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  1. Postmarket Drug Safety Information for Patients and Providers

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 IssuanceApplication Type & NumberDrug NameApplicant
(Applicant Addressed in the SLC Order Letter)		Link to SLC Order Letter
3/14/2025ANDA-070765, ANDA-070766Chlordiazepoxide and Amitriptyline HydrochlorideANDA REPOSITORY, LLCArchive
4/28/2023NDA-019758Clozaril (Clozapine)HERITAGE LIFE SCIENCES BARBADOS INCArchive
9/20/2021NDA-018936Prozac (Fluoxetine Hydrochloride)ELI LILLY AND COMPANY Archive
4/11/2019NDA-022526Addyi (Flibanserin)SPROUT PHARMACEUTICALS INCArchive
3/09/2018NDA-020839Plavix (Clopidogrel Bisulfate)SANOFI AVENTIS US LLCArchive
2/23/2017ANDA-071212, ANDA-071173, ANDA-071172, ANDA-071157, ANDA-071156HaloperidolFRONTIDA BIOPHANN INCArchive
2/23/2017ANDA-089903, ANDA-089523Prochlorperazine Edisylate WEST-WARD PHARMACEUTICALS CORPArchive
12/20/2016ANDA-075523Naloxone and Pentazocine SUN PHARMACEUTICAL INDUSTRIES, INCArchive
12/16/2016ANDA-081002Meperidine HydrochlorideWEST-WARD PHARMACEUTICAL CORPArchive
12/16/2016ANDA-070765, ANDA-070766,
ANDA-070683		Amitriptyline Hydrochloride and Chlordiazepoxide,
Oxazepam		FRONTIDA BIOPHARM INCArchive
12/16/2016ANDA-070444, ANDA-070445 Flurazepam Hydrochloride PAR PHARMACEUTICAL INCArchive
12/16/2016ANDA-075045, ANDA-075046Butorphanol Tartrate WEST-WARD PHARMACEUTICALS CORPArchive
12/16/2016ANDA-205001Acetaminophen and Hydrocodone Bitartrate PAR PHARMACEUTICAL, INCArchive
12/16/2016ANDA-089671, ANDA-089672 Acetaminophen and Codeine PhosphateFRONTIDA BIOPHARM INCArchive
11/08/2016ANDA-040805Hydroxyzine Hydrochloride HETERO USA, INC
U.S. AGENT FOR HETERO LABS LIMITED UNIT- III		Archive
10/21/2016ANDA-090387Testosterone Cypionate WEST-WARD PHARMACEUTICAL CORPArchive
10/21/2016ANDA-091244Testosterone Cypionate WEST-WARD PHARMACEUTICAL CORPArchive
9/07/2016NDA-022276Nicardipine HydrochlorideEXELA PHARMA SCIENCES, LLCArchive
5/09/2016ANDA-070088Ibuprofen BASF CORPORATIONArchive
5/09/2016ANDA-074819,
ANDA-079093		Etodolac,
Nabumetone		PROSAM LABS, LLCArchive
12/15/2014NDA-050824Omeclamox-Pak (Omeprazole, Amoxicillin, and Clarithromycin)GASTROENTERO-LOGIC, LLCArchive
9/18/2014ANDA-078969Granisetron Hydrochloride INC RESEARCH LLCArchive
9/09/2014ANDA-086498, ANDA-086499, ANDA-086500, ANDA-086501, ANDA-086502, ANDA-086503, ANDA-083827Amitriptyline Hydrochloride,
Imipramine Hydrochloride 		ALRA LABORATORIES, INCArchive
7/31/2014NDA-009470Xylocaine Viscous (Lidocaine Hydrochloride)FRESENIUS KABI USA LLCArchive
7/22/2014ANDA-076015Fluoxetine HydrochloridePHARMACEUTICAL ASSOCIATES, INCArchive
7/22/2014ANDA-040751, ANDA-040752, ANDA-040753Imipramine Hydrochloride PROSAM LABS, LLCArchive
7/22/2014ANDA-075525Fluoxetine HydrochlorideHI-TECH PHARMACAL CO., INCArchive
7/22/2014ANDA-071196,
ANDA-071258 		Trazodone Hydrochloride APOTEX INCArchive
7/03/2014NDA-014694Hexadrol (Dexamethasone Sodium Phospate)ORGANON USA INCArchive
6/03/2014ANDA-088184, ANDA-088185 Hydroxyzine Hydrochloride FRESENIUS KABI USA, LLCArchive
6/03/2014ANDA-040600, ANDA-040602, ANDA-040604Hydroxyzine Hydrochloride MIKAH PHARMA LLCArchive
6/03/2014ANDA-087014Orgatrax (Hydroxyzine Hydrochloride)ORGANON USA INCArchive
10/24/2013ANDA-040261Acetaminophen, Butalbital, and CaffeineWEST-WARD PHARMACEUTICALS CORPArchive
10/24/2013ANDA-087811Phrenilin (Acetaminophen and Butalbital)KELLER AND HECKMAN LLP
U.S. AGENT FOR VALEANT INTERNATIONAL BERMUDA		Archive
