NDA 20380 NONPRESCRIPTION ADAPALENE 0.1% BRIEFING DOCUMENT FOR APRIL 15, 2016 TOPICAL GEL NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEETING

FDA NONPRESCRIPTION DRUGS ADVISORY COMMITTEE BRIEFING DOCUMENT

Differin® Gel Adapalene 0.1% Topical Gel

Meeting Date: April 15, 2016



Available for Public Disclosure Without Redaction

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TABLE OF CONTENTS

LIST OF ABBREVIATIONS ...... 4 1 EXECUTIVE SUMMARY ...... 5 1.1 Program Overview ...... 5 1.2 Acne: Prevalence and Impact on Quality of Life ...... 5 1.3 Current Self-Management of Acne ...... 5 1.4 History of Adapalene ...... 6 1.5 Efficacy and Safety ...... 7 1.5.1 Clinical Studies ...... 7 1.5.2 Post-Marketing Surveillance ...... 8 1.5.3 Clinical Pharmacokinetic Studies ...... 8 1.5.4 Teratogenicity ...... 9 1.5.5 Potential Off-Label Use ...... 12 1.5.6 Other Safety Considerations ...... 13 1.6 Differin Gel OTC Development Program ...... 13 1.6.1 Label Comprehension Study ...... 13 1.6.2 Actual Use Study ...... 14 1.6.3 Targeted Self-Selection Study ...... 17 1.7 Benefit and Risk Considerations for Nonprescription Differin Gel ...... 18 1.8 Rationale for Nonprescription Access to Differin Gel ...... 19 2 BACKGROUND ...... 20 2.1 Overview of Acne ...... 20 2.2 Current Self-Management of Acne ...... 21 3 DEVELOPMENT OF DIFFERIN GEL ...... 23 3.1 Properties of Adapalene and the Differin Gel Formulation ...... 23 3.2 Regulatory History ...... 25 4 SUMMARY OF EFFICACY ...... 26 5 SUMMARY OF SAFETY ...... 27 5.1 Safety Data from Original Pivotal Clinical Studies ...... 27 5.1.1 Cutaneous Tolerability ...... 29 5.1.2 Adverse Events ...... 29 5.1.3 Serious adverse events ...... 32 5.2 Other Clinical Studies ...... 32 5.3 Post-Marketing Surveillance ...... 32 5.4 Clinical Pharmacokinetic Studies ...... 33 5.4.1 Maximal Use Pharmacokinetic Study 18115 ...... 33 5.4.2 Maximal Use Pharmacokinetic Study 18097 ...... 35 5.4.3 Maximal Use Pharmacokinetic Study 18254 ...... 38 5.4.4 Conclusion of Maximal Use Clinical Pharmacokinetic Studies ...... 46 5.5 Teratogenicity and Fetotoxicity ...... 46 5.5.1 Receptor-binding Properties of Adapalene ...... 47 5.5.2 Nonclinical Reproductive Toxicity Studies with Adapalene ...... 47 5.5.3 Calculation of Safety Margin ...... 49 5.5.4 Exposure During Pregnancy ...... 51 5.5.5 Evaluation of Additional Data Sources ...... 52 5.5.6 Summary of Teratogenic Risk ...... 53

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5.6 Other Safety Considerations ...... 54 5.6.1 Potential Off-Label Use ...... 54 5.6.2 Concomitant Use with Other Acne Medications and Topical Products ...... 55 5.6.3 Carcinogenesis and Mutagenesis ...... 56 5.6.4 Phototoxicity ...... 56 5.6.5 Lactation ...... 56 6 DEVELOPMENT OF NONPRESCRIPTION DIFFERIN GEL ...... 57 6.1 Label Comprehension Testing ...... 58 6.2 Actual Use Study ...... 61 6.2.1 Study Design ...... 61 6.2.2 Disposition of Subjects ...... 67 6.2.3 Actual Use Results ...... 67 6.3 Targeted Self-Selection Study ...... 79 6.3.1 Study Design ...... 79 6.3.2 Study Population ...... 80 6.3.3 Study Results ...... 80 6.4 Conclusions of Differin Gel Nonprescription Development Program ...... 81 6.5 Differin Gel Nonprescription DFL ...... 81 7 BENEFIT AND RISK CONSIDERATIONS ...... 83 7.1 Benefits of Nonprescription Differin Gel ...... 83 7.2 Adverse Event Profile of Differin Gel ...... 83 7.3 Teratogenicity ...... 84 7.4 Potential Off-label Use ...... 84 7.5 Other Safety Considerations ...... 84 7.6 Conclusion ...... 84 8 LITERATURE REFERENCES...... 86 9 APPENDIX ...... 88



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LIST OF ABBREVIATIONS

Abbreviation Definition AE Adverse Event AUC Area Under the Curve BPO Benzoyl Peroxide BSA Body Surface Area

Cmax Maximum Concentration DFL Drug Facts Label FAERS FDA Adverse Event Reporting System FDA Food And Drug Administration FDC Fixed-Dose Combination HRQoL Health-Related Quality of Life LB Lower Bound LOQ Limit Of Quantification MedDRA Medical Dictionary for Regulatory Activities NDA New Drug Application NOEL No Observable Effect Level NOAEL No Observed Adverse Effect Level OTC Over-the-Counter PK Pharmacokinetic(S) PSUR Periodic Safety Update Report REALM Rapid Estimate of Adult/Adolescent Literacy in Medicine REALM-TEEN Rapid Estimate of Adolescent Literacy in Medicine Rx Prescription SAE Serious Adverse Event SD Standard Deviation sNDA Supplemental New Drug Application WHO World Health Organization

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1 EXECUTIVE SUMMARY

1.1 Program Overview Galderma Laboratories, L.P., submitted a Supplemental New Drug Application (sNDA) in September, 2015 with data supporting the nonprescription availability of topical Differin® (adapalene) Gel, 0.1% (hereafter Differin Gel) for the treatment of acne. This Briefing Document will outline the benefits and potential risks associated with the nonprescription availability of Differin Gel and review the comprehensive development plan that was implemented to demonstrate over-the-counter (OTC) suitability.

Also summarized herein are the key efficacy and safety data that supported the initial NDA approval as a prescription drug in 1996, as well as, the extensive post-marketing experience, all demonstrating a safety and efficacy profile that is acceptable for an OTC medication.

1.2 Acne: Prevalence and Impact on Quality of Life Acne vulgaris is a common disease affecting approximately 50 million people in the United States and up to 85% of teenagers. 1 Acne can occur in most age groups and persists into adulthood. The prevalence of acne in adult women is about 12% and over 50% of adults at some point in their lives have acne.1 Acne affects all races and ethnicities and is one of the most common dermatologic diagnoses.2-4

Acne is a multi-factorial disease, characterized by follicular keratinocyte desquamation, anaerobic 3URSLRQLEDFWHULXPDFQHV (3DFQHV) proliferation, inflammatory response, and excess sebum production.6 The lifecycle of acne lesions involves follicular plugging when keratinocytes accumulate in the sebaceous follicle, and formation of the microcomedone. The microcomedone then progresses to a noninflammatory (comedo) or inflammatory lesion, with subclinical inflammation processes being present before and during microcomedone formation. Further inflammation progresses through the acne lesion life cycle, and as an immune response, is seen with the presence of sebum and 3DFQHV proliferation.

There is no mortality associated with acne, but there is often significant physical and psychological morbidity, such as permanent scarring, poor self-image, depression, and anxiety.1 Facial blemishes have been found to significantly impair health-related quality of life (HRQoL)7 scores while improvement of acne is correlated with improvement in HRQoL scores.8 Early, effective treatment of acne is essential to prevent later complications including scarring and psychosocial burden.9

1.3 Current Self-Management of Acne

Acne is a well-established OTC category in the United States and topical acne drug products can be legally marketed if compliant with the OTC Topical Acne Drug Products monograph regulations (21 CFR 333 Subpart D). Five (5) active ingredients [benzoyl peroxide (BPO), salicylic acid, sulfur, resorcinol, and resorcinol monoacetate] are included in the monograph,

Page 5 NDA 20380 NONPRESCRIPTION ADAPALENE 0.1% BRIEFING DOCUMENT FOR APRIL 15, 2016 TOPICAL GEL NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEETING thus Generally Recognized as Safe and Effective for nonprescription use by the FDA. Of these ingredients, the most widely available and used active ingredients are BPO and salicylic acid, which make up more than 99% of the acne medications available without a prescription.10 There have been no new active ingredients DYDLODEOH for the nonprescription treatment of acne since the FDA OTC Topical Acne Drug Products rulemaking began in 1982.

Nonprescription acne medications have been available to consumers for decades, meaning that it has previously been determined that consumers can understand labeling for acne products, can self-diagnose the condition and can safely self-treat acne. Self-treatment of acne is quite common, with over 78% of teenage acne sufferers (aged 13 to 17 years) and over 64% of adult acne sufferers reporting that they have never visited a doctor for their acne.31

However, no currently available OTC acne medication addresses the formation of the comedo or the underlying sub-clinical inflammation that may be present, aspects physicians are able to target through the use of topical retinoid prescription medications. In fact, topical retinoids are recommended as a first-line treatment for acne by dermatologists including a recent working group of physicians who, in conjunction with the American Academy of Dermatology, developed evidence-based guidelines for the treatment of the disease.1 BPO, primarily due to antimicrobial properties, is also recommended as a first-line treatment for mild acne. Salicylic acid, sulfur and resorcinol, the other currently approved OTC acne active ingredients, are not recommended in this treatment guideline.1

A new OTC acne treatment with an alternative, dermatologist recommended mechanism of action, would provide an additional approach to address this multi-factorial condition.

1.4 History of Adapalene Vitamin A (retinol) and vitamin A derivatives, such as retinoic acid, are referred to as “retinoids” and include a number of compounds including retinol, tretinoin (retinoic acid), isotretinoin, tazarotene and adapalene.

Adapalene is a synthetic third-generation retinoid compound designed to provide clinical efficacy while minimizing cutaneous irritation. Adapalene differs structurally from retinoic acid by the presence of a phenoxy-adamantyl group, which results in low percutaneous flux and thereby limits systemic exposure. The phenoxy-adamantyl group increases lipophilicity and thereby enhances penetration into the pilosebaceous follicles.11 Unlike other retinoids, the unstable double bonds of retinoic acid are replaced in the adapalene molecule by aromatic rings, resulting in greater stability when exposed to light and oxygen.12

Adapalene, formulated as a 0.1% gel, was first approved in the United States for the treatment of acne in May, 1996 (NDA 20380). Three additional dosage forms (solution, cream, and lotion) containing adapalene at a concentration of 0.1% and a gel dosage form at a concentration of 0.3%, have also been approved in the United States for the treatment of acne under the trade name of Differin®. Adapalene 0.1% Gel has been the most extensively prescribed adapalene- containing formulation globally, as it has been approved in 83 countries in the world since 1994

Page 6 NDA 20380 NONPRESCRIPTION ADAPALENE 0.1% BRIEFING DOCUMENT FOR APRIL 15, 2016 TOPICAL GEL NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEETING including Canada, Japan and Australia as well as most countries in Europe, Asia and South America.

Adapalene 0.1% Gel is also approved in Russia where it has been available as a nonprescription drug since 2001. Approximately 500,000 consumers have used Adapalene 0.1% Gel in Russia, without physician oversight, and extensive experience in this market of the identical formulation proposed for nonprescription availability in the United States is supportive of safe use.

A fixed-dose combination (FDC) gel containing adapalene 0.1% and benzoyl peroxide (BPO) 2.5% was also developed by Galderma and is approved in the United States (NDA 22320) under the trade name of Epiduo® Gel for the prescription treatment of acne.A higher strength FDC gel containing 0.3% adapalene and 2.5% BPO was also recently approved by the FDA in July, 2015 (Epiduo Forte“ Gel; NDA 207917).

Consequently, a wealth of efficacy and safety information has been accumulated for adapalene at concentrations of 0.1% and 0.3% alone and in combination with BPO, a commonly used OTC acne medication.

1.5 Efficacy and Safety

1.5.1 Clinical Studies The original clinical development program for Differin Gel consisted of 16 studies: 11 evaluated cutaneous safety, pharmacokinetics and pharmacodynamics in either healthy or acne subjects and five (5) studies assessed safety and efficacy in treating subjects with acne. In these studies, adapalene formulations were compared to either vehicle or to commercially available topical prescription acne medications (tretinoin gel).

