United States Food and Drug Administration Product Label Changes

aLeon Kircik, MD; bJulie C. Sung, BA; cLinda Stein-Gold, MD; bGary Goldenberg, MD aMount Sinai Medical Center, New York, New York; Indiana University School of Medicine, Indianapolis, Indiana; Physicians Skin Care PLLC, Louisville, Kentucky; bThe Icahn School of Medicine at Mount Sinai, Department of Dermatology, New York, New York; cDepartment of Dermatology, Henry Ford Medical Center, Detroit, Michigan

Disclosure: Dr. Kircik received funding from Leo, Valeant, PharmaDerm, and Aqua Pharmaceuticals either as an investigator, speaker, advisory board member, or consultant. Dr. Stein Gold is an advisor, investigator, and/or consultant for Leo and Valeant. Ms. Sung reports no relevant conflicts of interest. Dr. Goldenberg is a speaker, consultant, and/or investigator for Valeant, Leo, and PharmaDerm.


Once a drug has been approved by the United States Food and Drug Administration and is on the market, the Food and Drug Administration communicates new safety information through product label changes. Most of these label changes occur after a spontaneous report to either the drug manufacturing companies or the Food and Drug Administration MedWatch program. As a result, 400 to 500 label changes occur every year. Actinic keratosis treatments exemplify the commonality of label changes throughout the postmarket course of a drug. Diclofenac gel, 5-fluorouracil cream, imiquimod, and ingenol mebutate are examples of actinic keratosis treatments that have all undergone at least one label revision. With the current system of spontaneous reports leading to numerous label changes, each occurrence does not necessarily signify a radical change in the safety of a drug. (J Clin Aesthet Dermatol. 2016;9(1):39–48.)


The United States Food and Drug Administration (FDA) is specifically tasked with upholding the safety and efficacy of human drugs and medical devices to the highest standards. Once a product has undergone the rigorous approval process, the FDA continues to monitor the safety of every FDA-approved product through post-marketing surveillance. The current system of post-marketing surveillance frequently results in drug label changes. Drug labels are an essential tool for both drug manufacturers and the FDA to convey information about a product’s indication, dosage, pharmacology, and adverse effects. As a result, the FDA utilizes drug label changes as the primary communication method to the public regarding any new information about a drug.

Label changes, as the communication tool of the FDA, are a common occurrence with about 400 to 500 product label changes occurring every year.[1],[2] The process of product label changes originates from healthcare professionals, consumers, or drug companies who can report on safety information through MedWatch: The FDA Safety Information and Adverse Event Reporting Program.[3] The FDA receives approximately 500,000 reports each year.[4] Because the drug companies are mandated to report any adverse effects through the MedWatch Program, the majority of spontaneous reports from doctors and patients are first reported to the drug companies, which then must enter a report with the MedWatch Program.[3],[4] The rest occur via spontaneous reports from doctors and consumers who report directly to the FDA any new safety information.[4] Two separate studies of product label changes conducted in 2007–2009 and 2010 found that 59 and 52 percent of label changes arose from these spontaneous reports, respectively.[1],[5]

Newly reported information becomes a part of the FDA Adverse Event Reporting System (FAERS). Clinical reviewers in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) assess the reports from FAERS. If the reviewers identify a potential safety concern, then the issue may undergo further evaluation using emerging tools, such as the Sentinel Initiative. The Sentinel Initiative, which utilizes electronic medical records to investigate correlations of safety complaints and actual outcomes, was formed after the Food and Drug Administration Amendments Act of 2007.[3],[6],[7] Currently, however, the Sentinel Initiative is still a pilot project, and the initiative is undergoing extensive research on how to best identify safety signals generated in electronic databases.[7],[8] If the FDA cannot utilize the newly formed Sentinel Initiative, then clinical reviewers try to identify and focus on any serious, rare, and unexpected adverse events. The process beginning from spontaneous report and ending with review in the FAERS can then lead to a product label change if the reviewers determine enough evidence has been presented or a very serious adverse event occurred.[3]

Actinic keratosis treatments illustrate the continuous process of how label changes occur. Some examples are shown in Table 1 Part 1, Table 1 Part 2 , Table 1 Part 3, Table 1 Part 4, Table 1 Part 5,
Table 1 Part 6, Table 1 Part 7. Each of the drugs has undergone at least one label revision, which typically occurs 1 to 3 years after the initial release.[9] These changes mainly reflect reported adverse events following a few years of wider use as compared to clinical trial data, which, as to be expected, generally comprises a smaller, less diverse population.

