Aytu Biopharma

As part of its monitoring and surveillance program, the U.S. Food and Drug Administration (FDA) has reviewed the promotional communications, Aytu Biopharma’s (Aytu) sponsored links1 for ADZENYS XR-ODT (amphetamine) extended-release orally disintegrating tablets, CII (Adzenys XR-ODT). FDA has determined that the sponsored links are false or misleading. Thus, the sponsored links misbrand Adzenys XR-ODT and make the distribution of the drug in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). 21 U.S.C. 352(a), (e)(1)(B), (n); 321(n); 331(a). See 21 CFR 201.10(g)(1); 202.1(b)(1); 202.1 (e)(5); 314.81(b)(3)(i). These violations are especially concerning from a public health perspective because the promotional communications create a misleading impression about the safety and efficacy of Adzenys XR-ODT, a Schedule II controlled substance that bears a boxed warning due to the high potential for abuse and misuse, which can lead to overdose, death, and the development of a substance use disorder, including addiction.

Below are the indication and summary of the most serious and most common risks associated with the use of Adzenys XR-ODT.2 According to the INDICATIONS AND USAGE section of the FDA-approved Prescribing Information (PI):

ADZENYS XR-ODT is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older.

The PI for Adzenys XR-ODT contains a boxed warning regarding a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Adzenys XR-ODT is contraindicated in patients with a known hypersensitivity to amphetamine or other components of Adzenys XR-ODT and in patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping MAOIs. In addition, the PI for Adzenys XR-ODT includes warnings and precautions regarding risks to patients with serious cardiac disease; increased blood pressure and heart rate; psychiatric adverse reactions; long-term suppression of growth in pediatric patients; peripheral vasculopathy, including Raynaud’s phenomenon; serotonin syndrome; motor and verbal tics, and worsening of Tourette’s syndrome; and potential for overdose due to medication errors. The most common adverse reactions associated with single-entity amphetamine product extended-release capsules are loss of appetite, abdominal pain, insomnia, emotional lability, vomiting, nervousness, fever, nausea, infection, weight loss, accidental injury, asthenia, dyspepsia, dizziness, headache, dry mouth, diarrhea, agitation, anxiety, tachycardia, and urinary tract infection.

Prescription drug advertisements and labeling (promotional communications) misbrand a drug if they are false or misleading with respect to risk. The determination of whether a promotional communication is misleading includes, among other things, not only representations made or suggested in the promotional communication, but also the extent to which the promotional communication fails to reveal facts material in light of the representations made or with respect to consequences that may result from the use of the drug as recommended or suggested in the promotional communication.

The sponsored links are misleading because they include representations about the efficacy of Adzenys XR-ODT but fail to communicate any risk information. For example, the sponsored links for Adzenys XR-ODT appearing in searches include the statement “Adzenys XR-ODT for ADHD.”

We acknowledge that some variations of the sponsored links include the statements “Medication Guide”, “Important Safety Info”, and/or “Side Effects”; however, these statements, alone or in combination, do not mitigate the misleading omission of risk information. By omitting risk information associated with Adzenys XR-ODT, the sponsored links fail to provide material information about the consequences that may result from the use of the drug and create a misleading impression about the drug’s safety.

The established name of a prescription drug must be presented prominently, in direct conjunction with the proprietary name. The sponsored links fail to present the established name for Adzenys XR-ODT, thereby misbranding the product.

FDA regulations require any labeling or advertising devised for promotion of the drug product to be submitted at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product. Each submission is required to be accompanied by a completed transmittal Form FDA-2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product’s current professional labeling. A copy of the sponsored links was not submitted to FDA under cover of Form FDA-2253 at the time of initial publication as required by 21 CFR 314.81(b)(3)(i).

For the reasons discussed above, the sponsored links misbrand Adzenys XR-ODT and make the distribution of the drug in violation of the FD&C Act. 21 U.S.C. 352(a), (e)(1)(B), (n); 321(n); 331(a). See 21 CFR 201.10(g)(1); 202.1(b)(1); 202.1 (e)(5). Furthermore, Aytu did not comply with 21 CFR 314.81(b)(3)(i).

This letter notifies you of our concerns and provides you with an opportunity to address them. You should take immediate action to address any violations (including, for example, ceasing and desisting promotional communications that are misleading as described above). Failure to adequately address any violations may result in legal action without further notice, including, without limitation, seizure and injunction. Please submit a written response to this letter within 15 working days from the date of receipt, addressing the concerns described in this letter, listing all other promotional communications (with the 2253 submission date) for Adzenys XR-ODT that contain representations such as those described above, and explaining your plan for discontinuation of such communications, or for ceasing distribution of Adzenys XR-ODT.

If you believe that your products are not in violation of the FD&C Act, please include in your submission to us your reasoning and any supporting information for our consideration within 15 working days from the date of receipt of this letter.

Additionally, we request that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective communication(s) about the concern(s) discussed in this letter. The corrective communication(s) should be disseminated to the audience(s) that received the promotional communication(s) identified in the opening paragraph of this letter. We recommend that corrective communication(s) include a description of the promotional communication(s) identified in this letter, which misbrand Adzenys XR-ODT; include a summary of the concern(s) described in this letter; and provide information to correct each of these concern(s). Corrective communication(s) should be free of promotional claims and presentations. To the extent possible, corrective communication(s) should be distributed using the same media, and generally for the same duration of time and with the same frequency as the promotional communication(s) identified in the opening paragraph of this letter.

The concerns discussed in this letter do not necessarily constitute an exhaustive list of potential violations. It is your responsibility to ensure compliance with each applicable requirement of the FD&C Act and FDA implementing regulations.

Please direct your response to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Prescription Drug Promotion, 5901-B AmmendaleRoad, Beltsville, Maryland 20705-1266. A courtesy copy can be sent by facsimile to (301) 847-8444. Please refer to MA 303 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 Warning Letter. You are encouraged, but not required, to submit your response in eCTD format. All correspondence submitted in response to this letter should be placed under eCTD Heading 1.15.1.6. Questions related to the submission of your response letter should be emailed to CDEROPDP- RPM@fda.hhs.gov.