Common efficacy endpoints that were consistently met in clinical studies supporting approval included: reduction in inflammatory lesion count, reduction in non-inflammatory lesion count, reduction in total lesion count and global investigator assessment of acne severity. Significant superiority of treatment with Differin Gel, compared to vehicle, was confirmed with mean reduction in total acne lesion counts from baseline reported between about 30% and 50% by Week 12 of treatment.

Additional post-marketing clinical studies, ranging from 7 days to 12 months in duration, have also been conducted to further evaluate the efficacy and/or safety of adapalene. In total, more than 140 clinical studies have been conducted and 6000 subjects treated with adapalene- containing topical drugs. The most common adverse events reported have been dermatologic in nature and local to treatment, such as: dry skin, erythema, scaling, burning and itching. These adverse events have been reported as mild in the majority of cases and have typically resolved without additional medical intervention, thus representing a safety profile similar to that observed in the original clinical studies that supported NDA approval. Similar dermatologic side effects are also commonly observed during treatment with current OTC acne medications. Thus the proposed Differin GEL DFL is able to utilize similar labeling regarding potential side effects included in the OTC Topical Acne Drug Products monograph.13-14

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1.5.2 Post-Marketing Surveillance Galderma continually collects adverse events associated with use of various adapalene- containing products from clinical studies and reports received directly from health care providers and patients. The estimated number of patients exposed to adapalene-containing drug products, since global market introduction in 1995, is 41 million. During the annual post-marketing surveillance period of August 1, 2013 to July 1, 2014, a total of 215 confirmed adverse reactions were reported with use of adapalene products in 133 cases. The most common adverse events reported in this period were dermatologic and included erythema, dry skin and skin irritation, consistent with clinical trial experience and prior annual surveillance.

Since global market introduction in 1995, there have been 71 spontaneous reports of serious and unexpected adverse events (events that are not consistent in nature or severity with adverse events known to be associated with adapalene use). These events have no discernable pattern and, in most cases, due to limited information, relation to adapalene could not be confirmed or excluded. The most common of these events, by system organ class, include 13 spontaneous abortions, 13 immune system disorders, 12 skin and subcutaneous tissue disorders, 10 congenital, familial and genetic disorders, six (6) eye disorders and five (5) hepatobiliary disorders.

1.5.3 Clinical Pharmacokinetic Studies The approvals of the various adapalene-containing prescription drugs described previously were supported by numerous studies including clinical pharmacokinetic studies designed to simulate maximal use, two of which are summarized in this document (Study 18097 and 18115). Study 18097 evaluated systemic exposure after topical application of adapalene gel, 0.1% or the fixed- dose combination drug adapalene 0.1%/BPO 2.5% gel (Epiduo Gel) to evaluate if BPO impacted the systemic availability of adapalene. Study 18115 evaluated systemic exposure after topical application of adapalene gel, 0.1% or the higher strength adapalene gel, 0.3%.

To expand on these prior studies, an additional maximal use clinical pharmacokinetic study, Study 18254, was conducted to support Galderma’s proposed Rx-to-OTC switch of Differin Gel. The primary reasons for this study were to evaluate the systemic availability of the drug in adolescent subjects, evaluate exposure when the quantity of drug is not restricted, and utilize a more modern and sensitive assay method.

The same instructions for drug application were given in the initial studies 18097 and 18115: 2 grams of adapalene gel were to be applied on a daily basis on approximately 1000 cm² (2 mg/cm²) of skin. In the most recent Study 18254, to ensure that a sufficient amount of drug product was applied on the largest extent of skin surface potentially affected by acne, the study personnel were instructed to apply as much drug as needed (i.e., without restriction) in order to cover all the skin surface area potentially affected by acne, i.e. the face, shoulders, upper back and upper chest. The amount applied was recorded and, despite the absence of restriction in quantity used, the mean amount of drug applied was 2 g in adults and adolescents (range: 1.2 to 2.9 g), similar to the amount of drug used in previous studies.

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In Studies 18097 and 18115 most adapalene plasma concentrations were below the limit of quantification of the assay used at that time (LOQ; <0.1 ng/mL). Quantifiable concentrations were measured in only:

ƒ Three (3) of 12 subjects exposed to adapalene 0.1% in Study 18097 (up to 0.21 ng/mL); and ƒ Seven (7) of 25 subjects exposed to adapalene 0.1% in Study 18115 (up to 0.31 ng/mL). By contrast, due to the higher sensitivity of a new bioanalytical method (LOQ of 0.02 ng/mL), all 24 subjects enrolled in Study 18254 had quantifiable concentrations at the end of the treatment period:

ƒ In the adult group, the maximal plasma concentrations observed was 0.09 ng/mL (Day 15). The mean Cmax was 0.041±0.009 ng/mL (range: 0.031 to 0.050 ng/mL), and the mean AUC0- 24h was 0.73±0.15 ng.h/mL (range: 0.58 to 0.98 ng.h/mL); and ƒ In the adolescent group, the maximal plasma concentrations observed was 0.17 ng/mL (Day 29). The mean Cmax was 0.052±0.035 ng/mL (range: 0.025 to 0.171 ng/mL), and the mean AUC0-24h was 0.87±0.56 ng.h/mL (range: 0.50 to 2.90 ng.h/mL).

No subject in the recent study (18254) experienced higher exposure than reported in previous studies. The development of an analytical method with a lower limit of quantification allowed a thorough PK assessment of adapalene 0.1% gel and the repeated application of drug resulted in quantifiable systemic exposure in all subjects enrolled in this study. Analysis of the PK parameters show that there was no drug accumulation over the 29-day treatment period and the calculated elimination half-life was 15 hours.

These data also show that systemic exposure to adapalene is similar and low in adolescent subjects and adult subjects receiving daily application of adapalene 0.1% gel. Of note, the presence of BPO in the FDC of Adapalene 0.1%/Benzoyl Peroxide 2.5% Gel had no effect upon the systemic absorption of adapalene (Study 18097). This is important in the context of potential concomitant use in the OTC environment.

1.5.4 Teratogenicity

Vitamin A (retinol) and vitamin A derivatives, such as retinoic acid, are essential for proper embryo-fetal development in humans and animals.15 Retinol deficiency during pregnancy causes specific developmental abnormalities to the cardiovascular, ocular, urogenital and central nervous (CNS) systems, and can affect embryonic growth and survival.

Excess retinoid exposure during pregnancy can also disrupt normal embryonic development in a wide range of experimental animals, targeting cardiovascular, CNS, craniofacial and skeletal development.15-16 In humans, oral administration of retinoids has been associated with developmental abnormalities to the CNS (hydrocephalus, hypoplastic or malformed cerebellar or cerebral cortices), craniofacial region (cleft palate, external ear defects), heart, thymus and limbs.16

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Due to differences in molecular structure, members of the retinoid class exhibit varying biologic activity and the teratogenic effects of retinoids are exposure related. For example, the potent oral retinoid isotretinoin was approved by the FDA in 1982 as a Pregnancy Category X drug, meaning that there is special labeling warning that the drug must not be used by female patients who are or may become pregnant as the risks of use of the drug by pregnant or breast-feeding women clearly outweigh potential benefits. Subsequently the requirement for a negative pregnancy test and extensive patient counseling was implemented prior to dispensing the drug.

In contrast, topical adapalene-containing products, formulated at various strengths between 0.1% and 0.3%, and in combination with benzoyl peroxide, have all been approved by the FDA as Pregnancy Category C drugs, with labeling stating that the drug should be used during pregnancy only if the potential benefit justifies risks. It should be noted that the prescription drug labeling regarding use by pregnant or lactating women was recently changed by FDA and “Pregnancy Categories” will no longer be used.

1.5.4.1 Nonclinical Reproductive Toxicity Studies In animal studies, no teratogenic effects were observed in rats treated with oral doses of 0.15 to 5.0 mg adapalene/kg/day, equivalent to up to 25 times (mg/m2/day) the estimated maximum human dose of 2 grams of adapalene 0.1%. Teratogenic changes were observed in rats and rabbits when treated with oral doses of • 25 mg adapalene/kg/day representing 123 and 246 times the estimated maximum human dose (2 grams), respectively. In contrast, no such malformations were seen in topical studies in rats and rabbits at doses of 0.6 to 6.0 mg adapalene/kg/day [25 to 59 times (mg/m2) the estimated maximum human dose].

1.5.4.2 Calculation of Safety Margin

To fully characterize systemic exposure, data obtained in nonclinical reproductive toxicity studies are used in conjunction with exposure data obtained in human pharmacokinetic studies, described previously, to establish a margin of safety. The safety margin is the ratio of the lowest systemic exposure (AUC) in animal studies at the No Observed Adverse Effect Level (NOAEL) for teratogenicity in the most sensitive animal species (in the case of adapalene, the rat) to the highest human systemic exposure (AUC) determined under maximized conditions in subjects with moderate to severe acne. Enrollment of a more severe acne population was important due to potential increased systemic exposure of damaged/inflamed skin.

Using this approach, safety margins from the initial pharmacokinetic studies, 18115 and 18097, ranged from 59 to 102 in adults. In the most recent maximal use pharmacokinetic study, Study 18254, the safety margin for Adapalene 0.1% Gel in adolescent and adult subjects with acne vulgaris was 70 for the most exposed subject, and 234 based on the mean systemic exposure at steady state. It is also important to note that the margin of exposure would be even higher under normal use situations.

These safety margins indicate that systemic exposure to topical adapalene is consistently very low, even under maximal use conditions, and large margins of safety exist to ensure safe use of Differin Gel in a nonprescription environment.

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1.5.4.3 Exposure During Pregnancy Galderma has screened the company's global reporting database for adapalene exposure during pregnancy. At the time of submission of the application proposing nonprescription use of Differin Gel, 336 cases of topical adapalene use during pregnancy had been identified in clinical trials (60 cases) or post-marketing surveillance (276 cases) including four (4) that occurred in the Actual Use study recently conducted and described in this document.

The largest number of exposures during pregnancy in Galderma studies occurred in a 12-month trial conducted in support of the registration of Differin Gel in Japan. In this study there were 14 pregnancies reported. Pregnancy outcomes included normal delivery for 9 subjects, premature delivery for 2 subjects, miscarriage for 1 subject, intra-uterine death for 1 subject, and elective abortion for 1 subject. None of the (11) babies born had any malformation or illness reported.

After loss to follow-up and excluding cases that ended in voluntary termination, 122 prospectively reported cases with known outcomes were identified including 112 full-term births. Prospectively reported cases (those cases where exposure to adapalene was identified prior to outcome being reported) were selected to attempt to eliminate reporting bias.

Major structural or genetic birth defects affect approximately 3% of births in the United States.28 In prospectively identified cases of adapalene-exposure during pregnancy, malformations occurred in two (2) out of 112 cases full-term infants (1.8%) and there was no identifiable pattern of malformations and the malformations reported are not known to be associated with teratogenicity induced by oral retinoids.16, 27

Seven (7) miscarriages occurred out of the 122 prospective cases with known outcomes (5.7%), a rate consistent with the reported rate of approximately 6% in the United States.29

In addition to the data collected by Galderma, external sources of data related to adapalene use during pregnancy were also investigated including the FDA Adverse Event Reporting System (FAERS) database, VigiBase (WHO database) and literature. Eight (8) cases of potential exposure to adapalene during pregnancy were identified in the FDA and/or WHO databases and three (3) included information related to malformations. None of the malformations reported were known to be associated with teratogenicity induced by oral retinoids.

With regard to literature, one publication described a meta-analysis that had been conducted which included a total of 654 pregnant women who were exposed to topical retinoids and 1375 unexposed control pregnant women. However, this meta-analysis included only 24 subjects exposed to adapalene and noted one major malformation in adapalene-exposed subjects (anophtalmia) not known to be associated with systemic retinoid therapy.

Although the totality of the available human pregnancy outcome data are limited and not sufficient to draw a strong conclusion when taken in isolation, they are supportive of the lack of reproductive toxicity of topical adapalene and are in agreement with the integrated analysis of the preclinical data with adapalene and the human pharmacokinetic studies conducted.

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1.5.4.4 Summary of Teratogenic Risk The animal and clinical pharmacokinetic studies described herein indicate a clinically important safety margin for risk with topical use, under normal or maximal use conditions. Although the current OTC pregnant and breastfeeding mother’s warning is required only for drugs intended for systemic absorption, which would not include topical Differin Gel, Galderma has proposed to include this same warning (“if pregnant or breastfeeding, ask a health professional before use”) in the Differin Gel nonprescription label. This well-established language appears on many OTC medications today. While the proposed DFL includes this language, the data demonstrate no meaningful incremental risk if Differin Gel is used during pregnancy.

