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September 9, 2025

RE: BLA 125350/1472
HIZENTRA (Immune Globulin Subcutaneous (Human))

WARNING LETTER

Dear Ms. Aubrey-Larcinese:

The U.S. Food and Drug Administration (FDA) has reviewed the Direct-to-Consumer broadcast advertisement (DTC TV ad), Live in Strength: Supermarket (USA-HIZ-0963), submitted at time of first use by CSL Behring (CSL) for HIZENTRA (Immune Globulin Subcutaneous (Human)) under cover of Form FDA 2253.¹ FDA has determined that this DTC TV ad overstates the effectiveness and minimizes the information about the safety of HIZENTRA. Thus, the DTC TV ad misbrands HIZENTRA and makes distribution of the drug in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). See 21 U.S.C. §§ 352(n), 321(n), & 331(a); cf. 21 CFR § 202.1(e)(1) & (e)(5). This is concerning from a public health perspective because it creates the misleading impression that HIZENTRA is more effective than has been demonstrated by substantial evidence and minimizes the risks of treatment with HIZENTRA.

Background

According to the FDA-approved prescribing information (PI) for HIZENTRA:

HIZENTRA is a 20% liquid subcutaneous immune globulin (IGSC) indicated for the treatment of (1) primary humoral immunodeficiency in adults and pediatric patients 2 years of age and older and (2) chronic inflammatory demyelinating polyneuropathy (CIDP) in adults, as a maintenance therapy or to prevent relapse of neuromuscular disability and impairment.

HIZENTRA has a BOXED WARNING regarding the potential of thrombosis. It is contraindicated in patients who have 1) a history of anaphylactic or a severe systemic reaction to human immune globulin or ingredients such as polysorbate 80, 2) hyperprolinemia, or 3) IgA-deficiency with antibodies against IgA.

HIZENTRA’s WARNINGS AND PRECAUTIONS include, but are not limited to, hypersensitivity reactions, thrombosis, aseptic meningitis syndrome renal dysfunction or failure, hemolysis, and transfusion-related acute lung injury. The most common adverse reactions (>5%) are local infusion reactions, headache, diarrhea, fatigue, back pain, nausea, pain in extremity, cough, upper respiratory tract infection, rash, pruritus, vomiting, upper abdominal pain, migraine, arthralgia, pain, fall, and nasopharyngitis.

The FDA Center for Biologics Evaluation and Research’s Advertising and Promotional Labeling Branch (APLB) reviewed a storyboard for this advertisement, which was submitted by CSL for advisory comment on January 10, 2025. On April 7, 2025, APLB sent CSL an advisory letter, stating that the overall impression of the storyboard for this DTC TV ad misleadingly overstated the efficacy of HIZENTRA because an immune globulin infusion cannot protect anyone against all the bacteria and viruses that one would encounter in their environment. In addition, much of the risk information seemed to be in small font relegated to the bottom of each screen and only appeared in a small portion of the whole storyboard. Therefore, the storyboard failed to present important safety information in a manner that was reasonably comparable to the presentation of information relating to the benefits of HIZENTRA. APLB recommended revising the DTC TV ad to address these issues and reminded CSL that a storyboard does not enable FDA to evaluate all aspects of audio and video production that will be apparent when the advertisement is produced in final format. Thus, our comments were limited by what could be assessed from the materials presented.

Overstatement of Effectiveness

In Live in Strength: Supermarket, a woman enters a grocery store with computer generated imagery (CGI) “germs” depicted on various items she would touch, from the handle of her grocery cart to the produce she is selecting to the self-checkout screen. At first, she hesitates and worries about touching things. In another aisle, she encounters a young child in a shopping cart who sneezes directly at her, causing a spray of germs to cascade toward her. The sneeze causes her to do a spin that triggers a superpowered protection around her (depicted as swirls) and, as she spins, the germs scatter away from her. She says (in voiceover), “But now I’ve turned things around. With HIZENTRA, I’m more protected.” She also claims (in voiceover), “My immune system is being restored.” After this transformation, she navigates through the aisles and other shoppers with ease, eventually meeting a friend for coffee at the café.

The overall impression of this DTC TV ad, including its imagery and the above statements, misleadingly overstates the efficacy of HIZENTRA. HIZENTRA is indicated as replacement therapy for primary humoral immunodeficiency. Yet, in this DTC TV ad, the woman treated with HIZENTRA effectively is protected from all the germs around her, and her statement that her immune system is being restored is particularly concerning. Replacement therapy replaces what is missing or not functioning properly; it is not a cure and does not make one impervious or provide an extra layer of protection or effectiveness beyond that in the infusion, which is derived from normal human plasma.

Presentation of Risk Information

The presentation of limitations and risk information in the DTC TV ad is not reasonably comparable to the presentation of benefits. Specifically, the fast pacing and the compelling and attention-grabbing visuals during the presentation of risk information, all of which are unrelated to the risk message, compete for the viewers’ attention and make it difficult for the viewer to adequately process and comprehend the risks. Moreover, the presentation of the major statement is not presented in a clear, conspicuous, and neutral manner. The distractions, including frequent scene changes, quick camera movements, close-ups, and background music intensifying as the video progresses, interfere with the viewers’ ability to read the text portion of the major statement, which is not easily seen on the screen because the text is in small font, relegated to the bottom, and lacking contrast with the background. The overall effect undermines the communication of the risk information and the consequences that may result from the use of HIZENTRA.

Conclusion and Requested Action

For the reasons described above, the DTC TV ad misbrands HIZENTRA and makes the distribution of the drug in violation of the FD&C Act. See 21 U.S.C. §§ 352(n), 321(n), & 331(a); cf. 21 CFR § 202.1(e)(1) & (e)(5).

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 HIZENTRA that contain representations such as those described above, and explaining your plan for discontinuation of such communications, or for ceasing distribution of HIZENTRA.

If you believe that your product is 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 HIZENTRA; 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 its implementing regulations.

Please direct your response to the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Compliance and Biologics Quality, Building 71, 5th Floor, 10903 New Hampshire Avenue, Silver Spring, MD 20993. All correspondence should include a subject line that clearly identifies the submission as a Response to Warning Letter and refer to the BLA/STN numbers. Submit your response to your eCTD under the heading 1.15.1.6. We remind you that only written communications are considered official responses.

Questions related to the submission of your response letter should be emailed to CBERAPLB@fda.hhs.gov.

Sincerely,
/S/
Vinay Prasad M.D., M.P.H.
Director
Center for Biologics Evaluation and Research

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1 The Form FDA 2253 was submitted on May 2, 2025.