10/24/2013ANDA-040864Acetaminophen, Butalbital, and CaffeineMIRROR PHARMACEUTICALS LLCArchive
10/24/2013ANDA-088831Phrenilin Forte (Acetaminophen and Butalbital)KELLER AND HECKMAN LLP
U.S. AGENT FOR VALEANT INTERNATIONAL BERMUDA		Archive
10/24/2013ANDA-040336Acetaminophen, Butalbital, and Caffeine WEST-WARD PHARMACEUTICALS CORPArchive
10/24/2013ANDA-040688Acetaminophen, Caffeine, and Dihydrocodeine BitartrateWRASER PHARMACEUTICALSArchive
10/24/2013ANDA-040883Acetaminophen, Butalbital, and Caffeine MIRROR PHARMACEUTICALS LLCArchive
8/19/2013ANDA-077417, ANDA-077809Ciprofloxacin WATSON LABORATORIES, INC. - FLORIDAArchive
8/19/2013ANDA-078712Ciprofloxacin SANDOZ, INCArchive
5/10/2013ANDA-088704Triacin-C® Cough Syrup (Codeine Phosphate, Pseudoephedrine Hydrochloride, and Triprolidine Hydrochloride)CLINSMART LLC
U.S. AGENT FOR STI PHARMA LLC		Archive
5/10/2013ANDA-087006Acetaminophen and Codeine PhosphateWOCKHARDT EU OPERATIONS (SWISS) AGArchive
5/10/2013ANDA-040223Acetaminophen and Codeine PhosphateBARR LABORATORIES, INCArchive
5/10/2013ANDA-040441Acetaminophen and Codeine PhosphateWATSON LABORATORIES, INC - FLORIDAArchive
5/10/2013ANDA-040447, ANDA-040488Acetaminophen and Codeine PhosphateWATSON LABORATORIES, INC - FLORIDAArchive
5/10/2013ANDA-089997, ANDA-089998, ANDA-089999Acetaminophen and Codeine PhosphateWATSON LABORATORIES, INCArchive
5/10/2013ANDA-040688Acetaminophen, Caffeine, and Dihydrocodeine BitartrateWRASER PHARMACEUTICALSArchive
5/10/2013ANDA-040701Acetaminophen, Caffeine, and Dihydrocodeine BitartrateBOCA PHARMACAL, INC.Archive
5/10/2013ANDA-089671, ANDA-089672Acetaminophen and Codeine PhosphateFRONTIDA BIOPHARM INCArchive
5/10/2013ANDA-040443Acetaminophen and Codeine PhosphateWATSON LABORATORIES, INC - FLORIDAArchive
4/11/2013ANDA-073143, ANDA-074436Cyclobenzaprine Hydrochloride WATSON LABORATORIES, INCArchive
4/11/2013ANDA-072854Cyclobenzaprine Hydrochloride SANDOZ, INCArchive
4/11/2013ANDA-077209, ANDA-077291Cyclobenzaprine Hydrochloride PROSAM LABS, LLCArchive
12/20/2010NDA-021358MultiHance Multipack (Gadobenate Dimeglumine)BRACCO DIAGNOSTICS, INCArchive
11/02/2010ANDA-074900, ANDA-074901Atracurium Besylate BEDFORD LABORATORIESArchive
11/02/2010ANDA-074944,
ANDA-074945		Atracurium Besylate WATSON PHARMACEUTICALS, INCArchive
11/02/2010ANDA-090243Vecuronium Bromide AKORN-STRIDES, LLCArchive
11/02/2010ANDA-078562Mivacurium ChloridePISGAH LABS, INCArchive
11/02/2010ANDA-074334Vecuronium BromideWATSON PHARMACEUTICALS, INCArchive
11/02/2010ANDA-075218Vecuronium Bromide BAXTER HEALTHCARE CORPORATIONArchive
6/02/2010NDA-020692,
NDA-021077,
NDA-021254		Serevent Diskus (Salmeterol Xinafoate),
Advair Diskus (Fluticasone Propionate and Salmeterol), Advair HFA (Fluticasone Propionate and Salmeterol)		GLAXOSMITHKLINE Archive
6/02/2010NDA-021929Symbicort (Budesonide and Formoterol Fumarate Dihydrate)ASTRAZENECA LP Archive
3/09/2010NDA-019309Vasotec (Enalapril Maleate)BIOVAIL LABORATORIES INTERNATIONAL SRLArchive
1/21/2010NDA-006188Propylthiouracil DAVA PHARMACEUTICALS, INCArchive
7/19/2009NDA-020592, NDA-021253; NDA-021086Zyprexa (Olanzapine), Zyprexa Zydis (Olanzapine)ELI LILLY AND COMPANYArchive
7/19/2009NDA-021520Symbyax (Olanzapine and Fluoxetine)ELI LILLY AND COMPANYArchive
7/30/2008BLA-103234Epogen/Procrit (Epoetin Alfa)AMGEN, INCORPORATEDArchive
7/30/2008BLA-103951Aranesp (Darbepoetin Alpha)AMGEN, INCORPORATEDArchive
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