1.5.5 Potential Off-Label Use

Differin Gel has been approved and marketed as a prescription medication only for the treatment of acne and there are no additional indications for adapalene approved globally. Topical retinoids, including adapalene, have been studied for the treatment of fine lines, wrinkles, photoaging and other dermatoses such as hyperpigmentation. Topical tretinoin, also a retinoid, is approved by the FDA as an adjunctive agent for use in the palliation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin. Salicylic acid and benzoyl peroxide, currently approved OTC acne medications, have also been studied and used to treat a variety of non-acne dermatoses.

According to published literature, when topical retinoid products are used to treat fine lines, wrinkles, photoaging and other non-acne dermatoses the drug is typically applied to skin in a similar manner as when treating acne (i.e. a thin layer). It is, therefore, not surprising that no new safety risks have been identified in clinical studies that evaluated adapalene for the treatment of non-acne conditions, as the commonly reported side effects align to those reported for acne treatment and include dry skin, erythema, skin irritation and skin discomfort.17-18

The potential for off-label use was also evaluated in the Actual Use study conducted to support the nonprescription use of Differin Gel and, as described herein, the product was used for acne (only) by greater than 98% of subjects in the study. This study was recruited as an all-comers population responding to ads for the product indication (acne) as is common for actual use studies. Since acne is a self-diagnosable condition, the consumers’ acne was not confirmed and they were not coached on how to use the product, so subjects had the opportunity to use the product for purposes other than acne, if they chose to do so.

Differin Gel will only be labeled to treat acne. Consumer study results have shown that people understand the indication for Differin Gel and how to use it, as expected for an existing, well- established OTC condition such as acne. Although off-label use can occur with any OTC drug, the risks of it occurring with adapalene are low, and the clinical sequelae of any off-label use are also low as any adverse events associated with such use would be dermatologic and generally mild, similar to those that can occur during acne treatment.

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1.5.6 Other Safety Considerations Additional safety aspects that have been carefully considered include drug interactions and concomitant use with other products, phototoxicity and photoallergic potential. Other safety considerations that are commonly considered when evaluating an Rx-to-OTC switch include the ability to self-diagnose and properly use the medication for the indicated condition, carcinogenicity, drug abuse and dependence. These aspects are not areas of concern for nonprescription Differin Gel.

1.6 Differin Gel OTC Development Program Acne is a well-established OTC category. Currently approved nonprescription topical acne medications are applied in a similar manner to Differin Gel and have been used by consumers for decades. Thus, self-diagnosis and self-selection were not a focus during the OTC development program. Rather, the studies conducted focused on key differences between existing OTC acne medication labeling and that of Differin Gel, primarily in the directions for use including once- daily application. This is important because current nonprescription acne medications are labeled for use up to three-times daily.

To evaluate consumer understanding and behavior, the following consumer studies were conducted: x A Label Comprehension study to primarily evaluate novel labeling information in the proposed nonprescription Differin Gel label; x An Actual Use study to evaluate consumer behavior as they use the product over time in a simulated actual use environment; and x A Targeted Self-Selection study to provide information on the effectiveness of the codified (currently required by law) OTC warning statement for pregnant or breast- feeding women proposed for the Differin Gel label. This study was conducted despite the totality of the evidence supporting safety if used during pregnancy.

1.6.1 Label Comprehension Study

A pivotal label comprehension study was conducted in accordance with the FDA Guidance for Industry: Label Comprehension Studies for Nonprescription Drug Products to assess consumer comprehension of key communication messages in the drug facts label (DFL). The DFL is required by FDA and is designed to use simple language and an easy-to-read format to help consumers compare and select OTC medicines and follow dosage instructions. As the nonprescription Differin Gel DFL includes some elements from the existing OTC Topical Acne Drug Products monograph, label comprehension studies focused primarily on differences to ensure consumer understanding.

Galderma developed and refined the DFL through a series of 4 iterative label comprehension pre-tests with a total of 141 subjects. The DFL was then evaluated in the pivotal Label Comprehension study (Study 100544) in 586 unique subjects, 12 years of age and older. There were 2 populations: the General Population (Cohort 1, N=515) and the Low Health Literacy Population (Cohort 2, N=130).

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This pivotal label comprehension study evaluated 2 primary communication objectives related to important warnings and directions regarding the safe use of the drug and, also, 10 secondary communication objectives conveying important considerations regarding product use.

Primary Analysis Label comprehension scores for the 2 primary communication objectives within the General Population exceeded the pre-specified 85% lower bound (LB) threshold, with General Population subjects achieving 97.5% correct comprehension (n=502; LB 95.7%) for the objective “Do not use on damaged skin (cuts, abrasions, eczema, sunburned)” and 95.9% correct comprehension (n=494; LB 93.8%) for the objective “Directions: Use once daily”.

Secondary Analysis Among the General Population, scores for 8 of the 10 secondary communication objectives in this study ranged from 87.6% (n=451) to 100.0% (n=515). The lowest scoring secondary objectives were “Stop use and ask a doctor if irritation becomes severe” (77.5%; n=399) and “When using this product, irritation (redness, itching, dryness, burning) is more likely to occur if using more than one topical acne medication at a time” (62.7%; n=323). When acceptable verbatim responses are added to the formal correct responses, the point estimates for these scores increase to 87.0% and 84.7%, respectively. Although some lack of comprehension was identified this is unlikely to lead to increased clinical risk. It is important to note that these two statements are both taken from the OTC Topical Acne Drug Products monograph and appear on nonprescription acne medications today.

Overall, subjects in this study demonstrated comprehension of the DFL and those of lower health literacy had similar rates of comprehension compared with those of normal health literacy. These results were expected as acne is a well-established OTC condition and consumers are generally familiar with similar labeling as that proposed for Differin Gel.

1.6.2 Actual Use Study An Actual Use study assesses how study participants actually use the drug product in their home environment without the input of a healthcare provider and based only on the information appearing on the DFL. Actual Use Studies are “all comer” studies. As such, participants are generally recruited by advertising for the condition or symptoms for which the medication is intended in an effort to simulate a real-world scenario when the product is commercialized. Actual Use studies are generally single-arm, open-label, uncontrolled studies, with few study visits, designed to enable consumers to have adequate access to study medication to enable overuse or misuse of the study product if they elect to do so.

An observational, open-label, six-week Actual Use study (Study 100931) was conducted to evaluate ongoing use behavior in subjects 12 years of age and older who self-reported having acne, thus representing potential consumers of Differin Gel. The study was conducted at 31 geographically dispersed pharmacies in the United States and targeted enrollment of approximately 1200 male and female subjects who self-reported acne to achieve at least 800 completed subjects.

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The primary objectives were: x To evaluate the frequency of use (i.e., no more than once daily in the same location); and x To determine whether the product was used for acne only (i.e., not for “off-label” conditions).

The secondary objectives were: x To evaluate if the product was used on the correct body areas (i.e., was not used on damaged skin and contact with eyes, lips, or mouth were avoided); and x To determine if pregnant or breastfeeding women stated they would ask a health professional before use as instructed in the warnings section of the Drug Fact Label.

Other data collected included extent of exposure (amount of product used), use on eczematous skin, concomitant medications and adverse events. Once enrolled, subjects were given a diary to be used to record when and on what part of the body the study product was used, as well as any changes in medical conditions or concomitant medications. Subjects relied on the DFL label on the package for directions for use; they were not instructed as to how to apply the study product or for what condition the study product should be used, but rather took the product home to use as they normally would if it was an approved nonprescription product. Subjects were permitted to return to the pharmacy site to repurchase additional study product at any time during the actual use period. A maximum purchase limit of 2 boxes per visit and 3 boxes total per subject was established; each box included a 45 g tube of study product. Based on normal use estimation of between 0.5 and 1 gram per day, a single 45 gram tube of product was expected to last the duration of the study although this was not communicated to the study subjects. The diary was collected at the time of repurchase and a new diary was dispensed.

Evaluation of once daily use

Based on final correct actual use determinations, 844 of 947 subjects (89.1%) in the actual use population used the study product no more than once daily in the same location (95% confidence interval [CI] = 87.0%, 91.0%). Since the lower limit of the 95% CI was > 85%, the endpoint result was considered successful.

The proportions of subjects in the normal literacy and low literacy groups who used the study product correctly were similar (89.1% and 89.6%, respectively). Results were also similar across age groups.

Evaluation of use exclusively in acne

Based on final correct actual use determinations, 938 of 945 subjects (99.3%) in the actual use population used the study product only to treat acne (95% CI = 98.5%, 99.7%). Since the lower limit of the 95% CI was > 85%, the endpoint result was considered successful.

The proportions of subjects in the normal literacy and low literacy groups who used the study product correctly were similar (99.3% and 99.2%, respectively). Results were also similar across age groups.

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The proportions of subjects in the normal literacy and low literacy groups who used the study product correctly were similar (99.5% and 99.2%, respectively). Results were also similar across age groups.

Use on Correct Body Area

Based on final correct actual use determinations, 921 of the 945 subjects (97.5%) in the actual use population used the study product on the correct body location (95% CI = 96.2%, 98.4%). The proportions of subjects in the normal literacy and low literacy groups who used the study product correctly were similar (97.4% and 97.6%, respectively). Results were also similar across age groups.

Analysis of Women Who Were Pregnant or Breastfeeding on Entry

Although the Actual Use study was not designed to evaluate potential usage during pregnancy, the usage by pregnant or breast-feeding women was collected. In this study, at the initial study visit, six (6) women were pregnant and 10 women were breastfeeding.

Of the six (6) women who were pregnant, one (1) correctly stated she should ask a health professional before using the study product. Two of the women did not know they were pregnant until the pregnancy test was administered and the remaining three (3) women did not state that they would ask a health professional before using the study product. None of the pregnant women were permitted to enter the actual use period of the study.

Of the ten (10) women at the initial visit who were breastfeeding, four (4) correctly stated they should ask a health professional before using the study product. None of the breastfeeding women were permitted to enter the actual use period of the study.

Adverse Events

In the Actual Use study, subjects used Differin Gel daily for up to six (6) weeks. Over the six- week study period, the subjects reported any AEs to the pharmacies verbally or by diary review. In addition, subjects could call a Central Medical Operations Group (CMOG), which was a centralized group of medical professionals trained in conducting clinical research, at any time to report an AE.

No subject died and there were no serious AEs in this study. Nearly all of the subjects (938 of 947 subjects [99.0%]) who were included in the actual use/safety population completed the actual use period (used the product until the final visit). A total of 8 subjects (0.8%) discontinued due to AEs. These events were associated with skin and subcutaneous tissue disorders and included acne, dry skin, erythema, pruritus, skin exfoliation, and skin irritation. One (1) subject dropped out due to unreliable/questionable conduct.

Overall, 471 of the 947 subjects (49.7%) in the actual use population experienced at least one (1) self-reported AE during the study. The most commonly reported AEs were headache (155 of 947 subjects [16.4%]), dry skin (100 of 947 subjects [10.6%]), and erythema (44 of 947 subjects

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[4.6%]). A majority of the subjects (57.7% [272 of 471]) who experienced an AE had AEs that were not considered by the CMOG to be related to the study drug. Four subjects had positive pregnancy tests at the Study Close-Out visit and these pregnancies were reported as AEs.

Of the events considered by the CMOG to be related to the study drug, all but 3 (sunburn, headache, and facial pain) were application site reactions. The most commonly reported, treatment-related AEs in the actual use population were dry skin (99 of 947 subjects [10.5%]), erythema (42 of 947 subjects [4.4%]), and skin burning sensation and skin exfoliation (37 of 947 subjects each [3.9%]).

The largest percentage of subjects (88.3% [416 of 471]) reported AEs that were mild in severity. This was true within both literacy levels and both age categories. Five of the subjects reported severe AEs. The specific events, which were reported by 1 subject each, included asthma, headache, migraine, sinusitis, and viral infection; none were considered by the CMOG to be related to study drug.

Conclusions from Actual Use Study

In conclusion, Differin Gel, when applied once daily for six (6) weeks for the treatment of acne in an unsupervised setting, was used appropriately. The drug was used per the label instructions at an acceptable rate and there were no trends or potential safety concerns that would alter the known safety profile of the study product. The study results were consistent regardless of subgroup evaluated including age and literacy level.

