading, suggesting that these drugs are useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. 
Specifically, the sponsored link for Femara misleadingly broadens the indication for Femara by implying that the drug is approved to treat the broad population of women with breast cancer (“Breast Cancer Information…Online Resource for Women with Breast Cancer.  Review Treatments.” in conjunction with the drug name), when this is not the case.  Rather, Femara’s indication for breast cancer is limited to the treatment of postmenopausal women in the adjuvant, extended adjuvant, advanced, and metastatic breast cancer settings.  In addition, there are important limitations of Femara’s use in the adjuvant and extended adjuvant breast cancer settings, none of which are conveyed in the link.

The sponsored link for Exjade misleadingly broadens the indication for Exjade by implying that all patients with iron overload are candidates for Exjade therapy (“No more pumps or infusions for Iron Overload” in conjunction with the drug name), when this is not the case.  Rather, Exjade is indicated for the treatment of chronic iron overload due to blood transfusions in patients two years of age and older.

Failure to Use Required Established Name

None of the sponsored links present the full established name of the drugs being promoted, despite the requirement to do so.  See 21 CFR 201.10(g)(1) & 202.1(b)(1). 

Conclusions and Requested Action

For the reasons discussed above, the sponsored links misbrand Femara, Diovan, Exforge, Exjade, and Gleevec, in violation of the Act and FDA regulations.  See 21 U.S.C. 352(a) & (n), 321(n); 21 CFR 201.10(g)(1), 202.1(b)(1), (e)(3)(i), (ii) & (e)(6)(i).

DDMAC requests that Novartis immediately cease the dissemination of violative promotional materials for Femara, Diovan, Exforge, Exjade, and Gleevec, such as those described above.  Please submit a written response to this letter on or before April 9, 2009, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) in use for these drugs 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 materials.  Finally, we encourage you to review your promotional materials for the other prescription drug products that Novartis promotes in the United States and to discontinue or revise any materials with the same or similar violations, and request that your response address this issue as well.

Please direct your response to the undersigned 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, facsimile at 301-847-8444.  In all future correspondence regarding this matter, please refer to MACMIS # 17313 in addition to the NDA numbers.  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 Femara, Diovan, Exforge, Exjade, and Gleevec comply with each applicable requirement of the Act and FDA implementing regulations.
 

Sincerely,
 

Shefali Doshi, M.D. 
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications