FDA DMEPA Labeling Recommendations for Self-Injection Devices: IFU and Carton/Container Revisions in NDA and BLA Reviews

DMEPA labeling recommendations for self-injection devices: IFU and carton/container revisions in NDA and BLA reviews

FDA's Division of Medication Error Prevention and Analysis (DMEPA) reviews the Instructions for Use (IFU), carton labeling and container labels of autoinjectors, prefilled pens and prefilled syringes during NDA and BLA review. Its recommendations follow recurring patterns across the products reviewed below, approved over roughly the past decade. When human factors (HF) validation participants make a use error, DMEPA usually asks for a targeted labeling change: more prominence, a reworded step, a new or corrected figure, or a label on the device itself. Carton and container comments focus on established-name prominence, package-type and "discard unused portion" statements, route and storage statements, and differentiation between presentations.

The sections below group the revisions DMEPA requested by theme, with product-level examples taken from Drugs@FDA review documents.

IFU revisions

Dose-completion cues and hold time

Premature removal of an autoinjector is the use error most often linked to IFU revisions.

• Repatha (SureClick autoinjector, BLA 125522, 2015): Participants in the reviewed HF study lifted the activated autoinjector too early, which produced wet injections and incomplete doses ²⁶⁷²⁶⁶. DMEPA asked Amgen to put more emphasis on the completion signals (the window changing from white to yellow and a possible second click) and to state that the injection may take longer than most subcutaneous injections ²⁶⁶.
• Praluent (autoinjector pen, BLA 125559, 2015): DMEPA made the same request. It asked for emphasis on the window color change and second click, and on the longer injection time caused by the product's viscosity, after users lifted the pen too early ²²⁹²³⁰.
• Bimzelx (BLA 761151, 2023): HF participants made errors holding the autoinjector until the second click. DMEPA asked the sponsor to make the Step 10 statement that the second click occurs about 15 seconds after the first more prominent, using color, boxing or another method ²²⁷.
• Zegalogue (autoinjector, NDA 214231, 2021): Participants removed the device before the window turned fully red, and feedback suggested a partly red window could be read as a full dose ²³⁵. DMEPA recommended presenting the 10-second count, the second click and a fully red window as one dose-confirmation task, for example by combining the "Push...10 seconds" and "Check window...remove" steps in the IFU and on the autoinjector container label ²³⁵.
• Zymfentra (BLA 761358, 2023): DMEPA asked Celltrion to consider adding autoinjector instructions that had been left out. These included that the second click can take up to 10 seconds, that a grey stopper in the window is normal, that the same injection site should not be used each time, and that the cap goes in an FDA-cleared sharps container ²³¹²³².

Preparation steps and room-temperature equilibration

• Dawnzera (autoinjector, NDA 219407, 2025): Study participants read the Step 1 title, but the title did not mention the waiting period. DMEPA recommended a retitled step, for example "Remove from the refrigerator 30 minutes before you inject." The rationale was injection discomfort if the device is used cold ²²³.
• Idacio (BLA 761255, 2022): The revised IFU tells users to let the pen sit at room temperature for 15 to 30 minutes and not to warm it in a microwave, in hot water or in direct sunlight. The review states that the applicant implemented all Agency recommendations ³⁵⁰³⁵¹.
• Zymfentra: For the "wait 30 minutes" prefilled syringe instruction, DMEPA asked that the room-temperature range be defined in both °F and °C to avoid administration of degraded product ⁹².
• Mounjaro (autoinjector, NDA 215866, 2022): DMEPA recommended numbering "Preparing to inject Mounjaro" as a step, because an unnumbered preparation section may be skipped ²³⁷.

Cap removal and device orientation

• Entyvio (prefilled pen, BLA 761133, 2023): Five participants first tried to inject with the cap on, and some expected medication to come out of the white end. DMEPA recommended adding a figure to the cap-removal instruction ⁸².
• Xyosted (autoinjector, NDA 209863, 2018): DMEPA asked for the IFU to make clear when to remove the cap, because removing it too early could raise the risk of contamination and infection ³⁹⁴⁰.

Injection-site selection and figures

• Dawnzera: DMEPA asked the applicant to reinstate the vertical line separating the Step 3 injection-site images and to emphasize "Only caregivers may choose the back of upper arm" ²²⁴.
• Zegalogue: A participant misread the site image and injected into the lower back. DMEPA recommended images of an unclothed body with the front and back views labeled ²³⁴.
• Entyvio: Three injection-naïve participants chose the forearm. DMEPA recommended revising the site information and redrawing the back-of-arm figure to show the anatomy more clearly ⁸⁰⁸¹.
• Zymfentra: DMEPA asked that Figure E be identified as showing the front of the body, to prevent wrong-site injections ⁹⁰⁹¹.
• Wegovy (NDA 215256): Some participants did not pinch the skin. DMEPA recommended splitting the combined pinch-and-insert instruction into two sequential steps and considering revised figures for Steps 5 to 7 ¹⁹²¹⁹³.
• Rivfloza (prefilled syringe, NDA 215842, 2023): DMEPA asked for a clearer Step 9 title and text to make sure users fully insert the needle, after some participants used a different angle ⁸⁷⁸⁸.
• Symjepi (epinephrine prefilled syringe, NDA 207534, 2017): DMEPA asked for more prominence on the instruction to inject into a muscular area, after six participants failed that task ¹⁹⁴. It also asked the sponsor to consider making the needle-guard deployment instruction more prominent. The review recorded 54 failures to deploy the guard and also attributed them partly to device design ¹⁹⁵.