1.6.3 Targeted Self-Selection Study Galderma has proposed to include in the DFL for Differin Gel the OTC pregnancy and breast- feeding warning that is required by FDA for many OTC drugs currently marketed:

“if pregnant or breastfeeding, ask a health professional before use”.

The data discussed in this document make clear that Differin Gel does not pose a risk if used during pregnancy. Nonetheless, a self-selection study was conducted to evaluate if pregnant and/or breast-feeding subjects who self-reported acne could make a correct self-selection decision based on this widely used OTC labeling.

Female subjects age 18 or older were recruited by intercept from 25 retail malls geographically dispersed in the United States. Selection criteria were masked so that potential subjects were unaware which criteria affected study qualification. Younger subjects (i.e., ages 13 to 17) were recruited from specialty sites (i.e., pregnancy support group, clinic, etc.).

To identify participant health literacy levels, the Rapid Estimate of Adult/Adolescent Literacy in Medicine (REALM) test was administered to subjects ages 18 and older and the Rapid Estimate of Adolescent Literacy in Medicine (REALM-Teen) test was administered to subjects 13-17 years of age. Following literacy testing, each subject was provided the Differin Gel OTC package (Principal Display Panel and DFL) and participated in an interview; adolescents were

Page 17 NDA 20380 NONPRESCRIPTION ADAPALENE 0.1% BRIEFING DOCUMENT FOR APRIL 15, 2016 TOPICAL GEL NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEETING permitted to self-administer the interview on a computer. Pregnancy was confirmed via urinary pregnancy test at the end of the interview for subjects who were 18 or older.

In this study, about three quarters (74%) of pregnant or breastfeeding women who self-reported acne stated that they would ask a health professional prior to using Differin Gel. The final correct self-selection point estimate (PE) for the general population was 74.4% (n=180) and the lower bound (LB) of a two-sided 95% confidence limit was 68.4%. The primary endpoint (95% correct) was therefore not met.

The statement evaluated in this study is a standard warning that has long use with a large number of OTC products that are currently marketed. Although these study results support the fact that the currently codified (required by law) and used OTC warning statement proposed for the Differin Gel labeling is generally understood and followed, not all pregnant or breast-feeding women who would consider using Differin Gel or other medications with this warning may adhere to the direction.

1.7 Benefit and Risk Considerations for Nonprescription Differin Gel Acne can profoundly impact quality of life, often resulting in significant physical and psychological morbidity, such as permanent scarring, poor self-image, depression, and anxiety.1 Early, effective treatment of acne is essential to prevent later complications including scarring and psychosocial burden, aspects that can be mitigated by effective therapy.9, 19

Additional nonprescription acne treatment options are needed to more completely address this multi-factorial condition. No currently available OTC acne medication addresses the formation of the microcomedo or the underlying sub-clinical inflammation that may be present, aspects physicians are able to target through the use of topical retinoid prescription medications. In fact, topical retinoids are recommended as a first-line treatment for acne by dermatologists. BPO, primarily due to antimicrobial properties, is also recommended as a first-line treatment for mild acne while salicylic acid, sulfur and resorcinol, the other currently approved OTC acne active ingredients, are not recommended.1

In addition, the efficacy of Differin Gel has been observed in a broad range of patients and skin types.20, 21 Adapalene is also an appropriate choice for patients with dark skin, and has been shown to reduce the post-inflammatory hyperpigmentation that is typically associated with inflammatory acne lesions in this population.22 It is also of note that Differin Gel employs a simplified regimen due to its once-daily use, whereas current OTC acne medications are labeled for use up to three (3) times per day. This once-daily regimen has the potential to promote patient compliance, an important factor in successful treatment of acne in an OTC setting.

The adverse events reported during use of Differin Gel are comparable to other acne medications currently available OTC. Commonly reported adverse events are dermatologic in nature and local to treatment, such as: dry skin, erythema, scaling, burning and itching. These adverse events are most commonly seen during the first month of therapy and decrease in frequency and severity thereafter, are reported as mild in the majority of cases and typically resolve without additional medical intervention.

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Given the very low systemic exposure demonstrated under conditions of maximal use, the risk of teratogenicity is extremely low with a very wide margin of safety. Further, a review of the pregnancies reported following use with adapalene indicate that there is no increase in the rate of fetal malformations. In addition, the malformations seen showed no pattern of teratogenicity induced by oral retinoids.16, 27

Additional safety aspects that have been carefully considered include off-label use, drug interactions and concomitant use with other products and phototoxic and photoallergic potential. As described in this document, there are no significant risks in any of these areas that would arise from nonprescription usage.

Other safety considerations that are commonly considered when evaluating an OTC switch include the ability to self-diagnose the condition and self-select and self-treat based on the DFL, carcinogenicity, drug abuse and dependence. These aspects are not areas of concern for nonprescription Differin Gel.

Lastly, the consumer behavior studies conducted demonstrate that Differin Gel would be used appropriately in a nonprescription environment without physician oversight.

1.8 Rationale for Nonprescription Access to Differin Gel Galderma believes that Differin Gel meets all of the qualifications to be a nonprescription drug. A comprehensive OTC development program has been carried out to carefully evaluate nonprescription use and, combined with the extensive data generated from the development program through post-marketing use periods, these data support that Differin Gel should be approved for nonprescription availability.

Differin Gel is an ideal candidate for Rx-to-OTC switch and would fit well alongside current nonprescription acne medications based upon the following:

1. Adapalene has been available as an approved safe, effective and widely used prescription drug in various dosage forms and strengths in the United States since 1996; 2. The drug is applied topically, similar to current OTC acne products, and requires no special handling or storage conditions; 3. Differin Gel has a different, dermatologist recommended, mechanism of action compared to current OTC medications and offers consumers another option for treating their acne;

4. Differin Gel meets all of the well-accepted criteria for evaluation of drugs for OTC use including:

ƒ The consumer must be able to self-diagnose the condition proposed to be treated x Consumers have self-diagnosed and self-treated their acne with topical OTC drugs for decades;

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ƒ The consumer must be able to read and understand the product labeling to ensure proper usage x Consumer studies have demonstrated that the Differin Gel DFL is well understood and followed;

ƒ The product must be effective when used as recommended x Numerous clinical studies have confirmed effectiveness; and

ƒ The drug must be safe for self-use x Clinical pharmacokinetic studies confirm that the systemic exposure to topical adapalene is consistently very low, even under maximal use conditions, and large margins of safety exist to ensure that Differin Gel does not pose a risk of teratogenicity in a nonprescription environment; and x Adverse events are dermatologic in nature, local, transient, generally mild and become less frequent with continued treatment.

Nonprescription Differin Gel would provide broad access to a once-daily, safe and effective treatment for acne, a common condition that can adversely impact the quality of life of acne sufferers, often leading to self-consciousness, depression, lack of confidence, embarrassment, shame and social withdrawal.23

2 BACKGROUND

2.1 Overview of Acne Acne vulgaris is a common disease affecting approximately 50 million people in the United States and up to 85% of teenagers1. Acne can occur in most age groups and persists into adulthood. The prevalence of acne in adult women is about 12% and over 50% of adults at some point in their lives have acne.1 Acne affects all races and ethnicities and is one of the most common dermatologic diagnoses.2-4 The Global Burden of Disease study covering 187 countries found acne to be among the top 10 most prevalent diseases worldwide.5

Acne is a multi-factorial disease, characterized by abnormal follicular keratinocyte desquamation, anaerobic Propionibacterium acnes (P. acnes) proliferation, inflammatory response, and excess sebum production.6 The lifecycle of acne lesions involves follicular plugging when keratinocytes accumulate in the sebaceous follicle, and resultant formation of the microcomedo. The microcomedo then progresses to a noninflammatory (comedo) or inflammatory lesion, with subclinical inflammation processes being present before and during microcomedo formation. Further, inflammation progresses through the acne lesion life cycle, and is amplified by an immune response with the presence of sebum and P. acnes proliferation. Inflammation (involving inflammatory mediators and cellular infiltrates) persists after the resolution phase of acne lesions, often associated with scarring. An overview of the progression of an acne lesion is presented in Figure 1.

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Figure 1: Acne Lesion Progression

While there is no mortality associated with acne, there is often significant physical and psychological morbidity, such as permanent scarring, poor self-image, depression, and anxiety.1 Facial blemishes have been found to significantly impair health-related quality of life (HRQoL)7 scores while improvement of acne is correlated with improvement in HRQoL scores.8 Early, effective treatment of acne is essential to prevent later complications including scarring and psychosocial burden.9

2.2 Current Self-Management of Acne

Acne is a well-established OTC drug category since the proposed rulemaking that began in March of 1982 and culminated in August of 1991 when the final OTC Topical Acne Drug Products monograph was published (56FR41008) and codified (21 CFR Part 333 Subpart D). Thus it has previously been established that consumers can safely and effectively self-diagnose and self-treat their acne, as directed in the product labeling, without physician oversight. Self- treatment of acne is quite common, with over 78% of teenage acne sufferers (aged 13 to 17 years) and over 64% of adult acne sufferers reporting that they have never visited a doctor for their acne. A summary of the OTC Topical Acne Drug Products monograph regulations that include active ingredients approved for use along with required labeling is provided in Appendix 1.

Five (5) active ingredients (BPO, salicylic acid, sulfur, resorcinol, and resorcinol monoacetate) or combinations of active ingredients are currently generally recognized as safe and effective under 21 CFR Part 333 Subpart D. Of these, the most widely available and used active ingredients are BPO and salicylic acid which make up 99% of the medicated acne OTC market.10

There have been no new active ingredients DYDLODEOH for the nonprescription treatment of acne since the FDA OTC rulemaking began in 1982 and no currently available OTC acne medication

Page 21 NDA 20380 NONPRESCRIPTION ADAPALENE 0.1% BRIEFING DOCUMENT FOR APRIL 15, 2016 TOPICAL GEL NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEETING addresses the formation of the comedo or the underlying sub-clinical inflammation that may be present, aspects physicians are able to target through the use of topical retinoid prescription medications. In fact, topical retinoids are recommended as a first-line prescription treatment for acne by dermatologists including by a recent working group of physicians who, in conjunction with the American Academy of Dermatology, which developed evidence-based guidelines for the treatment of the disease.1

Salicylic acid is reported to have keratolytic properties, meaning it works by softening and shedding the outer layer of the skin. Benzoyl peroxide, also recommended as a first-line treatment for mild acne in the recent guideline, mainly impacts acne lesions by exerting antimicrobial effects on P. acnes, thus impacting formation of lesions. Salicylic acid, sulfur and resorcinol, the other currently approved OTC acne active ingredients, are not recommended in the recent treatment guideline.1

An overview of the mechanism of action impact within the acne lesion cycle of the primarily used OTC active ingredients (BPO and salicylic acid), along with adapalene, is provided in Figure 2. It is clear that additional nonprescription acne treatment options are needed to more completely address this multi-factorial condition.

Figure 2: Mechanism of Action Targets of Adapalene, Salicylic Acid and Benzoyl Peroxide

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3 DEVELOPMENT OF DIFFERIN GEL

3.1 Properties of Adapalene and the Differin Gel Formulation

Vitamin A (retinol) and vitamin A derivatives, such as retinoic acid, are referred to as “retinoids” and include a number of compounds including retinol, tretinoin (retinoic acid), isotretinoin, tazarotene and adapalene.

Adapalene is a synthetic third-generation retinoid compound designed to provide clinical efficacy while minimizing cutaneous irritation. Adapalene differs structurally from retinoic acid by the presence of a phenoxy-adamantyl group, which results in low percutaneous flux and thereby limits systemic exposure. The phenoxy-adamantyl group increases lipophilicity and thereby enhances penetration into the pilosebaceous follicles.11 Unlike other retinoids, the unstable double bonds of retinoic acid are replaced in the adapalene molecule by aromatic rings, resulting in greater stability when exposed to light and oxygen.12 A comparison of the molecular structures of Vitamin A, tretinoin and adapalene is provided in Figure 3.