One topical treatment for actinic keratosis, diclofenac sodium (3%), specifically under the brand name Solaraze Gel (PharmaDerm, Part of Fougera Pharmaceuticals Inc., Melville, New York), was originally approved for use in 2000. It has undergone one labeling revision in 2011 that was initiated by the drug company to include new information about absorption and drug interactions.[9] Specifically, the drug company added disclaimers to the label regarding bioavailability of diclofenac gel under different circumstances, such as various dosing regimens and when used under occlusion. In addition, the newly revised label made note of systemic absorption of the product, which could lead to nonsteroidal anti-inflammatory drugs (NSAID)-related adverse effects, such as gastrointestinal ulcers and renal toxicity, when used with other NSAIDs. Because of the systemic absorption, the company also made another disclaimer that the interactions between diclofenac gel and other medications have not been tested.

5-fluorouracil cream (0.5%), under the brand name Carac® cream (Valeant Pharmaceuticals North America LLC), is another medication approved for the topical treatment of actinic keratoses in 2000. In 2003, after the FDA wrote an action letter to the drug company, the company submitted a label revision for the cream due to a reported case of severe systemic side effects in a patient lacking dihydropyrimidine dehydrogenase (DPD) activity after using topical 5% fluorouracil. The warning specifies, “symptoms included severe abdominal pain, bloody diarrhea, vomiting, fever, and chills. Physical examination revealed stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, inflammation of the esophagus, stomach, and small bowel. Although this case was observed with 5% fluorouracil cream, it is unknown whether patients with profound DPD enzyme deficiency would develop systemic toxicity with lower concentrations of topically applied fluorouracil.”[9] Even though this label revision was based on one case, this example demonstrates how the FDA is moved to action when a rare but very serious adverse effect is correlated with the use of a medication.

5-fluorouracil cream indicated for actinic keratosis is also known under the brand names of Efudex® (5%) (Valeant Pharmaceuticals International) and Fluoroplex® (1%) (Aqua Pharmaceuticals, West Chester, Pennsylvania) and was approved in 1970 and 1971, respectively.[9] Because Efudex and Fluoroplex were approved more than 40 years ago, the historical labels and exact label revisions are not publicly available; however, Efudex underwent four label revisions and Fluoroplex underwent two label revisions, again illustrating that drugs typically undergo numerous label changes throughout its course.

Another example of an actinic keratosis field treatment to undergo extensive label changes is imiquimod (3.75%), which under the brand name Zyclara® cream (Valeant Pharmaceuticals North America LLC), was originally approved in 2010 and indicated for actinic keratoses of the face and scalp. In 2011, the medication underwent three separate labeling changes. First, imiquimod was approved for the additional indication of external genital and perianal warts in patients 12 years and older, and as a result, a labeling change was initiated. Another labeling revision was submitted when the company created a new dosage of 2.5% for the treatment of actinic keratoses of the face or balding scalp. The drug company initiated these first two changes. However, similar to 5-fluorouracil, the final label revision was in response to an action letter from the FDA. This new drug label was released to include new data on the limitation of use of imiquimod in treating molluscum contagiosum in children. The newest label also made clear that imiquimod is not to be used for oral, ophthalmic, intra-anal, or intravaginal use. In the warnings section, users are warned that if imiquimod is placed on female external genitalia, it could lead to such a severe inflammatory reaction that the resultant swelling could lead to urinary retention.[9]

Imiquimod (5%), formulated under the brand name Aldara® (Medicis Pharmaceutical Corp), was originally approved in 1997 and has undergone six labeling revisions. The original label is not publicly available, but the drug manufacturer initiated all the labeling changes and the changes were associated with new pharmacology information, new indications and usage such as safety and efficacy down to 12 years of age, additional safety information such as avoiding application to vaginal area, and precautions involving usage with pregnancy.[9]

