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FDA Advertising and Promotion Enforcement Activities: Update

December 10, 2020, Covington Alert

This e-alert is part of a series of e-alerts summarizing publicly available FDA enforcement letters (i.e., warning letters and untitled letters) relating to the advertising and promotion of prescription drugs, medical devices, and biologics.

In November, the Office of Prescription Drug Promotion (OPDP) posted the following untitled letter on FDA’s website:

  • Untitled Letter to Azurity Pharmaceuticals, Inc., re: NDA 208400 XATMEP® (methotrexate) oral solution, MA 50 (Nov. 24, 2020) (Xatmep Untitled Letter)

The Xatmep Untitled Letter is the sixth enforcement letter OPDP has issued this year.The Office of Product Evaluation and Quality (OPEQ) at the Center for Devices and Radiological Health (CDRH) and the Office of Medical Device and Radiological Health Operations (OMDRHO) in the Office of Regulatory Affairs (ORA) did not post any enforcement letters related to advertising and promotion in November. FDA’s Advertising and Promotional Labeling Branch (APLB) in the Office of Compliance and Biologics Quality (OCBQ) has not posted any enforcement letters in 2020.

This alert merely summarizes the allegations contained in FDA’s letter. It does not contain any analyses, opinions, characterizations, or conclusions by or of Covington & Burling LLP. As a result, the information presented herein does not necessarily reflect the views of Covington & Burling LLP or any of its clients.

Office of Prescription Drug Promotion (OPDP)

Xatmep Untitled Letter (November 2020)

OPDP’s untitled letter to Azurity Pharmaceuticals, Inc. (Azurity), states that an email to healthcare professionals (XTM-27) misbrands Xatmep.OPDP alleges that the email, which Azurity submitted under cover of Form FDA 2253, makes false or misleading claims about the drug’s risks and efficacy.The agency further states that “[t]hese violations are especially concerning from a public health perspective because they create a misleading impression about the safety and effectiveness of Xatmep, a drug used in a vulnerable pediatric patient population and that bears a Boxed Warning due to the possibility of serious and life-threatening risks.”

The untitled letter notes that OPDP provided advisory comments in in 2017 to Silvergate Pharmaceuticals, Inc., the original New Drug Application (NDA) holder for Xatmep.[1] OPDP explains that “Azurity appears to be promoting Xatmep without presenting the serious risks of the drug in a truthful and non-misleading manner, despite concerns previously expressed by OPDP.”

False or Misleading Risk Presentation

OPDP alleges that the email is misleading because it “presents numerous benefit claims” while omitting “important warnings and precautions.”For example, OPDP states that the email includes a claim about “easy dose titration” but fails to disclose pertinent information regarding the risk of improper dosing.The Xatmep Prescribing Information (PI) states that “[b]oth the physician and pharmacist should emphasize to the patient that the recommended dose is taken one time weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity.”The PI also “warns that a household teaspoon is not an accurate measuring device and could lead to overdosage.”

OPDP acknowledges that the email includes the Boxed Warning for Xatmep.However, OPDP states that, while the benefit claims are included in the body of the email, the Boxed Warning is “presented after the signature block, which typically signals the close or end of a correspondence.”OPDP further says that statements directing readers to the full PI and the Xatmep website “do[] not mitigate the email’s failure to present the Boxed Warning with sufficient prominence or the omission of other risk information from the email.By minimizing the Boxed Warning and omitting the other material information related to the serious risks associated with Xatmep, the email misleadingly suggests that Xatmep is safer than has been demonstrated.”

False or Misleading Benefit Presentation

OPDP alleges that the email also is misleading with respect to Xatmep’s benefits because it “fails to adequately communicate the full approved indication.”Specifically, the body of the email states, “I wanted to let you know that Xatmep® (methotrexate) oral solution is available for your patients with Acute Lymphoblastic Leukemia.”According to OPDP, this claim is “particularly concerning because it suggests the drug is approved for use in patients of all ages without consideration for the necessity of other treatments as part of a combination therapy.”OPDP notes that “Xatmep is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen” (emphasis by OPDP).OPDP states that the inclusion of the full indication below the signature block (following the heading “Important Safety Information” and the Boxed Warning) “does not mitigate the misleading impression.”

If you have any questions concerning the material discussed in this client alert, please contact the following members of our Food, Drugs, and Devices practice.


[1] In 2017, CutisPharma, Inc., acquired Silvergate Pharmaceuticals, Inc., and renamed the unified company Azurity Pharmaceuticals, Inc.


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