The increased stability of adapalene in the presence of light and oxygen has been demonstrated by analyses of adapalene and tretinoin formulations mixed with equal volumes of 10% BPO and subsequent light exposure of 24 hours. These studies revealed that the combination of BPO and light led to over 50% degradation of tretinoin in 2 hours and 95% in 24 hours while adapalene remained completely stable (see Figure 4).25

The effectiveness of topical adapalene in the treatment of acne is thought to be due to affecting the processes of abnormal epidermal keratinization and differentiation of follicular epithelial cells, reducing comedogenesis, clearing comedones and exerting anti-inflammatory properties, important features in the pathogenesis of acne vulgaris.11

Differin Gel was formulated to be well tolerated, non-comedogenic, and non-sensitizing, and has a creamy texture on the skin due to microcrystals of the lipophilic molecule which are evenly distributed in the aqueous medium. The function of the formulation ingredients can be found in Table 1. The vehicle is an alcohol-free aqueous gel, formulated to avoid the irritation that can be caused by alcohol-based vehicles. Another component of Differin Gel’s composition is propylene glycol, which acts as an emollient and moisturizer.

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Figure 3: Molecular Structure of Vitamin A, Tretinoin and Adapalene

Figure 4: Stability of Adapalene in the Presence of Light and Benzoyl Peroxide

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Table 1: Composition of Differin Gel Ingredient Function Adapalene Active ingredient; 0.1% Carbomer 940 Gelling agent Propylene glycol Emollient and moisturizer Poloxamer 182 Wetting agent Edetate disodium Stabilizing agent Methylparaben Preservative Sodium hydroxide pH adjustment Hydrochloric acid pH adjustment (if needed) Purified water Vehicle

3.2 Regulatory History

Adapalene, formulated as a 0.1% gel, was first approved in the United States for the treatment of acne in May, 1996 (NDA 20380). Three additional dosage forms (solution, cream, and lotion) containing adapalene at a concentration of 0.1% and a gel dosage form at a concentration of 0.3%, have also been approved in the United States for the treatment of acne under the trade name of Differin®. Adapalene 0.1% Gel has been the most extensively prescribed adapalene- containing formulation globally, as it has been approved in 83 countries in the world since 1994 including Canada, Japan and Australia as well as most countries in Europe, Asia and South America.

Adapalene 0.1% Gel is also approved in Russia where it has been available as a nonprescription drug since 2001. Approximately 500,000 consumers have used Adapalene 0.1% Gel in Russia, without physician oversight. The extensive experience in this market of the identical formulation proposed for nonprescription availability in the United States is supportive of safe use.

A fixed-dose combination (FDC) gel containing adapalene 0.1% and benzoyl peroxide (BPO) 2.5% was also developed by Galderma and is approved in the United States (NDA 22320) under the trade name of Epiduo® Gel for the prescription treatment of acne vulgaris.A higher strength FDC gel containing 0.3% adapalene and 2.5% BPO was also recently approved by the FDA in July, 2015 (Epiduo Forte“ Gel; NDA 207917).

Consequently, a wealth of efficacy and safety information has been accumulated for adapalene at concentrations of 0.1% and 0.3% alone and in combination with BPO, a commonly used OTC acne medication. A listing of the various adapalene-containing prescription medications approved by FDA is provided in Table 2.

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Table 2: Approved New Drug Applications for Adapalene Alone or in Combination with Benzoyl Peroxide

Drug NDA Approval Date Differin® (Adapalene) Gel, 0.1% 20380 May 1996 May 1996 Differin® (Adapalene) Solution, 0.1% 20338 (Discontinued)a Differin® (Adapalene) Cream, 0.1% 20748 May 2000 Differin® (Adapalene) Gel, 0.3% 21753 June 2007 Differin® (Adapalene) Lotion, 0.1% 22502 March 2010 Epiduo® (benzoyl peroxide, 2.5%/ adapalene, 22320 December 2008 0.1%) Gel Epiduo® Forte (benzoyl peroxide, 2.5%/ 207917 July 2015 adapalene, 0.3%) Gel a Differin (adapalene) solution, 0.1% was discontinued for marketing reasons not related to safety or efficacy.

4 SUMMARY OF EFFICACY

The original clinical development program for Differin Gel consisted of 16 studies: 11 evaluated cutaneous safety, pharmacokinetics and pharmacodynamics in either healthy or acne subjects and five (5) studies assessed safety and efficacy in treating subjects with acne. In these studies, adapalene formulations were compared to either vehicle or to commercially available topical prescription acne medications containing tretinoin.

The following five phase 2 and phase 3 studies were considered the pivotal studies that supported approval of NDA 20380 in May, 1996:

x A Phase 2 multicenter, randomized, parallel, double-blind 12-week study of Adapalene 0.1% Gel in comparison to its Vehicle Gel in the treatment of subjects ages 12 and older with mild to moderate acne vulgaris. x A Phase 2 multicenter, randomized, parallel, double-blind study of Adapalene 0.1% Gel in comparison to its Vehicle Gel and Tretinoin Gel in the treatment of subjects ages 12 and older with mild to moderate acne vulgaris. Subjects were treated once daily for 12 weeks and then given the option to enroll in a 14-week open-label extension. x A Phase 2 multicenter, randomized, parallel, investigator-blind 12-week study of Adapalene 0.1% Gel in comparison to Adapalene 0.03% Gel and Tretinoin Gel in the treatment of subjects ages 12 and older with acne. x A phase 2 multicenter, randomized, parallel, investigator-blind study of Adapalene 0.1% Gel in comparison to Tretinoin Gel in the treatment of subjects ages 12 and older with mild to moderate acne vulgaris. Subjects were treated once daily for 12 weeks and then given the option to enroll in a 14-week open-label extension.

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x A phase 3 multicenter, randomized, parallel, investigator-blind 12-week study of Adapalene 0.1% Gel in comparison to Tretinoin Gel in the treatment of subjects ages 12 and older with mild to moderate acne vulgaris.

Common efficacy endpoints that were consistently met in these clinical studies included: reduction in inflammatory lesion count, reduction in non-inflammatory lesion count, reduction in total lesion count and global investigator assessment of acne severity. Significant improvement in subjects treated with Differin Gel, compared to vehicle, was shown with mean reduction in total acne lesion counts from baseline reported between about 30% and 50% by Week 12 of treatment (see Table 3). Statistically significant improvement in total lesions, compared to baseline, was also shown as early as Week 2 of treatment.

Taken together, these studies robustly demonstrated the efficacy of Differin Gel in the treatment of acne.

Table 3: Mean Percent Change from Baseline to Week 12 in Original Vehicle-Controlled Studies

Study Non-Inflammatory Lesions Inflammatory Lesions Total Lesions Number (Subjects)a Adapalene Vehicle Adapalene Vehicle Adapalene Vehicle 0.1% 0.1% 0.1% C-89-61b -48% -35% -46% -36% -47% -36% (57/34) 9105- -26% 0% -34% -12% -28% -2% CD271G-EVc (111/100) a Number of subjects in each study group presented in parenthesis as follows (adapalene/vehicle) b Numerical, not statistical, significance shown due to low number of subjects in each group. c Adapalene 0.1% gel demonstrated statistical significance over vehicle in all lesion endpoints [non-inflammatory (p=0.001), inflammatory (p=0.0005) and total (p=0.0001)]

5 SUMMARY OF SAFETY

5.1 Safety Data from Original Pivotal Clinical Studies As discussed previously, five (5) clinical studies were considered pivotal in support of the approval of NDA 20380 for Differin Gel. Two (2) of the five (5) studies were vehicle controlled, one was a dose-ranging study and the final two (2) multicenter trials were active controlled (tretinoin gel, 0.025%). The active-controlled studies were conducted under investigator-masked conditions (due to slight color difference between the gels). Tretinoin 0.025% was the highest retinoic acid gel concentration available in both US and European markets at the time of the clinical investigations. Subjects were treated once daily for 3 months, and some continued treatment for up to six (6) months in the context of an open-label extension (Studies C-89-61 and C-89-32).

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Certain cutaneous signs and symptoms such as erythema, dryness, scaling, burning or pruritus are expected with the topical application of retinoid drug products. Therefore, these side effects and their intensity were evaluated by the investigators using a 4-point scale (none, mild, moderate, severe) at each post-Baseline visit and are thus were reported separately from adverse events tabulations.

Medical events, hereafter referred to as Adverse Events (AEs), were defined as any significant change whether expected (i.e., listed in the Investigator’s Brochure) or unexpected in a subject’s general health that occurred during the course of the study. Serious events, hereafter referred to as Serious Adverse Events (SAEs), were defined in these studies as any events that caused or prolonged hospitalization, were life threatening, fatal, permanently disabling, a congenital anomaly, cancer or overdose. Study Investigators made an assessment of causality for each AE.

Table 4: Overall Actual Extent of Exposure in Clinical Efficacy and Safety Studies Supporting Approval of NDA 20380

Study Number Study Number of Subjects Treatment Duration Type Adapalene Adapalene Tretinoin Vehicle 0.1% Gel 0.03% Gel 0.025% Gel C-89-61 Phase 2 72 --- 72 36 12 weeks, with efficacy optional 3-month and safety extension C-89-61 (14 Week Phase 2 27a ------26 weeks total for Extension) safety subjects randomized extension to adapalene 9105-CD271G-EV Phase 2 129 -- -- 126 12 weeks efficacy and safety CR 88051 Phase 2 30 29 30 -- 12 weeks efficacy and safety CR 89064 Phase 3 134 -- 134 -- 12 weeks efficacy and safety C-89-32 Phase 2 162 -- 161 -- 12 weeks efficacy and safety C-89-32 (14 Week Phase 2 176 b ------26 weeks total for Extension) safety subjects randomized extension to adapalene Total subjects on adapalene gel=661 (632 on the 0.1% gel plus 29 on the 0.03% gel); tretinoin gel=397; vehicle=162 a 11 subjects continued treatment with adapalene and 16 subjects crossed over to adapalene from tretinoin (10) and vehicle (6) b 87 subjects continued treatment with adapalene and 89 subjects crossed over to adapalene from tretinoin

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5.1.1 Cutaneous Tolerability Dryness, erythema, scaling, pruritus and burning were evaluated at each study visit by either the investigators (for erythema, scaling and dryness) or subjects (pruritus and burning) using a 4- point scale (none, mild, moderate, severe). A summary of the tolerability results from the five (5) controlled clinical studies follows:

x Dryness and erythema were the most common cutaneous symptoms reported, occurring in approximately 40% of subjects.

x Scaling was reported in approximately 30% of subjects.

x Pruritus was reported in approximately 20% of subjects.

x Burning was reported in approximately 10% of subjects.

The majority of these cases were mild as the mean score for all subjects, for each tolerability measure, was less than 1 (on a 4 point scale) at each visit. The majority of cases DOVRoccurred during the first two (2) weeks of the studies and, during the subsequent weeks, these effects declined in both frequency and intensity.

5.1.2 Adverse Events Overall, 212 subjects (32.1%) treated with adapalene 0.1% gel reported 233 AEs across the five clinical studies, 176 subjects (44.3%) reported 184 AEs in the tretinoin gel group, and 72 subjects (44%) reported 90 AEs in the vehicle group (see Table 5). Dermatologic AEs which were determined by the Investigator to be related or possibly related to study drug included 40 AEs (in 40 subjects) in the adapalene gel group, 51 AEs (in 50 subjects) in the tretinoin gel group, and two (2) AEs (in two (2) subjects) in the vehicle group (see Table 6). These related dermatologic AEs were mild or moderate in severity, transient, and did not lead to study discontinuation.

The most commonly reported related dermatologic AE in the adapalene gel group was skin dry (1.1%); all other related dermatologic AEs and all possibly related dermatologic AEs were reported by less than 1% of subjects in that group.

An additional 36 dermatological AEs considered as unrelated to study drug were reported in 35 subjects, each with a less than 1% incidence in the adapalene group. These AEs were mild in intensity.

The most frequently reported non-dermatologic AEs in the adapalene gel group included flu syndrome (6.5%), headache (3.9%), pharyngitis (1.7%), allergy seasonal (coded as allergic reaction and anaphylactoid reaction) (1.1%), and accidental injury (1.1%). All other non- dermatologic AEs in the adapalene gel group were reported in less than 1% of subjects. These AEs were not considered to be related to study drug, were mild to moderate in severity, and resolved with continued therapy.