Syringe component call-outs and figure accuracy

• Praluent (prefilled syringe): A participant pulled out the plunger while removing the cap. The plunger and cap used in the study were both gray. DMEPA asked the sponsor to consider labeling both parts in Step B.1 ¹⁸²¹⁸³.
• Ziextenzo (BLA 761045, 2019): DMEPA asked for the cap-removal figure to show the cap pulled straight off, as the text instructs, and for the syringe barrel to be labeled ¹⁸⁰¹⁸¹. It also asked for the injection-site figures to be labeled ¹⁷⁹.
• Nivestym (BLA 761080, 2018): DMEPA requested that the "conical base of the plunger stopper" be labeled, because the partial-dose instructions use that term ¹⁸⁷¹⁸⁸. It also asked for a separate step, with images, for checking air bubbles ¹⁹⁰¹⁹¹, and for an adhesive bandage to be listed under supplies ¹⁸⁹.
• Plegridy (prefilled pen, BLA 125499, 2014): Participants had trouble finding the injection status window and did not press hard enough to start the injection. DMEPA asked for figures showing the whole pen with the window marked, and for "firmly" to be moved into the first sentence of Section 6 ^169170171172.

Viscosity and plunger force

For the Praluent prefilled syringe, DMEPA asked the IFU to explain two points ^184185186:

• Users may feel resistance because of the product's viscosity but must keep pushing until the syringe is empty.
• The injection may take longer than most subcutaneous injections.

Three participants failed to inject the full dose, and repeated underdosing could reduce efficacy ^184185186.

Doses that need more than one device

• Bimzelx: DMEPA proposed the wording "A complete dose (320 mg) is 2 prefilled syringes (or autoinjectors). Use a new prefilled syringe (or autoinjector) and repeat Step 1 to Step 12," after knowledge-task errors on critical administration steps ²²⁸.
• Stelara (BLA 125261, 2013): DMEPA asked for the supplies list to avoid quantities that assume a single syringe, because a 90 mg patient may receive two 45 mg syringes ¹⁶⁷¹⁶⁸.

Making the IFU easy to find and use

• Andembry (BLA 761367, 2025): Participants threw away a leaflet they could not identify. DMEPA recommended folding the IFU so that its title faces up when the carton is opened ²²⁵.
• Bimzelx: The carton Quick Start Guide left out the step of checking the medicine for color and particles, and its reference to the full IFU was not prominent. DMEPA addressed this in its recommendations ²⁷⁵.
• Trulicity (BLA 125469, 2014): Patients missed bulleted lists placed under the numbered steps. DMEPA recommended revising the numbered instructions, for example "Pull off and throw away the needle cover" ⁷⁰⁷¹.
• Praluent: DMEPA recommended adding a cross-reference at the start of PI Section 2.1 telling users to see the IFU for injection-site selection and administration ³⁸.

Training and supervision statements

For Betaseron with the Betaconnect autoinjector (BLA 103471, 2015), most premature-removal failures happened in untrained participants ²⁷²²⁷³. DMEPA recommended adding a statement to the IFU and carton that users should be trained by their healthcare provider before use ²⁷¹. In the carton and Dosage and Administration section, it recommended requiring provider instruction before first use and provider supervision of the first injection ²⁷⁴.

Mixing devices

• Bydureon Pen (NDA 022200, 2014): DMEPA asked for the "Not Mixed Well" and "Mixed Well" diagrams to be labeled, for the text to be revised to "Check the mix. Your mix should look like 'Figure X'", and for "both sides" to be highlighted ⁷².
• Bydureon Bcise (NDA 209210, 2017): DMEPA asked for a warning that mixing may take more effort if the autoinjector was stored vertically ²⁶⁸²⁶⁹.

Consistency with the carton

• Qfitlia (NDA 219019, 2025): DMEPA asked for the expiration-date images in the IFU to use the YYYY-MM format printed on the carton and container ⁸⁶.
• Zymfentra: DMEPA's IFU comments asked the applicant to:
  • reconcile room-temperature storage durations across all labeling;
  • present strength as "120 mg/mL";
  • use "single-dose" as the package type ⁹⁰;
  • make the route statement more prominent through larger type, boxing or red type to avoid wrong-route errors ⁹³.

