Azurity Pharmaceuticals Inc. — NDA 208400 XATMEP® (methotrexate) oral solution (2020-11-24)

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Food and Drug Administration Silver Spring, MD 20993 TRANSMITTED BY FACSIMILE

Korie Osborn Director, Regulatory Affairs

841 Woburn Street Wilmington, MA 01887

RE: NDA 208400 XATMEP (methotrexate) oral solution MA 50

Dear Ms. Osborn:

The Office of Prescription Drug Promotion (OPDP) of the U.S. Food and Drug Administration (FDA) has reviewed the healthcare professional email (XTM-27) for XATMEP (methotrexate) oral solution (Xatmep) submitted by Azurity Pharmaceuticals Inc. (Azurity) under cover of Form FDA 2253. The email makes false or misleading claims and/or representations about the risks and efficacy associated with Xatmep. Thus, the email misbrands Xatmep within the meaning of the Federal Food, Drug and Cosmetic Act (FD&C Act) and makes its distribution violative. 21 U.S.C. 352(a), (n); 321(n); 331(a). See 21 CFR 202.1(e)(3)(i); (e)(5); (e)(7)(viii). These 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.

Background

Below are the indications and summary of the most serious and most common risks associated with the use of Xatmep. According to the INDICATIONS AND USAGE section of the FDA-approved product labeling (PI) (in pertinent part):

Xatmep is associated with a number of serious risks. According to the PI, Xatmep contains a Boxed Warning that describes severe toxic reactions, including embryo-fetal toxicity.

Xatmep is contraindicated in patients who are pregnant with non-malignant diseases or who

This information is for background purposes only and does not necessarily represent the risk information that should be included in the promotional piece(s) cited in this letter.

device and could lead to overdosage, which can result in serious adverse reactions.

Furthermore, promotional materials are misleading if they fail to present information about risks associated with a drug with a prominence and readability reasonably comparable with the presentation of information relating to the effectiveness of the drug. The email prominently presents benefit claims for Xatmep in the body of the email in a bulleted list. In contrast, the limited risk information (i.e., the Boxed Warning) included in the email is presented after the signature block, which typically signals the close or end of a correspondence. As such, the email fails to also present the limited risk information included in the email with a prominence and readability reasonably comparable to the presentation of information relating to the benefits of the drug.

We note that the email includes the statements, “ For Full Prescribing Information of Xatmep, please click here: Full Prescribing Information ” and “ For more information on Xatmep, please click here: Xatmep Website ” (emphasis original). However, this does 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

The body of the email presents the following claim for Xatmep:

• I wanted to let you know that Xatmep (methotrexate) oral solution is available for your patients with Acute Lymphoblastic Leukemia.

This claim is misleading because it fails to adequately communicate the full approved indication for Xatmep. Specifically, the INDICATIONS AND USAGE section of the PI states the following (underlined emphasis added):

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. We acknowledge that the full indication is presented at the bottom of the email, after the signature block (which, as noted above, typically signifies the end of a correspondence), the heading “ Important Safety Information ,” and the Boxed Warning (emphasis original). However, this does not mitigate the misleading impression.

Conclusion and Requested Action

For the reasons discussed above, the email misbrands Xatmep within the meaning of the FD&C Act, and make its distribution violative. 21 U.S.C. 352(a), (n); 321(n); 331(a). See 21 CFR 202.1(e)(3)(i); (e)(5); (e)(7)(viii).

OPDP requests that Azurity immediately cease any violations of the FD&C Act. Please submit a written response to this letter on or before December 8, 2020, addressing the concerns described in this letter, listing all promotional materials (with the 2253 submission date) for Xatmep that contain representations described above, and explaining your plan for discontinuing use of such materials. If you believe that your products are not in violation of the FD&C Act, include your reasoning and any supporting information for our consideration.

Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Prescription Drug Promotion, 5901- B Ammendale Road, Beltsville, Maryland 20705-1266 . A courtesy copy can be sent by facsimile to (301) 847-8444. To ensure timely delivery of your submissions, please use the full address above and include a prominent directional notation (e.g. a sticker) to indicate that the submission is intended for OPDP. Please refer to MA 50 in addition to the NDA number in all future correspondence relating to this particular matter. All correspondence should include a subject line that clearly identifies the submission as a Response to Untitled Letter.

The issues discussed in this letter do not necessarily constitute an exhaustive list of potential violations. It is your responsibility to ensure that your promotional materials for Xatmep comply with each applicable requirement of the FD&C Act and FDA implementing regulations.

Sincerely,

{See appended electronic signature page}

Trung-Hieu Brian Tran, PharmD, MBA Team Leader Division of Advertising & Promotion Review 1 Office of Prescription Drug Promotion

Signature Page 1 of 1 -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------

TRUNG-HIEU B TRAN 11/24/2020 03:47:49 PM