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Table 5: Overview of Adverse Events in Clinical Studies Supporting Approval of NDA 20380

Adapalene Gel Tretinoin Gel Vehicle N=661 N=397 N=162 Adverse Events by Body No. AEs No. Subjects No. AEs No. Subjects No. AEs No. Subjects System (%) (%) (%) Related AEs a Dermatologic 28 28 (4.2%) 43 42 (10.6%) 0 0 Non-dermatologic 0 0 0 0 1 1 (0.6%) Total 28 28 (4.2%) 43 42 (10.6%) 1 1 (0.6%) Possibly Related AEs a Dermatologic 12 12 (1.8%) 8 8 (2.0%) 2 2 (1.2%) Non-dermatologic 0 0 2 2 (0.5%) 0 0 Total 12 12 (1.8%) 10 10 (2.5%) 2 2 (1.2%) Not Related AEs a Dermatologic 15 15 (2.3%) 19 18 (4.5%) 2 2 (1.2%) Non-dermatologic Body Whole 128 106 (16.0%) 60 55 (13.9%) 57 43 (26.5%) Musculoskeletal 3 3 (0.5%) 2 2 (0.5%) 3 3 (1.9%) Cardiovascular 0 0 1 1 (0.3%) 0 0 Nervous 1 1 (0.2%) 3 3 (0.8%) 0 0 Digestive 10 10 (1.5%) 3 3 (0.8%) 3 3 (1.9%) Endocrine 0 0 0 0 1 1 (0.6%) Metabolic & Nutritional 0 0 3 3 (0.8%) 0 0 Respiratory 25 23 (3.5%) 21 21 (5.3%) 12 11 (6.8%) Special Senses 3 3 (0.5%) 5 5 (1.3%) 1 1 (0.6%) Urogenital 12 11 (1.7%) 14 13 (3.3%) 8 5 (3.1%) Total 197 172 (26.0%) 131 124 (31.2%) 87 69 (42.6%) Grand Total (N, %) 233 212 (32.1%) 184 176 (44.3%) 90 72 (44%) a Related=definitely related or probably related; Possibly=possibly related or maybe related; Not related=unlikely related or definitely not related Events coded according to Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) terminology

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Table 6: Related and Possibly Related Dermatologic AEs in the Clinical Studies Supporting Approval of NDA 20380

Adapalene Gel Tretinoin Gel Vehicle N=661 N=397 N=162 Adverse Events by No. AEs No. Incidence No. No. Incidence No. No. Incidence Body System Subjects (%) b AEs Subjects (%) b AEs Subjects (%) b Related Dermatologic AEs a Erythema 6 6 0.9 7 7 1.8 0 0 -- Skin Dry 7 7 1.1 16 16 4.0 0 0 -- Skin Discomfort c 4 4 0.6 8 8 2.0 0 0 -- Skin Irritation 4 4 0.6 5 4 1.0 0 0 -- Acne (Flare) 3 3 0.5 2 2 0.5 0 0 -- Pruritus 2 2 0.3 2 2 0.5 0 0 -- Sunburn 1 1 0.2 1 1 0.3 0 0 -- Dermatitis 1 1 0.2 1 1 0.3 0 0 -- Skin Infection 0 0 -- 1 1 0.3 0 0 -- Possibly Related Dermatologic AEs a Acne Flare 2 2 0.3 1 1 0.3 0 0 -- Skin Discomfort 1 1 0.2 1 1 0.3 0 0 -- Erythema 1 1 0.2 0 0 -- 0 0 -- Pruritus 1 1 0.2 0 0 -- 0 0 -- Dermatitis 1 1 0.2 0 0 -- 0 0 -- Contact Dermatitis 1 1 0.2 0 0 -- 0 0 -- Herpes Simplex 1 1 0.2 0 0 -- 0 0 -- Vesicular Rash 1 1 0.2 0 0 -- 0 0 -- Cyst (face) 1 1 0.2 0 0 -- 0 0 -- Skin Dry 0 0 -- 1 1 0.3 0 0 -- Sunburn 2 2 0.3 4 4 1.0 2 2 1.2 Mouth Ulceration 0 0 -- 1 1 0.3 0 0 -- a Related=definitely related or probably related; Possibly=possibly related or maybe related; Not related=unlikely related or definitely not related b Incidence=Number of subjects with AE divided by total number of subjects in that group c Skin Discomfort=AEs described as burning or stinging Events coded according to Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART) terminology

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5.1.3 Serious adverse events Overall, four (4) SAEs (all deemed unrelated to therapy) were reported in four (4) subjects: one (1) (accidental injury) in the adapalene group, one (1) (anaphylactoid reaction) in the tretinoin group, and two (2) (flu syndrome, myalgia) in the vehicle group.

Overall, 25 subjects (2.0%) discontinued due to AE in the five pivotal clinical efficacy and safety studies supporting approval of NDA 20380. Of these, 10 subjects were in the adapalene gel group, 12 were in the tretinoin group, and three (3) were in the vehicle group. In the adapalene gel group, eight (8) out of 10 subjects discontinued the study due to a related or possibly related AE including two (2) subjects with acne flare and one (1) subject each with skin irritation/erythema, skin irritation, erythema/ pruritus/ vesicular rash, contact dermatitis, cyst on face, and sunburn. Two (2) adapalene-treated subjects discontinued from these studies due to events deemed not related to treatment, one due to otitis and the other due to a gastrointestinal disorder.

5.2 Other Clinical Studies Additional post-marketing clinical studies, ranging in duration from 7 days to 12 months, have also been conducted to further evaluate the efficacy and/or safety of adapalene. In total, more than 140 clinical studies have been conducted and 6000 subjects treated with adapalene- containing topical drugs. The most common adverse events across these studies are dermatologic in nature and local to treatment, such as: dry skin, erythema, scaling, burning and itching. These adverse events have been reported as mild in the majority of cases and have typically resolved without additional medical intervention, thus representing a safety profile similar to that observed in the original clinical studies that supported NDA approval. Similar dermatologic side effects are also commonly observed during treatment with current OTC topical acne medications. Thus the proposed Differin *HO DFL is able to utilize similar labeling regarding potential side effects included in the current OTC Topical Acne Drug Products monograph.13-14

5.3 Post-Marketing Surveillance Galderma continually collects adverse events associated with use of various adapalene- containing products from clinical studies in addition to reports received directly from health care providers and patients. The estimated number of patients exposed to adapalene-containing drug products, since global market introduction in 1995, is 41 million. During the annual post- marketing surveillance period of August 1, 2013 to July 1, 2014, a total of 215 confirmed adverse reactions were reported with use of adapalene products in 133 cases. The most common adverse events reported in this period were dermatologic and included erythema, dry skin and skin irritation, consistent with clinical trial experience and prior annual surveillance.

Since global market introduction in 1995, there have been 71 spontaneous reports of serious and unexpected adverse events (events that are not consistent in nature or severity with adverse events known to be associated with adapalene use). These events have no discernable pattern and, in most cases, due to limited information, causal relation to adapalene could not be excluded. The most common of these events, by system organ class, include 13 spontaneous

Page 32 NDA 20380 NONPRESCRIPTION ADAPALENE 0.1% BRIEFING DOCUMENT FOR APRIL 15, 2016 TOPICAL GEL NONPRESCRIPTION DRUGS ADVISORY COMMITTEE MEETING abortions, 13 immune system disorders, 12 skin and subcutaneous tissue disorders, 10 congenital, familial and genetic disorders, six (6) eye disorders and five (5) hepatobiliary disorders.

5.4 Clinical Pharmacokinetic Studies Galderma conducted clinical pharmacokinetic studies to evaluate the systemic exposure of adapalene under simulated maximal use conditions for 28 to 30 days in support of the approval of the seven (7) adapalene-containing drugs described previously. Two (2) of these studies are particularly relevant and are thus summarized herein, along with the results of a new maximal use study recently conducted by Galderma.

These studies were as follows:

ƒ Study 18115 HYDOXDWHGV\VWHPLFH[SRVXUHDIWHUWRSLFDODSSOLFDWLRQRI adapalene 0.1% gel RUWKH KLJKHUVWUHQJWKDGDSDOHQHJHO ƒ Study 18097 HYDOXDWHGV\VWHPLFH[SRVXUHDIWHUWRSLFDODSSOLFDWLRQRI adapalene 0.1%JHORUWKH IL[HGGRVHFRPELQDWLRQGUXJDGDSDOHQHbenzoyl peroxide 2.5% gel (SLGXR*HO WRHYDOXDWHLI%32 LPSDFWHGWKHV\VWHPLFDYDLODELOLW\RIDGDSDOHQHDQG ƒ Study 18254 was conducted most recently to further evaluate the systemic exposure of adapalene 0.1% JHOin support of the Rx-to-OTC switch of Differin Gel.

5.4.1 Maximal Use Pharmacokinetic Study 18115

ƒ Study Design

Study 18115 was a double-blind, randomized (in a 1:1 ratio), parallel group study designed to assess the systemic exposure to adapalene after topical applications of Differin 0.3% Gel or Differin 0.1% Gel under conditions of maximal use. A dose of about 2 mg/cm² (2 g of Differin 0.3% Gel or Differin 0.1% Gel) was applied once-daily to 51 subjects with acne vulgaris for 30 days on approximately 1000 cm² BSA of the face, upper part of chest, and upper part of back.

Blood samples for determination of adapalene plasma concentrations were drawn on Day 1, Day 15, and Day 30 before the morning study medication application (pre-dose) and 1, 2, 4, 6, 8, 10, 12, 16 and 24 hours after application of study medication on these days. Additionally, after the last study medication application (End of Treatment / Day 30) samples were obtained at 32, 36, 48 and 72 hours post-dose.

The plasma concentration of adapalene was determined using HPLC and fluorescence detection after enzymatic hydrolysis with Helix pomatia juice and liquid-liquid extraction. The method allowed the quantification of the compound with an LOQ of 0.1 ng/mL.

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ƒ Results

A total of 51 subjects received either Differin 0.3% Gel (N=26) or Differin 0.1% Gel (N=25). Of the 26 subjects receiving Differin 0.3% Gel, only 25 were evaluable at Day 1, 15 and 30. In the Differin 0.1% Gel group, all 25 subjects provided PK blood samples at each study period.

A summary of PK parameters obtained on all sampling days is given in Table 7.

After one single topical application of Differin 0.1% Gel (Day 1), plasma concentrations were <0.1 ng/mL for 21 of the 25 subjects. A plasma concentration-time profile could be established for only four (4) subjects.

After a 15-day once-daily topical application of Differin 0.1% Gel, plasma concentrations were <0.1 ng/mL for 18 of the 25 subjects. A plasma concentration-time profile could be established for only seven (7) subjects.

After a 30-day once-daily topical application of Differin 0.1% Gel, plasma concentrations were <0.1 ng/mL for 21 of the 25 subjects. A plasma concentration-time profile could be established for only four (4) subjects. The last time point with quantifiable adapalene ranged from 12 hours to 24 hours after application. A flat PK profile was observed for these four (4) subjects whose plasma adapalene concentrations peaked within 12 hours post-dose (range: 0.10-0.20 ng/mL) and slowly decreased thereafter.

Despite these flat PK profiles, systemic exposure parameters (AUC, Cmax) determined after repeated topical application of Differin 0.1% Gel were similar to those observed after one single application. In addition, non-quantifiable plasma pre-dose concentrations (Ctrough) were obtained at Day 15 and Days 30 for all subjects (with the exception of Subject 555 having Ctrough: 0.10 ng/mL at Day 15), suggesting that there was no accumulation.

The highest exposures observed (Subject 555) were a plasma concentration of adapalene (Cmax) of 0.31 ng/mL, and an AUC0-24h value of 3.43 ng.h/mL at Day 15, and a Cmax of 0.20 ng/mL and an AUC0-24h value of 3.47 ng.h/mL at Day 30.

ƒ Conclusion

This study demonstrated that after 30 days of once-daily topical application of Differin Gel systemic availability was low, and there was no evidence of increased systemic exposure with a 30-day application compared to a 15-day application.

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Table 7: Summary of Pharmacokinetic Parameters of Differin 0.1% Gel Group (N=25) in Study 18115

PARAMETERS DAY 1 DAY 15 DAY 30

Cmax (ng/mL): Min-Max BLQ - 0.17 BLQ - 0.31 BLQ - 0.20 Quantifiable N 4 7 4 Mean±SD a 0.02±0.06 0.04±0.08 0.03±0.06

Tmax (h): Min-Max 8 - 16 2 - 16 8 - 16 Mean±SD 11±4 11±5 12±3

AUC0-24h (ng.h/mL): Min-Max BLQ- 2.32 BLQ- 3.43 BLQ- 3.47 Quantifiable N 4 7 4 Mean±SD a 0.31±0.73 0.50±0.99 0.42±1.03

AUC0-24h=area under the concentration-time curve from time 0 to 24 hours after application; BLQ=below limit of quantification; Cmax=maximum concentration achieved; N=Number of subjects with quantifiable values; Max=maximum value; Min=minimum value; NA=Not applicable (no quantifiable concentration or less than 3 consecutive quantifiable concentrations); Tmax=time to maximum concentration a) Mean values were calculated for the 25 subjects; BLQ data were imputed as zero.

