Safety Labeling Change Orders
Safety Labeling Changes (SLC) Overview
Section 505(o)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(o)(4)) authorizes FDA to require application holders for certain drugs1 to make labeling changes based on new safety information2 (including information related to reduced effectiveness) that becomes available after approval of the drug.
SLC Procedures
Once FDA has determined that there is new safety information (NSI)2 that should be included in labeling, FDA sends a Safety Labeling Change (SLC) notification letter to the application holder(s). After receiving notification of the required SLC, the application holder(s) must either:3
- Submit a supplement with proposed labeling changes to reflect the NSI; or
- Notify FDA that it does not believe a labeling change is warranted and submit a statement detailing the reasons why such a change is not warranted (a rebuttal statement).
When the applicant submits a supplement with proposed labeling changes:
- If the proposed labeling can be approved without discussion with the application holder, FDA will approve the labeling supplement promptly and notify the application holder by sending a supplement approval letter.
- If the labeling supplement proposes changes to the language or placement of the proposed labeling changes to what was provided in the SLC notification letter, the FDA may initiate a discussion period with the application holder to review and discuss the proposed revisions.4 The FDA will issue an action letter within 15 calendar days after the end of the discussion period.
When the applicant submits a rebuttal:
- If the application holder submits a rebuttal statement and FDA accepts the reasons why labeling changes are not warranted, FDA intends to promptly notify the application holder.
- If the application holder submits a rebuttal statement and FDA does not accept the reasons why labeling changes are not warranted, FDA will initiate a discussion period with the application holder.4
Within 15 calendar days of the conclusion of the 30-day discussion period (and any extension period, if applicable), FDA will proceed as follows:
- If FDA and the application holder reach consensus on the proposed labeling, FDA will notify the application holder by sending a supplement approval letter.
- If FDA does not agree with the application holder’s proposed labeling changes or rebuttal statement and FDA and the application holder cannot reach consensus, FDA can order the application holder to make the required labeling changes.5
SLC Order Issuance
If, at the conclusion of the 30-day discussion period (or extension, if applicable), FDA determines that the application holder’s proposed labeling changes do not adequately address the NSI or finds unacceptable the application holder’s reasons why the labeling changes are not warranted, FDA can issue an SLC order to change the product labeling. FDA can also issue an SLC order if a labeling supplement or rebuttal statement is not submitted within 30 calendar days of the date of the SLC notification letter.6 SLC Order letters will be issued within 15 calendar days of the conclusion of the 30-day discussion period (or extension, if applicable).
All SLC Order letters issued by CDER will be posted on this FDA’s website.
For additional information, please refer to the guidance for industry “Safety Labeling Changes—Implementation of Section 505(o)(4) of the FD&C Act” .
1Drug products approved under section 505 of the FD&C Act (21 U.S.C. 355) and biological products licensed under section 351 of the Public Health Service Act (42 U.S.C. 262) that are regulated as drugs.
2New safety information is defined as: “information derived from a clinical trial, an adverse event report, a postapproval study (including a study under section 505(o)(3) [of the FD&C Act]), or peer-reviewed biomedical literature; data derived from the postmarket risk identification and analysis system under section 505(k) [of the FD&C Act]; or other scientific data deemed appropriate by [FDA] about 1) a serious risk or an unexpected serious risk associated with use of the drug that [FDA] has become aware of (that may be based on a new analysis of existing information) since the drug was approved, since the risk evaluation and mitigation strategy (REMS) was required, or since the last assessment of the approved REMS for the drug, or 2) the effectiveness of the approved REMS for the drug obtained since the last assessment of such strategy.” (505-1(b) of the FD&C Act (21 U.S.C. 355-1(b))
