United States Food and Drug Administration Product Label Changes

Abstract

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.

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. 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.

TABLE 1.

Clinically relevant key information from current labels of FDA-approved topical treatments for actinic keratosis11-15

DRUG	PICATO® GEL	ALDARA®	FLUOROPLEX®
Generic name	ingenol mebutate	imiquimod	fluorouracil
Brand names	Picato® Gel, 0.05% and 0.015%	Aldara® Cream, 5%	FLUOROPLEX® Topical Cream, 1%
Therapeutic class	Cell death inducer	Immune modulator	Antimetabolite
Approved indications	Indicated for the topical treatment of AK	Indicated for the topical treatment of: 1) Clinically typical, nonhyper-keratotic, nonhypertrophic AK on the face or scalp in immunocompetent adults 2) Biopsy-confirmed, primary sBCC in immunocompetent adults; maximum tumor diameter of 2.0cm on trunk, neck, or extremities (excluding hands and feet), only when surgical methods are medically less appropriate and patient follow-up can be reasonably assured 3) External genital and perianal warts/condyloma acuminata in patients 12 years old or older	Indicated for the topical treatment of multiple actinic (solar) keratoses
Mechanism of action	The mechanism of action by which Picato gel induces cell death in treating AK lesions is unknown.	Aldara Cream is an immune response modifier; the mechanism of action of Aldara Cream in treating AK and sBCC lesions is unknown.	FLUOROPLEX Topical Cream is an antineoplastic/antimetabolite product for dermatologic use. There is evidence that fluorouracil (or its metabolites) blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this fashion, fluorouracil interferes with the synthesis of DNA and, to a lesser extent, inhibits the formation of RNA
Absorption	The systemic PK profile of Picato gel and its metabolites has not been characterized in humans due to an absence of quantifiable serum levels following topical administration. In vitro study results demonstrate that Picato gel does not inhibit or induce human cytochrome P450 isoforms.	Systemic absorption of imiquimod across the affected skin of 58 subjects with AK was observed with a dosing frequency of 3 applications per week for 16 weeks. Mean peak serum drug concentrations at the end of Week 16 were approximately 0.1, 0.2, and 3.5ng/mL for the applications to face (12.5mg imiquimod, 1 single-use packet), scalp (25mg, 2 packets) and hands/arms (75mg, 6 packets), respectively.	There is a possibility of increased absorption through ulcerated or inflamed skin.

DRUG	ZYCLARA®	CARAC®	EFUDEX®	SOLARAZE®
Generic name	imiquimod	fluorouracil	fluorouracil	diclofenac sodium
Brand names	ZYCLARA® Cream, 3.75%	Carac® Cream, 0.5%	EFUDEX® Solution and EFUDEX® Cream, 5%	Solaraze® Gel
Therapeutic class	Immune modulator	Antimetabolite	Antimetabolite	NSAID
Approved indications	Indicated for the topical treatment of: 1) Clinically typical, visible or palpable AK of the full face or balding scalp in immunocompetent adults 2) External genital and perianal warts/condyloma acuminata in patients 12 years or older	Indicated for the topical treatment of multiple actinic or solar keratoses of the face and anterior scalp	Indicated for the topical treatment of: 1) Multiple actinic or solar keratoses 2) In the 5% strength, it is also useful in the treatment of sBCCs when conventional methods are impractical, such as with multiple lesions or difficult treatment sites	Indicated for the topical treatment of AK
Mechanism of action	The mechanism of action of ZYCLARA Cream in treating AK and EGW is unknown. Imiquimod is a Toll-like receptor 7 agonist that activates immune cells. Topical application to skin is associated with increases in markers for cytokines and immune cells.	There is evidence that fluorouracil (or its metabolites) blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this fashion, fluorouracil interferes with the synthesis of DNA, and, to a lesser extent, inhibits the formation of RNA.	There is evidence that the metabolism of fluorouracil in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid. In this manner, fluorouracil interferes with the synthesis of DNA and, to a lesser extent, inhibits the formation of RNA.	The mechanism of action of diclofenac sodium in the treatment of AK is unknown. The contribution to efficacy of individual components of the vehicle has not been established.
Absorption	Following 18.75mg imiquimod/day dosing of ZYCLARA Cream applied to the face and/or scalp in 17 subjects for ≤3 weeks, systemic absorption of imiquimod was observed in all subjects. The mean peak serum imiquimod concentration was ~0.323ng/mL, and the median time to maximal concentration (Tmax) occurred 9 hours after dosing. Based on the plasma half-life of imiquimod observed at the end of the study (29.3±17.0 hours), steady-state concentrations can be anticipated to occur by Day 7 with once-daily dosing.	There is a possibility of increased absorption through ulcerated or inflamed skin.	Systemic absorption studies of topically applied fluorouracil have been performed on patients with AK using tracer amounts of 14C- labeled fluorouracil added to a 5% preparation. At the peak of the inflammatory reaction (after 2-3 weeks of treatment), 1 g of labeled preparation was applied to the entire face and neck and left in place for 12 hours. After 3 days, the total amount recovered through urine ranged between 0.48% and 0.94%, with an average of 0.76%, indicating that approximately 5.98% of the topical dose was absorbed systemically. If applied twice daily, this would indicate systemic absorption of topical fluorouracil to be in the range of 5 to 6mg per daily dose of 100mg. In an additional study, negligible amounts of labeled material were found in plasma, urine, and expired CO2 after 3 days of treatment with topically applied 14C-labeled fluorouracil.	Blood drawn at the end of treatment from 60 patients with AK lesions treated with Solaraze Gel in 3 adequate and well-controlled clinical trials was assayed for diclofenac levels. Each patient was administered 0.5g of Solaraze Gel twice a day for ≤=105 days for ≤=3 treatment sites (5x5cm each) on the face, forehead, hands, forearm, or scalp. Serum concentrations of diclofenac were, on average, <=20ng/mL. These data indicate that systemic absorption of diclofenac in patients treated topically with Solaraze Gel is much lower than that occurring after oral daily dosing of diclofenac sodium.