5.4.2 Maximal Use Pharmacokinetic Study 18097

ƒ Study Design Study 18097 was a single-center, double-blind, randomized, active-controlled, parallel-group study to assess adapalene plasma concentration over a 30-day treatment period. A total of 24 subjects with acne vulgaris between 18 and 34 years of age were enrolled and randomized in a 1:1 ratio to one of the following treatment groups: FDC of adapalene 0.1%/benzoyl peroxide 2.5% gel (Epiduo Gel) or adapalene gel, 0.1% monad. Subjects reported to the clinic every morning on each study day up to Day 30 to have the study medication applied by trained personnel. Each subject received a once-daily 2 gram application of the study medication to the face, upper part of the chest, and upper part of the back. The study medication was applied to a total BSA of approximately 1000 cm² (i.e., 2 mg/cm2).

Blood samples for the determination of adapalene plasma concentrations were collected on Days 1, 10, 21, and 30 before the morning study medication application (pre-dose), and 2, 4, 6, 8, 10, 12, and 24 hours following application (post-dose). A additionally, samples were collected at 36, 48, and 72 hours following the last study medication application at End of Treatment / Day 30.

Total adapalene (free and conjugated compound) was determined in the plasma samples by HPLC with fluorescence detection after enzymatic hydrolysis with Helix Pomatia juice (E-glucuronidase/arylsulfatase mixture) and liquid-liquid extraction. The method allowed the quantification of the compound with an LOQ of 0.1 ng/mL.

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ƒ Results Of the 24 subjects enrolled in this study, 11 were males and 13 were females. The mean age was 22.8 years, ranging from 18 to 34 years. The percentage of treated BSA was evaluated at Baseline, with observed mean values of 5.5% for the Epiduo Gel group and 5.3% for the adapalene gel, 0.1% group.

Daily application of 2 grams of Epiduo Gel or adapalene gel, 0.1% on approximately 1000 cm² skin surface area resulted in low systemic exposure to adapalene. Plasma concentrations were <0.1 ng/mL in most subjects (Table 8). Adapalene concentrations were quantifiable (up to 0.2 ng/mL) in two (2) subjects of the Epiduo Gel group and three (3) subjects of the adapalene gel, 0.1% group. For the five (5) subjects with quantifiable adapalene concentrations, only two (2) (Subject 013 and Subject 001) had quantifiable concentrations in at least three (3) consecutive plasma samples during any sampling period. Quantifiable concentrations were also obtained for 1 subject in the Epiduo Gel group (Subject 016) and two (2) subjects in the adapalene gel, 0.1% group (Subjects 015 and 021).

Thus, only three (3) plasma profiles were obtained, and none showed any peak concentrations above 0.21 ng/ml. There was no meaningful difference in the systemic exposure to adapalene between the two (2) treatment groups. The highest adapalene plasma concentrations (Cmax) were 0.21 ng/mL and 0.16 ng/mL after repeated application of Epiduo Gel and adapalene gel, 0.1%, respectively. The highest AUC0-24h values were 1.99 ng.h/mL and 2.65 ng.h/mL in the Epiduo Gel and adapalene gel, 0.1% groups, respectively (Table 9).

The most exposed subject (Subject 001) was in the adapalene gel, 0.1% group. This was a 26 year-old female, treated on 5.6% of total BSA. Highest systemic exposure in this subject was observed at Day 10, with a Cmax of 0.16 ng/mL and an AUC0-24h of 2.65 ng.h/mL.

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Table 8: Summary of Subjects with Quantifiable Adapalene Plasma Concentrations (Study 18097)

Number of Subjects Treatment Day Evaluable With only non- With at least 1 With at least quantifiable quantifiable 3 consecutive concentrations concentration quantifiable concentrations 1 12 12 0 0 10 11 11 0 0 Epiduo Gel a 21 10 9 1 1 30 10 9 1 0 1 12 12 0 0 10 11 10 1 1 Adapalene gel, 0.1% 21 11 10 1 1 30 10 8 2 0 a) Fixed-dose combination of adapalene 0.1%/benzoyl peroxide 2.5% gel

Table 9: Individual PK Parameters for Subjects with Quantifiable Adapalene Plasma Concentrations (Study 18097)

Administration Subject Day Cmax (ng/mL) Tmax (h) AUC0-24h (ng.h/mL) Epiduo Gel a 13 21 0.1266 0 1.9945 16 30 0.2086 12 NA Adapalene gel, 0.1% 1 10 0.1611 12 2.6481 1 21 0.1261 6 1.2623 15 30 0.1392 24 NA 21 30 0.1101 6 NA

AUC0-24h=area under the concentration-time curve from time 0 to 24 hours after application; Cmax=maximum concentration achieved; NA=Not applicable (no quantifiable concentration or less than 3 consecutive quantifiable concentrations); Tmax=time to maximum concentration a) Fixed-dose combination of adapalene 0.1%/benzoyl peroxide 2.5% gel

ƒ Conclusion Daily application of 2 grams of Epiduo Gel or adapalene gel, 0.1% for 30 days on the face, upper part of chest, and upper part of back resulted in low systemic exposure to adapalene, with plasma concentrations less than 0.1 ng/mL (the LOQ) in most subjects. Adapalene concentrations reached quantifiable levels (between 0.1 and 0.2 ng/mL) in two (2) subjects treated with Epiduo Gel and three (3) subjects treated with adapalene gel, 0.1%. There was no evidence of adapalene accumulation during the course of the study in either treatment group.

The most exposed subject was in the adapalene gel, 0.1% group and was a 26 year-old female, treated on 5.6% of total BSA. This highest systemic exposure was observed at Day 10 and there was no evidence of BPO effect on adapalene exposure.

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5.4.3 Maximal Use Pharmacokinetic Study 18254 To expand on prior pharmacokinetic studies, Study 18254 was designed to evaluate the potential systemic exposure to topical adapalene in subjects with acne aged 12 years and older under maximal use conditions (applied to a wider surface area than would be used in normal circumstances) for 29 days. Importantly, improvements in analytical methods enabled a LLQ of 0.02 ng/mL and allowed for a better definition of pharmacokinetic properties after topical administration.

The same instructions for drug application were given in Studies 18097 and 18115: 2 grams of adapalene gel was to be applied on a daily basis on approximately 1000 cm² (2 mg/cm²) of skin. In Study 18254, to ensure that a sufficient amount of drug product was applied on the largest extent of skin surface potentially affected by acne, the study personnel were instructed to apply as much drug as needed (i.e., without restriction) in order to cover the face, shoulders, upper back and upper chest. The actual amount applied was recorded. Despite the absence of restriction in quantity used, the mean amount of drug applied was 2 grams in adults and adolescents (range: 1.2 to 2.9 g), similar to the amount of drug used in previous studies.

Demographics and disease characteristics at baseline are presented in Table 10.

ƒ Study design This was a multicenter, open-label study, involving 24 subjects grouped as follows: 18 adolescent subjects (10 males and 8 females) and six (6) adult subjects (three (3) males and three (3) females).

The subjects were treated with QD applications during a 29-day treatment period, then followed for two (2) additional days after last dose. Study drug was applied as a thin layer to the face, shoulders, upper chest and upper back. Qualified study personnel performed daily study drug applications on site. The actual amount of applied product was recorded (weighed) for each subject at Baseline and the same amount was applied for the duration of the treatment.

Subjects aged 16 years and older had facial acne with a severity grade of 4 on the IGA scale at both screening and Baseline. Subjects aged 12 to 15 years had facial acne with a severity grade of 3 or 4 on the IGA scale at both screening and Baseline.

Blood samples were drawn at scheduled time points for determination of adapalene concentrations in plasma. Three 24-hour PK profiles were carried out, on Day 1, Day 15 and Day 29. Blood samples were also drawn during the follow-up period to investigate the elimination process of adapalene over the subsequent 48 hours. The blood sampling schedule was adapted to adolescent subjects. Thus, two sampling schedules were used in this study, as presented in Table 11 (adult subjects) and Table 12 (adolescent subjects).

Adapalene plasma concentrations were determined using a highly sensitive assay, by HPLC coupled with tandem mass-spectrometry (HPLC-MS/MS). Sample analyses were performed using an improved bioanalytical method. The LOQ of the method was 0.02 ng/mL.

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Table 10: Demographics and Disease Characteristics at Baseline in Study 18254

Males Females 12 to 17 years 18+ years Total (N=13) (N=11) (N=18) (N=6) (N=24) Age Mean 18.8 17.4 15.5 26.2 18.2 Median 16.0 16.0 16.0 23.0 16.0 (min, max) (13, 43) (14, 23) (13, 17) (18, 43) (13, 43) Gender Male 13 (100.0%) NA 10 (55.6%) 3 (50.0%) 13 (54.2%) Female NA 11 (100.0%) 8 (44.4%) 3 (50.0%) 11 (45.8%) Race White 13 (100.0%) 11 (100.0%) 18 (100.0%) 6 (100.0%) 24 (100.0%) Ethnicity Hispanic or Latino 8 (61.5%) 8 (72.7%) 14 (77.8%) 2 (33.3%) 16 (66.7%) Not Hispanic or 5 (38.5%) 3 (27.3%) 4 (22.2%) 4 (66.7%) 8 (33.3%) Latino IGA Score at Baseline 3=Moderate 0 3 (27.3) 3 (16.7) 0 3 (12.5) 4=Severe 13 (100.0%) 8 (72.7) 15 (83.3) 6 (100.0) 21 (87.5) IGA Score at Baseline for 12 to 15 Years 3=Moderate 0 3 (27.3%) NA NA 3 (12.5%) 4=Severe 4 (30.8%) 1 (9.1%) NA NA 5 (20.8%) IGA Score at Baseline for 16+ Years 3=Moderate 0 0 NA NA 0 4=Severe 9 (69.2%) 7 (63.6%) NA NA 16 (66.7%) NA=not applicable; IGA=Investigator’s Global Assessment

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Table 11: Study Period and Time Points for Adult Subjects in Study 18254

PK Sampling Day 1 Day 2 Day 10 Day 15 Day 16 Day 22 Day 29 / Early Day 30 Day 31 Day Termination Plasma 2, 4, 6, 8, 10, 12, 24 hours after Predose Predose, 2, 4, 6, 8, Day Predose Predose, 2, 4, 6, 8, 10, 24 hours 48 hours after samples time and 16 hours initial dose 10, 12, and 15 dose 12, and 16 hours after after last last dose on pointsa after the initial (Predose) 16 hours after the (Predose) the morning dose dose on Day 29 dose morning dose 24 hours Day 29 after SREe)

Systemic PK Cmax, Tmax, Ctrough Ctrough Ctrough, Cmax, Tmax, Ctrough Ctrough Ctrough, Cmax, Tmax, AUC0-24h, AUC0-t, AUC0-inf, R2, parameters AUC0-t, AUC0-24h AUC0-t, AUC0-24h, R3, Kel, T1/2 R1

AUC0-inf=area under the concentration-time curve from time 0 extrapolated to infinity; AUC0-t=area under the concentration-time curve from time 0 to time t after application; AUC0-24h=area under the concentration-time curve from time 0 to 24 hours after application; BLQ=Below limit of quantification ; Cmax=maximum concentration achieved; Ctrough=predose plasma concentration; Kel=elimination rate constant; N=Number of subjects with quantifiable values; NA=Not applicable (no quantifiable concentration or less than 3 consecutive quantifiable concentrations); PK=pharmacokinetic(s); R=accumulation ratio; R1: AUC0-24h D15/ AUC0-24h Day 1; R2: AUC0-24h D29/ AUC0-24h Day 1; R3: AUC0-24h D29/ AUC0-24h Day 15; Tmax=time to maximum concentration; T1/2=elimination half-life

Table 12: Study Period and Time Points for Adolescent Subjects in Study 18254

PK Sampling Day 1 Day 2 Day 15 Day 16 Day 29 / Early Day 30 Day 31 Day Termination Plasma samples 2, 4, 8, 10, 12, and 24 hours after Predose, 2, 4, 8, 10, 24 hours after Predose, 2, 4, 8, 10, 12, 24 hours 48 hours after time pointsa 14 hours after the initial dose 12, and 14 hours after Day 15 dose and 14 hours after the after last last dose on initial dose (Predose) the morning dose (Predose) morning dose dose on Day Day 29 29

Systemic PK Cmax, Tmax, AUC0-t, Ctrough Ctrough, Cmax, Tmax, Ctrough Ctrough, Cmax, Tmax, AUC0-24h, AUC0-t, AUC0-inf, R2, R3, parameters AUC0-24h AUC0-t , AUC0-24h, R1 Kel, T1/2

AUC0-inf=area under the concentration-time curve from time 0 extrapolated to infinity; AUC0-t=area under the concentration-time curve from time 0 to time t after application; AUC0-24h=area under the concentration-time curve from time 0 to 24 hours after application; BLQ=Below limit of quantification ; Cmax=maximum concentration achieved; Ctrough=predose plasma concentration; Kel=elimination rate constant; N=Number of subjects with quantifiable values; NA=Not applicable (no quantifiable concentration or less than 3 consecutive quantifiable concentrations); PK=pharmacokinetic(s); R=accumulation ratio; R1: AUC0-24h D15/ AUC0-24h Day 1; R2: AUC0-24h D29/ AUC0-24h Day 1; R3: AUC0-24h D29/ AUC0-24h Day 15; Tmax=time to maximum concentration; T1/2=elimination half-life a Sampling times = from time of the application start

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ƒ Extent of Exposure The planned treatment duration was 29 days, and there was a 2-day follow-up period. In this study, no subject discontinued early. A majority of subjects (22 of 24 subjects) had 29 days of actual study drug exposure. Two (2) subjects missed one application.