3Section 505(o)(4)(B)(i) and (ii) of the FD&C Act
4Section 505(o)(4)(C) of the FD&C Act
5Section 505(o)(4)(E) of the FD&C Act
6Section 505(o)(4)(B) of the FD&C Act
| Date of SLC Order Issuance | Application Type & Number | Drug Name | Applicant (Applicant Addressed in the SLC Order Letter) |
Link to SLC Order Letter |
|---|---|---|---|---|
| 4/28/2023 | NDA-019758 | Clozaril (Clozapine) | HERITAGE LIFE SCIENCES BARBADOS INC | Archive |
| 9/20/2021 | NDA-018936 | Prozac (Fluoxetine Hydrochloride) | ELI LILLY AND COMPANY | Archive |
| 4/11/2019 | NDA-022526 | Addyi (Flibanserin) | SPROUT PHARMACEUTICALS INC | Archive |
| 3/09/2018 | NDA-020839 | Plavix (Clopidogrel Bisulfate) | SANOFI AVENTIS US LLC | Archive |
| 2/23/2017 | ANDA-071212, ANDA-071173, ANDA-071172, ANDA-071157, ANDA-071156 | Haloperidol | FRONTIDA BIOPHANN INC | Archive |
| 2/23/2017 | ANDA-089903, ANDA-089523 | Prochlorperazine Edisylate | WEST-WARD PHARMACEUTICALS CORP | Archive |
| 12/20/2016 | ANDA-075523 | Naloxone and Pentazocine | SUN PHARMACEUTICAL INDUSTRIES, INC | Archive |
| 12/16/2016 | ANDA-081002 | Meperidine Hydrochloride | WEST-WARD PHARMACEUTICAL CORP | Archive |
| 12/16/2016 | ANDA-070765, ANDA-070766, ANDA-070683 |
Amitriptyline Hydrochloride and Chlordiazepoxide, Oxazepam |
FRONTIDA BIOPHARM INC | Archive |
| 12/16/2016 | ANDA-070444, ANDA-070445 | Flurazepam Hydrochloride | PAR PHARMACEUTICAL INC | Archive |
| 12/16/2016 | ANDA-075045, ANDA-075046 | Butorphanol Tartrate | WEST-WARD PHARMACEUTICALS CORP | Archive |
| 12/16/2016 | ANDA-205001 | Acetaminophen and Hydrocodone Bitartrate | PAR PHARMACEUTICAL, INC | Archive |
| 12/16/2016 | ANDA-089671, ANDA-089672 | Acetaminophen and Codeine Phosphate | FRONTIDA BIOPHARM INC | Archive |
| 11/08/2016 | ANDA-040805 | Hydroxyzine Hydrochloride | HETERO USA, INC U.S. AGENT FOR HETERO LABS LIMITED UNIT- III |
Archive |
| 10/21/2016 | ANDA-090387 | Testosterone Cypionate | WEST-WARD PHARMACEUTICAL CORP | Archive |
| 10/21/2016 | ANDA-091244 | Testosterone Cypionate | WEST-WARD PHARMACEUTICAL CORP | Archive |
| 9/07/2016 | NDA-022276 | Nicardipine Hydrochloride | EXELA PHARMA SCIENCES, LLC | Archive |
| 5/09/2016 | ANDA-070088 | Ibuprofen | BASF CORPORATION | Archive |
| 5/09/2016 | ANDA-074819, ANDA-079093 |
Etodolac, Nabumetone |
PROSAM LABS, LLC | Archive |
| 12/15/2014 | NDA-050824 | Omeclamox-Pak (Omeprazole, Amoxicillin, and Clarithromycin) | GASTROENTERO-LOGIC, LLC | Archive |
| 9/18/2014 | ANDA-078969 | Granisetron Hydrochloride | INC RESEARCH LLC | Archive |
| 9/09/2014 | ANDA-086498, ANDA-086499, ANDA-086500, ANDA-086501, ANDA-086502, ANDA-086503, ANDA-083827 | Amitriptyline Hydrochloride, Imipramine Hydrochloride |
ALRA LABORATORIES, INC | Archive |
| 7/31/2014 | NDA-009470 | Xylocaine Viscous (Lidocaine Hydrochloride) | FRESENIUS KABI USA LLC | Archive |
| 7/22/2014 | ANDA-076015 | Fluoxetine Hydrochloride | PHARMACEUTICAL ASSOCIATES, INC | Archive |
| 7/22/2014 | ANDA-040751, ANDA-040752, ANDA-040753 | Imipramine Hydrochloride | PROSAM LABS, LLC | Archive |
| 7/22/2014 | ANDA-075525 | Fluoxetine Hydrochloride | HI-TECH PHARMACAL CO., INC | Archive |
| 7/22/2014 | ANDA-071196, ANDA-071258 |
Trazodone Hydrochloride | APOTEX INC | Archive |
| 7/03/2014 | NDA-014694 | Hexadrol (Dexamethasone Sodium Phospate) | ORGANON USA INC | Archive |
| 6/03/2014 | ANDA-088184, ANDA-088185 | Hydroxyzine Hydrochloride | FRESENIUS KABI USA, LLC | Archive |
| 6/03/2014 | ANDA-040600, ANDA-040602, ANDA-040604 | Hydroxyzine Hydrochloride | MIKAH PHARMA LLC | Archive |
| 6/03/2014 | ANDA-087014 | Orgatrax (Hydroxyzine Hydrochloride) | ORGANON USA INC | Archive |
| 10/24/2013 | ANDA-040261 | Acetaminophen, Butalbital, and Caffeine | WEST-WARD PHARMACEUTICALS CORP | Archive |