Carton and container labeling revisions

Labels on the device itself

• Mounjaro: The container label had a color-coded arrow with no text. DMEPA asked Lilly to consider adding text that identifies the needle end. Using the device upside down could cause injury, injection of another person or eye exposure ²³⁶.
• Dawnzera: Participants had trouble finding the needle or held the device backward, sometimes mistaking the orange shield for a button. DMEPA recommended a needle-end label on the container ⁴⁴.
• Taltz (BLA 125521, 2016): HF participants could miss the lock/unlock symbols. DMEPA asked for the symbols to be enlarged or for the words "lock" and "unlock" to be placed next to them ³⁵.

Established-name prominence

DMEPA cited 21 CFR 201.10(g)(2) for both Taltz and the Bydureon Pen. For each, it asked that the established name be at least half the size of the proprietary name and have commensurate prominence on cartons and container labels ³¹³²⁷³.

Package type, "single-dose" and "discard unused portion"

• Taltz: On principal display panels, DMEPA asked for bold "For Subcutaneous Use Only" beneath the strength, followed by bold "Single-Dose Only." It also asked for a larger, bold net quantity to tell package sizes apart ³⁶³⁷.
• Tyenne (BLA 761275, 2024): DMEPA asked for "Discard unused portion." to sit with "1 single-dose [prefilled syringe/autoinjector]" and for "For one-time use only" on the back panel. The applicant made both changes ¹³⁷.
• Hulio (BLA 761154, 2020): DMEPA asked for "for Single Dose Only" to become "is for one time use only" to match the tray. The applicant made the change ²⁹³⁰.
• Releuko (BLA 761082, 2022): DMEPA asked for "Single Use Prefilled Syringe" to be replaced with "Single-Dose Prefilled Syringe," for "mL" to be added at the last syringe marking ¹³⁴, and for the strength statement to follow USP General Chapter <7> ¹³⁶.
• Otulfi, Nypozi and Bomyntra/Conexxence: DMEPA made similar requests to place "Discard unused portion" next to the package-type term and to clean up how it is presented ^132102124.

Route and storage statements

• Kesimpta (supplement to BLA 125326, 2020): Four participants did not identify that the product needs refrigeration. DMEPA asked for "REFRIGERATE" on the principal display panel ⁸⁹.
• Qfitlia: DMEPA asked for the storage statement to begin "Store refrigerated at 2°C to 8°C (36°F to 46°F)..." ⁴⁵. It also asked for a space to record the beyond-use date ("Discard after //_____") because room-temperature storage changes the expiration date ⁴⁷.
• Taltz: DMEPA asked for "DO NOT SHAKE" on the autoinjector container label ³⁴.
• Nypozi (BLA 761126, 2024): DMEPA asked for the route to read "For Subcutaneous or Intravenous Use Only" to match the prescribing information ¹⁰².
• Otulfi: DMEPA asked for the storage wording "Keep in carton to protect from light" ¹³¹.

Telling presentations and strengths apart

• Cosentyx (BLA 125504, 2015): DMEPA flagged that the "Single Use Prefilled SensoReady Pen" and "Single Use Prefilled Syringe" presentations looked alike and could lead to selection errors. It also noted that dosage-form and "Discard Unused Portion" statements were missing ⁷⁴⁷⁵⁷⁶.
• Tyenne: DMEPA recommended more prominent device images on the blister labels. It also asked the sponsor to consider color, boxing or other means to tell syringe cartons from autoinjector cartons ¹¹¹.
• Sogroya (BLA 761156, 2020): A boxed "10 mg" next to "Once weekly" could be read as a 10 mg weekly dose, but the pen dials only up to 4 mg ⁷⁹. DMEPA recommended text describing the dose increments and total content. The applicant's alternative, "10 mg pen" plus shortened increment and content text, was accepted ⁷⁷⁷⁸.
• Yesintek (BLA 761406, 2025): DMEPA asked for legible names, strength and route on the small syringe label, and for the full strength in the blister net quantity ¹²⁹¹³⁰.

Required elements

For Xyosted, DMEPA found the revised labels unacceptable for two reasons ⁴¹:

• The autoinjector label had no linear barcode, which 21 CFR 201.25(c)(2) requires.
• The NDC on the 100 mg carton did not match PI Section 16.1.

Recurring patterns

Practical implications for sponsors

DMEPA links most IFU comments to specific use errors or knowledge-task failures in the HF validation study ^22723582. If a critical task failed, sponsors should expect a labeling recommendation even when they argue that residual risk is acceptable. DMEPA often supplies replacement wording, and some reviews record that the applicant adopted it or offered an alternative FDA accepted ^291377778.

Labeling on the device itself is also in scope. In several reviews DMEPA asked for needle-end identification, lock/unlock wording and dose-confirmation cues directly on the autoinjector label ^2364435235. Its carton comments repeatedly stress the following, and checking final artwork against them before submission can reduce late-cycle labeling rounds:

• consistent terms ("single-dose," "Discard unused portion") ¹³⁴¹³⁷;
• route and storage statements on the principal display panel ³⁶⁸⁹;
• matching storage, expiration-format and strength presentation across the IFU, carton and PI ⁸⁶⁹⁰.