DRUG	PICATO® GEL	ALDARA®	FLUOROPLEX®
Distribution	Not listed in PI	Not listed in PI	Not listed in PI
Metabolism	In vitro studies demonstrated that [3H]-ingenol mebutate undergoes extensive metabolism in human hepatocytes. In vitro studies demonstrated that ingenol mebutate does not inhibit human cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce CYP 1A2, 2C9, and 3A4.	Not listed in PI	Not listed in PI
Elimination	Not listed in PI	Not listed in PI	Not listed in PI
Contraindications	Picato is contraindicated in patients with known hypersensitivity to ingenol mebutate or any component of the formulation. Anaphylaxis as well as allergic reactions leading to hospitalization have been reported in postmarketing use with Picato	None	Fluorouracil is contraindicated in women who are or may become pregnant. This product should not be used by patients who are allergic to any of its components.
Warnings/precautions	Eye disorders, including severe eye pain, eyelid edema, eyelid ptosis, and periorbital edema, can occur after exposure. Patients should wash hands well after applying Picato gel and avoid transfer of the drug to the periocular area during and after application. If accidental exposure occurs, the area should be flushed with water and the patient should seek medical care as soon as possible. Severe skin reactions in the treated area, including erythema, crusting, swelling, vesiculation/pustulation, and erosion/ulceration, can occur after topical application of Picato gel. Administration of Picato gel is not recommended until the skin is healed from any previous drug or surgical treatment.	Intense local inflammatory reactions can occur (e.g., skin weeping, erosion). Dosing interruption may be required. Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling and urinary retention; in these cases, dosing should be interrupted or discontinued. Flu-like systemic signs and symptoms, including malaise, fever, nausea, myalgias and rigors, may occur. Dosing interruption may be required. Avoid exposure to sunlight and sunlamps. Wear sunscreen daily. Safety and efficacy have not been established for repeat courses of treatment to the same area for AK. Aldara Cream is not recommended for treatment of BCC subtypes other than the superficial variant (i.e., sBCC). Treatment of urethral, intravaginal, cervical, rectal or intra-anal viral disease is not recommended. Safety and efficacy in immuno- suppressed patients have not been established.	There exists the potential for a delayed hypersensitivity reaction to fluorouracil. Patch testing to prove hypersensitivity may be inconclusive. If an occlusive dressing is used, there may be an increase in the incidence of inflammatory reactions in the adjacent normal skin. The patient should avoid prolonged exposure to sunlight or other forms of UV irradiation during treatment with FLUOROPLEX Cream, as the intensity of the reaction may be increased.