| 10/24/2013 | ANDA-087811 | Phrenilin (Acetaminophen and Butalbital) | KELLER AND HECKMAN LLP U.S. AGENT FOR VALEANT INTERNATIONAL BERMUDA |
Archive |
| 10/24/2013 | ANDA-040864 | Acetaminophen, Butalbital, and Caffeine | MIRROR PHARMACEUTICALS LLC | Archive |
| 10/24/2013 | ANDA-088831 | Phrenilin Forte (Acetaminophen and Butalbital) | KELLER AND HECKMAN LLP U.S. AGENT FOR VALEANT INTERNATIONAL BERMUDA |
Archive |
| 10/24/2013 | ANDA-040336 | Acetaminophen, Butalbital, and Caffeine | WEST-WARD PHARMACEUTICALS CORP | Archive |
| 10/24/2013 | ANDA-040688 | Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate | WRASER PHARMACEUTICALS | Archive |
| 10/24/2013 | ANDA-040883 | Acetaminophen, Butalbital, and Caffeine | MIRROR PHARMACEUTICALS LLC | Archive |
| 8/19/2013 | ANDA-077417, ANDA-077809 | Ciprofloxacin | WATSON LABORATORIES, INC. - FLORIDA | Archive |
| 8/19/2013 | ANDA-078712 | Ciprofloxacin | SANDOZ, INC | Archive |
| 5/10/2013 | ANDA-088704 | Triacin-C® Cough Syrup (Codeine Phosphate, Pseudoephedrine Hydrochloride, and Triprolidine Hydrochloride) | CLINSMART LLC U.S. AGENT FOR STI PHARMA LLC |
Archive |
| 5/10/2013 | ANDA-087006 | Acetaminophen and Codeine Phosphate | WOCKHARDT EU OPERATIONS (SWISS) AG | Archive |
| 5/10/2013 | ANDA-040223 | Acetaminophen and Codeine Phosphate | BARR LABORATORIES, INC | Archive |
| 5/10/2013 | ANDA-040441 | Acetaminophen and Codeine Phosphate | WATSON LABORATORIES, INC - FLORIDA | Archive |
| 5/10/2013 | ANDA-040447, ANDA-040488 | Acetaminophen and Codeine Phosphate | WATSON LABORATORIES, INC - FLORIDA | Archive |
| 5/10/2013 | ANDA-089997, ANDA-089998, ANDA-089999 | Acetaminophen and Codeine Phosphate | WATSON LABORATORIES, INC | Archive |
| 5/10/2013 | ANDA-040688 | Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate | WRASER PHARMACEUTICALS | Archive |
| 5/10/2013 | ANDA-040701 | Acetaminophen, Caffeine, and Dihydrocodeine Bitartrate | BOCA PHARMACAL, INC. | Archive |
| 5/10/2013 | ANDA-089671, ANDA-089672 | Acetaminophen and Codeine Phosphate | FRONTIDA BIOPHARM INC | Archive |
| 5/10/2013 | ANDA-040443 | Acetaminophen and Codeine Phosphate | WATSON LABORATORIES, INC - FLORIDA | Archive |
| 4/11/2013 | ANDA-073143, ANDA-074436 | Cyclobenzaprine Hydrochloride | WATSON LABORATORIES, INC | Archive |
| 4/11/2013 | ANDA-072854 | Cyclobenzaprine Hydrochloride | SANDOZ, INC | Archive |
| 4/11/2013 | ANDA-077209, ANDA-077291 | Cyclobenzaprine Hydrochloride | PROSAM LABS, LLC | Archive |
| 12/20/2010 | NDA-021358 | MultiHance Multipack (Gadobenate Dimeglumine) | BRACCO DIAGNOSTICS, INC | Archive |
| 11/02/2010 | ANDA-074900, ANDA-074901 | Atracurium Besylate | BEDFORD LABORATORIES | Archive |
| 11/02/2010 | ANDA-074944, ANDA-074945 |
Atracurium Besylate | WATSON PHARMACEUTICALS, INC | Archive |
| 11/02/2010 | ANDA-090243 | Vecuronium Bromide | AKORN-STRIDES, LLC | Archive |
| 11/02/2010 | ANDA-078562 | Mivacurium Chloride | PISGAH LABS, INC | Archive |
| 11/02/2010 | ANDA-074334 | Vecuronium Bromide | WATSON PHARMACEUTICALS, INC | Archive |
| 11/02/2010 | ANDA-075218 | Vecuronium Bromide | BAXTER HEALTHCARE CORPORATION | Archive |
| 6/02/2010 | NDA-020692, NDA-021077, NDA-021254 |
Serevent Diskus (Salmeterol Xinafoate), Advair Diskus (Fluticasone Propionate and Salmeterol), Advair HFA (Fluticasone Propionate and Salmeterol) |
GLAXOSMITHKLINE | Archive |
| 6/02/2010 | NDA-021929 | Symbicort (Budesonide and Formoterol Fumarate Dihydrate) | ASTRAZENECA LP | Archive |
| 3/09/2010 | NDA-019309 | Vasotec (Enalapril Maleate) | BIOVAIL LABORATORIES INTERNATIONAL SRL | Archive |
| 1/21/2010 | NDA-006188 | Propylthiouracil | DAVA PHARMACEUTICALS, INC | Archive |
| 7/19/2009 | NDA-020592, NDA-021253; NDA-021086 | Zyprexa (Olanzapine), Zyprexa Zydis (Olanzapine) | ELI LILLY AND COMPANY | Archive |
| 7/19/2009 | NDA-021520 | Symbyax (Olanzapine and Fluoxetine) | ELI LILLY AND COMPANY | Archive |
| 7/30/2008 | BLA-103234 | Epogen/Procrit (Epoetin Alfa) | AMGEN, INCORPORATED | Archive |
| 7/30/2008 | BLA-103951 | Aranesp (Darbepoetin Alpha) | AMGEN, INCORPORATED | Archive |