The most recent of these drugs to undergo the process of label change is ingenol mebutate gel (Picato®, Leo Pharma Inc., Parsippany, New Jersey). In 2012, ingenol mebutate gel was approved in two concentrations for the treatment of actinic keratoses on the face and scalp (0.015%) and on the trunk and extremities (0.05%). In August 2015, the FDA issued a drug safety communication warning of severe adverse side effects, which mandated a label change. The communication cited reports of severe allergic reactions and herpes zoster associated with ingenol mebutate use. In addition, the communication mentioned that severe eye injuries and skin reactions were occurring because the ingenol mebutate was not being used as indicated on the label.[10] As a result, similarly to previous actinic keratosis treatments, in October 2015, ingenol mebutate underwent a label revision, which specifically addressed the reported adverse events and the increased warnings about use in the periocular area.

Hundreds of medications go through the process of label changes every year, including numerous actinic keratosis treatments. The majority of label changes begin with spontaneous reports that are either reported to drug companies or directly to the FDA, and while this gives consumers and doctors a prominent voice in drug safety, spontaneous reports are easily generated leading to a regular need for label revisions. The current system allows case reports, especially those reporting a severe, adverse event, to drive the process of label changes. The case reports can indicate a correlation with the usage of a drug, but are not perfect indicators of causation. The FDA has been trying to create a more reliable process through the Sentinel Initiative. However, the pilot project for this initiative is ongoing, and as a result, the effects of the Sentinel Initiative remain to be seen.[7],[8] While waiting for more advanced technologies and data, the public and FDA must still mainly rely on spontaneous reports, which will inevitably increase the number of needed label changes. These repeated revisions have become standard practice in the current system of post-marketing surveillance from the FDA, and each change should not be interpreted as a significant event.


1. Lester J, Neyarapally GA, Lipowski E, et al. Evaluation of FDA safety-related drug label changes in 2010. Pharmacoepidemiol Drug Saf. 2013;22(3):302–305.

2. Drug Safety Labeling Changes. US Food and Drug Administration. information/safety-relateddruglabelingchanges/default.htm. Accessed on November 18, 2015.

3. FDA Adverse Event Reporting System (FAERS). 2015;2015(10/24). ComplianceRegulatoryInformation/Surveillance/Adverse DrugEffects/ucm2007060.htm. Accessed on November 18, 2015.

4. Woodcock J, Behrman RE, Dal Pan GJ. Role of post-marketinging surveillance in contemporary medicine. Annu Rev Med. 2011;62:1–10.

5. Ishiguro C, Hall M, Neyarapally GA, Dal Pan G. Post-market drug safety evidence sources: an analysis of FDA drug safety communications. Pharmacoepidemiol Drug Saf. 2012; 21(10):1134–1136.

6. Robb MA, Racoosin JA, Sherman RE, et al. The US Food and Drug Administration’s Sentinel Initiative: expanding the horizons of medical product safety. Pharmacoepidemiol Drug Saf. 2012;21(Suppl 1):9–11.

7. Huang YL, Moon J, Segal JB. A comparison of active adverse event surveillance systems worldwide. Drug Saf. 2014;37(8): 581–596.

8. Platt R, Carnahan RM, Brown JS, et al. The US Food and Drug Administration’s Mini-Sentinel program: status and direction. Pharmacoepidemiol Drug Saf. 2012;21(Suppl 1):1–8.

9. Drugs@FDA. U.S. Food and Drug Administration. Accessed on November 18, 2015.

10. Picato (ingenol mebutate) Gel: Drug Safety Communication—FDA Warns of Severe Adverse Events, Requires Label Changes. In: Administration USFaD, ed. Safety Alerts for Human Medical Products: U.S. Department of Health and Human Services; 2015.

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13.…/20723s11s 12lbl.pdf. Accessed on November 18, 2015.

14. Accessed on November 18, 2015.

15. 20PI.pdf. Accessed on November 18, 2015.

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