DRUG	ZYCLARA®	CARAC®	EFUDEX®	SOLARAZE®
Distribution	Not listed in PI	Not listed in PI	Not listed in PI	Diclofenac binds tightly to serum albumin. The volume of distribution of diclofenac following oral administration is ~550mL/kg.
Metabolism	Not listed in PI	Not listed in PI	Not listed in PI	Biotransformation of diclofenac following oral administration involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, however, to a much smaller extent than diclofenac. Metabolism of diclofenac following topical administration is thought to be similar to that after oral administration. The small amounts of diclofenac and its metabolites appearing in the plasma following topical administration makes the quantification of specific metabolites imprecise.
Elimination	Not listed in PI	Not listed in PI	Not listed in PI	Diclofenac and its metabolites are excreted mainly in the urine after oral dosing. Systemic clearance of diclofenac from plasma is 263±56mL/min (mean±SD). The terminal plasma half-life is 1-2 hours. Four of the metabolites also have short terminal half-lives of 1-3 hours.
Contraindications	None	Fluorouracil is contraindicated in women who are or may become pregnant. Carac Cream should not be used in patients with DPD enzyme deficiency. Carac Cream is contraindicated in patients with known hypersensitivity to any of its components.	EFUDEX should not be used in patients with DPD enzyme deficiency. A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities. EFUDEX is contraindicated in women who are or may become pregnant during therapy. EFUDEX is also contraindicated in patients with known hypersensitivity to any of its components.	Solaraze Gel is contraindicated in patients with a known hypersensitivity to diclofenac, benzyl alcohol, polyethylene glycol monomethyl ether 350, and/or hyaluronate sodium.

DRUG	PICATO® GEL	ALDARA®	FLUOROPLEX®
Adverse reactions	Local skin reactions including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosion/ulceration, were seen during the clinical trials. The following adverse reactions have been identified during post approval use of Picato (ingenol mebutate) gel, 0.015%, and 0.05%: hypersensitivity, allergic contact dermatitis, herpes zoster, chemical conjunctivitis, and corneal burn. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.	The most common adverse reactions (incidence >28%) are application-site reactions or LSRs: itching, burning, erythema, flaking/scaling/dryness, scabbing/crusting, edema, induration, excoriation, erosion, and ulceration. Other reported reactions (≥=1%) include fatigue, fever, and headache.	Pain, pruritus, burning, irritation, inflammation, allergic contact dermatitis, and telangiectasia have been reported. Occasionally, hyperpigmentation and scarring have also been reported.
Dosage and Administration Additional notes	AK on the face or scalp: Apply Picato gel, 0.015%, to the affected area once daily for 3 consecutive days. AK on the trunk or extremities: Apply Picato gel, 0.05%, to the affected area once daily for 2 consecutive days.	AK: Apply 2 times per week for a full 16 weeks. Not for oral, ophthalmic, or intravaginal use.	The patient should be instructed to apply sufficient medication to cover the entire face or other affected areas. Apply medication twice daily with fingertips and wash hands afterwards; a treatment period of 2-6 weeks is usually required. Increasing the frequency of application and a longer period of administration may be required on areas other than the head/neck. When applied to keratotic skin, a response occurs with the following sequence: erythema, usually followed by scaling, tenderness, erosion, ulceration, necrosis, and re-epithelization. When the inflammatory reaction reaches the erosion, ulceration and necrosis stages, the use of the drug should be terminated. Responses may sometimes occur in areas which appear clinically normal. These may be sites of subclinical actinic (solar) keratosis that the medication is affecting.

DRUG	ZYCLARA®	CARAC®	EFUDEX®	SOLARAZE®
Warnings/precautions	Intense local inflammatory reactions can occur (e.g., skin weeping, erosion). Dosing interruption may be required. Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling and urinary retention; in these cases, dosing should be interrupted or discontinued. Flu-like systemic signs and symptoms, including fatigue, nausea, fever, myalgias, arthralgias, and chills, can occur. Dosing interruption may be required. Avoid exposure to sunlight and sunlamps. Wear sunscreen daily. Avoid concomitant use of ZYCLARA and any other imiquimod products in the same treatment area because of increased risk for adverse reactions. Treatment of urethral, intra-vaginal, cervical, rectal, or intra-anal human papilloma viral disease is not recommended as it has not been studied.	The potential for a delayed hypersensitivity reaction to fluorouracil exists. Patients should discontinue therapy with Carac Cream if symptoms of DPD enzyme deficiency develop. Application to mucous membranes should be avoided due to the possibility of local inflammation and ulceration.	Application to mucous membranes should be avoided due to the possibility of local inflammation and ulceration. Additionally, cases of miscarriage and a birth defect (ventricular septal defect) have been reported when EFUDEX was applied to mucous membrane areas during pregnancy. Occlusion of the skin with resultant hydration has been shown to increase percutaneous penetration of several topical preparations. If any occlusive dressing is used in treatment of BCC, there may be an increase in the severity of inflammatory reactions in the adjacent normal skin. A porous gauze dressing may be applied for cosmetic reasons without increase in reaction. Exposure to UV rays should be minimized during and immediately following treatment with EFUDEX because the intensity of the reaction may be increased. Patients should discontinue therapy with EFUDEX if symptoms of DPD enzyme deficiency develop. Rarely, life-threatening toxicities such as stomatitis, diarrhea, neutropenia, and neurotoxicity have been reported with intravenous administration of fluorouracil in patients with DPD enzyme deficiency.	As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to diclofenac. Diclofenac sodium should be given with caution to patients with the aspirin triad. The triad typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs.

DRUG	ZYCLARA®	CARAC®	EFUDEX®	SOLARAZE®
Adverse reactions	The most common adverse reactions (>2%) are LSRs (erythema, edema, weeping/exudate, flaking/scaling/dry- ness, scabbing/crusting erosion/ulceration), headache, fatigue, nausea and fever.	The following AEs were considered to be drug-related and occurred among >1% of patients treated with Carac® Cream: application-site reaction (94.6%) and eye irritation (5.4%). During clinical trials, facial irritation (erythema, dryness, burning, erosion, pain, and edema) generally began on day 4 and persisted for the remainder of treatment. Eye irritation AEs, described as mild to moderate in intensity, were characterized as burning, watering, sensitivity, stinging, and itching.	The most frequent adverse reactions to EFUDEX® occur locally and are often related to an extension of the pharmacological activity of the drug. These include burning, crusting, allergic contact dermatitis, pruritus, scarring, rash, soreness, and ulceration. Ulcerations, other local reactions, cases of miscarriage, and a birth defect (ventricular septal defect) have been reported when EFUDEX® was applied to mucous membrane areas. Leukocytosis is the most frequent hematological side effect. Although a causal relationship is remote, other adverse reactions that have been reported infrequently are: Central nervous system: Emotional upset, insomnia, irritability Gastrointestinal: Medicinal taste, stomatitis Hematological: Eosinophilia, thrombocytopenia, toxic granulation Integumentary: Alopecia, blistering, bullous pemphigoid, discomfort, ichthyosis, scaling, suppuration, swelling, telangiectasia, tenderness, urticaria, skin rash Special senses: Conjunctival reaction, corneal reaction, lacrimation, nasal irritation Miscellaneous: Herpes simplex	Of the 423 patients evaluable for safety in adequate and well-controlled trials, 211 were treated with Solaraze® Gel and 212 were treated with a vehicle gel. 183 of the Solaraze® Gel-treated patients (87%) and 178 of the vehicle-treated patients (84%) experienced ≥=1 AE. The majority of these reactions were mild to moderate in severity and resolved upon discontinuation of therapy. Application-site reactions were the most frequent AEs in both treatment groups; of note, contact dermatitis, rash, dry skin, and exfoliation (scaling) were significantly more prevalent in the Solaraze® Gel group compared to the vehicle group. AEs involving skin and the application site were experienced by 172 (82%) of Solaraze® Gel patients and 160 (75%) of vehicle patients.
Dosage and Administration Additional notes	AK: Apply once daily to the skin of the affected area (either the entire face or balding scalp) for two 2-week treatment cycles separated by a 2-week no-treatment period. For topical use only; not for oral, ophthalmic, intra-anal or intravaginal use.	Apply once a day to the skin where AK lesions appear, using enough to cover the entire area with a thin film. Do not apply near the eyes, nostrils, or mouth. Carac® Cream should be applied 10 minutes after thoroughly washing, rinsing, and drying the entire area. Carac® Cream may be applied using the fingertips; immediately after application, the hands should be thoroughly washed. Apply up to 4 weeks as tolerated. Continued treatment up to 4 weeks results in greater lesion reduction. Local irritation is not markedly increased by extending treatment from 2 to 4 weeks, and is generally resolved within 2 weeks of cessation of treatment.	When EFUDEX® is applied to a lesion, a response occurs with the following sequence: erythema, usually followed by vesiculation, desquamation, erosion, and re-epithelialization. EFUDEX® should be applied preferably with a nonmetal applicator or suitable glove. If EFUDEX® is applied with the fingers, the hands should be washed immediately afterward. AK: Apply cream or solution twice daily in an amount sufficient to cover the lesions. Medication should be continued until the inflammatory response reaches the erosion stage, at which time use of the drug should be terminated. The usual duration of therapy is from 2 to 4 weeks. Complete healing of the lesions may not be evident for 1 to 2 months following cessation of EFUDEX® therapy.	Solaraze® Gel is applied to lesion areas twice daily. It is to be smoothed onto the affected skin gently. The amount needed depends upon the size of the lesion site. Ensure that enough Solaraze® Gel is applied to adequately cover each lesion. Normally, 0.5 g of gel is used on each 5x5 cm lesion site. The recommended duration of therapy is from 60 days to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy. Lesions that do not respond to therapy should be carefully reevaluated and management reconsidered.

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 antiinflammatory 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 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.