The dose applied was determined at Day 1 for each subject. This dose remained the same throughout the study for that subject. The mean daily medication usage thus determined at Baseline was 1.95 g (range: 1.21 to 2.92 g) (Table 13). The mean total treated surface area was 1865 cm² (range: 1387 to 2894 cm²). The mean percent treated BSA was 9.2% (range: 6.8% to 13.0%).

Table 13: Summary of Treatment Exposure in Study 18254

Males Females 12-17 years 18+ years Total (N = 13) (N = 11) (N = 18) (N = 6) (N = 24) Daily Average Medication Usage (g/day) Mean 1.97 1.92 1.86 2.24 1.95 Min, Max 1.21, 2.92 1.38, 2.26 1.21, 2.81 1.83, 2.92 1.21, 2.92 Total Treated Surface Area (cm²) Mean 2092 1596 1812 2022 1865 Min, Max 1395, 2894 1387, 2197 1387, 2787 1417, 2894 1387, 2894 Percentage of Treated Surface Area (%) Mean 9.67 8.72 9.40 8.73 9.23 Min, Max 6.92, 13.05 6.80, 11.27 6.92, 13.05 6.80, 10.21 6.80, 13.05 Max=maximum value; Min=minimum value

Mean amounts of drug product applied per cm² of treated BSA (Table 14) ranged from 0.6 to 1.6 mg/cm² and the mean value was 1.1±0.2 mg/cm².

Table 14: Mean Amounts of Differin 0.1% Gel Applied in Study 18254 per Cm² of Treated BSA

Males Females 12-17 years 18+ years Total (N=13) (N=11) (N = 18) (N = 6) (N = 24) Mean r SD 1.0 r 0.2 1.2 r 0.2 1.1 r 0.2 1.2 r 0.3 1.1 r 0.2 (mg/cm²) Min, Max 0.6, 1.4 1.0, 1.6 0.6, 1.4 0.8, 1.6 0.6, 1.6 (mg/cm²) Median 1.0 1.2 1.0 1.1 1.1 (mg/cm²) Max=maximum value; Min=minimum value; SD=standard deviation

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ƒ Results Eleven (11) female and 13 male subjects were enrolled in this study. The overall mean and median ages were 18.2 years and 16.0 years, respectively. At Screening, mean Body Mass Index (BMI) was 30.2 and total mean BSA was 2.0 m². Disease severity at Baseline (IGA score) was moderate (IGA=3) for three (3) (female) of 24 subjects (12.5%), and severe (IGA=4) for 21 (13 males and 8 females) of 24 subjects (87.5%). Fifteen (15) of the 18 adolescent subjects (83.3%) had severe acne, and three (3) (16.7%) had moderate acne at Baseline. All (100%) adult subjects had severe acne at Baseline.

The mean adapalene plasma concentration-time profiles were as follows:

ƒ After the first topical application of Differin 0.1% Gel, adapalene plasma concentrations were quantifiable in 15 of 24 subjects (63%) with concentrations ranging from <0.02 ng/mL to 0.066 ng/mL). ƒ After two weeks of daily application, adapalene plasma concentrations were also quantifiable at low levels in 21 of 22 subjects (95%). Plasma concentrations ranged from <0.02 ng/mL to 0.144 ng/mL. ƒ At End of Treatment (Day 29), adapalene plasma concentrations were quantifiable at least at one time point in all subjects, ranging from <0.02 ng/mL to 0.171 ng/mL.

A summary of the main PK parameters (Cmax, Tmax, AUC0-24h, and AUC0-t) is given in Table 15.

Time to maximum concentration (Tmax) values remained constant (mean values of 12 to 14 hours) throughout the 29-day treatment duration. Similar predose (Ctrough) values (ranging from <0.02 to 0.087 ng/mL) were also observed throughout the treatment duration, suggesting that there was no accumulation upon repeated daily topical applications (Table 16). In addition, descriptive statistics of accumulation ratios based on AUC values obtained at Baseline/Day 1, Day 15, and Day 29 indicated that systemic exposure tended to be higher at Day 15 and Day 29 compared to Day 1, suggesting that the steady state was achieved by Day 15 (Table 17).

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Table 15: Summary of Main Pharmacokinetic Parameters in Study 18254

Cmax Tmax AUC0-24h AUC0-t (ng/mL) (h) (ng.h/mL) (ng.h/mL) Day 1 N=24, N quantifiable (%): 15 (63%) MeanrSD 0.033r0.015 14.3r5.4 0.57r0.14 0.41r0.27 CV% 45% 38% 25% 66% Min, Max 0.020, 0.066 8, 24 0.48, 0.96 0.15, 0.96 Day 15 N=22, N quantifiable (%): 21 (95%) MeanrSD 0.054r0.032 12.8r5.3 0.87r0.43 0.77r0.51 CV% 59% 42% 50% 67% Min, Max 0.020, 0.144 8, 24 0.48, 1.99 0.16, 2.00 Day 29 N=24, N quantifiable (%): 24 (100%) MeanrSD 0.049r0.030 11.9r4.5 0.83r0.49 0.85r0.86 CV% 62% 38% 59% 101% Min, Max 0.025, 0.171 0, 24 0.50, 2.90 0.17, 4.46

AUC0-t=area under the concentration-time curve from time 0 to time t after application; AUC0-24h=area under the concentration- time curve from time 0 to 24 hours after application; Cmax=maximum concentration achieved; Ctrough=predose plasma concentration; CV=coefficient of variation; Max=maximum value; LOQ=limit of quantitation; Min=minimum value; SD=standard deviation; Tmax=time to maximum concentration Notes: When all the concentrations of a profile were BLQ the following imputation rules were used: LOQ value (0.02 ng/mL) for the Cmax No imputation for the mean calculation of Tmax

Table 16: Mean Predose Plasma Concentration Values (Ng/Ml) Observed at Indicated Treatment Days in Study 18254

Day 2 Day 10 Day 15 Day 16 Day 22 Day 29 % subjects with quantifiable 46% 33% 30% 54% 50% 50% concentrations MeanrSD (ng/mL) a,b - - - 0.032r0.020 0.024r0.008 0.025r0.010 CV% - - - 62% 34% 40% <0.02, <0.02, <0.02, Min, Max (ng/mL) <0.02, 0.09 <0.02, 0.04 <0.02, 0.07 0.05 0.04 0.05 CV=Coefficient of variation; Max=maximum value; Min=minimum value; SD=standard deviation; a When less than 50% of the measured concentration were quantifiable (i.e., above the LOQ of 0.02 ng/mL), no mean values were calculated b When a mean value was calculated, concentrations below the LOQ were replaced by the LOQ value

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Table 17: Accumulation Ratios (Study 18254)

R1 R2 R3 N (n) a 24 (13) 24 (15) 24 (21) MeanrSD 1.7r0.7 1.4r0.7 1.0r0.4 CV (%) 43% 45% 38% Min, Max 0.9, 3.3 0.9, 3.4 0.3, 2.1 Median 1.4 1.2 0.9

CV=coefficient of variation; Max=maximum value; Min=minimum value; SD=standard deviation;R1: AUC0-24h D15/ AUC0-24h Day 1; R2: AUC0-24h D29/ AUC0-24h Day 1; R3: AUC0-24h D29/ AUC0-24h Day 15 c N= total number of subjects, n =number of subjects with evaluable AUC0-24h

The following observations were also made in this study:

ƒ Inferential statistical analyses confirmed that steady state was achieved by Day 15 and that there was no systemic accumulation of adapalene after a 4-week treatment period. The value for AUC0-24h at Day 15 was significantly (p<0.001) higher than that of AUC0-24h at Day 1, with an estimated AUC ratio of 1.42. Similarly, AUC0-24h at Day 29 was significantly (p<0.001) higher than AUC0-24h at Day 1, with an estimated AUC ratio of 1.36. However, there was no statistically significant difference between the AUC0-24h values obtained at Day 15 and Day 29 (estimated AUC ratio of 0.96, p=0.566). ƒ Whereas steady state was achieved at Day 15, disease severity continued to improve between Day 15 and Day 29, thus indicating that PK parameters were not impacted by the evolution of disease severity.

ƒ Statistical analyses also showed that PK parameters (AUC0-24h, Cmax, and Ctrough) were independent of gender and age group (adolescent vs. adult subjects). ƒ The subject with the highest exposure in this study was a 16 year-old male receiving daily applications of 1.89 g of study medication on 1899 cm² BSA. This subject had quantifiable plasma levels of adapalene throughout the assessment period and presented the highest systemic exposure at Day 29 with a Cmax value of 0.171 ng/mL and an AUC0-24h of 2.897 ng.h/mL. Based on an apparent terminal half-life (15.1 h), complete clearance of adapalene from this subject’s plasma was estimated to occur within 4 days after the last application.

ƒ Adverse Events

Overall, 17 AEs were reported by eight (8) subjects (33.3%) (Table 18). All AEs were either mild or moderate in severity. The most commonly reported AE in Study 18254 was skin irritation (three (3) subjects [12.5%]), followed by pruritus, headache, and seasonal allergy (two (2) subjects [8.3%] each). All other AEs occurred in one (1) subject (4.2%) each.

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Out of 17 AEs, seven (7) were considered related to study drug and were reported by three (3) subjects (12.5%). Dermatologic AEs included three (3) events of skin irritation, three (3) events of pruritus, and one (1) event of feeling hot; all were mild in severity.

There were no deaths, no SAEs, no pregnancies, and no discontinuations due to AE.

The overall incidence of AEs was higher in adults than in adolescents (50.0% versus 27.8%) and was comparable between males and females (30.8% versus 36.4%).

Table 18: Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (Safety Population) in Study 18254

Total (N=24) n (%) Event count Any Treatment-Emergent Adverse Event 8 (33.3) 17 Skin and subcutaneous tissue disorders 4 (16.7) 7 Skin irritation 3 (12.5) 3 Pruritus 2 (8.3) 3 Skin erosion 1 (4.2) 1 Nervous system disorders 2 (8.3) 3 Headache 2 (8.3) 3 Immune system disorders 2 (8.3) 2 Seasonal allergy 2 (8.3) 2 Infections and infestations 2 (8.3) 2 Body tinea 1 (4.2) 1 Pharyngitis streptococcal 1 (4.2) 1 Gastrointestinal disorders 1 (4.2) 1 Abdominal pain 1 (4.2) 1 General disorders and administration site 1 (4.2) 1 conditions Feeling hot 1 (4.2) 1 Injury, poisoning and procedural complications 1 (4.2) 1 Laceration 1 (4.2) 1 n=subject count; %=percent subjects Adverse events are coded using MedDRA version 16.0. If a subject had multiple occurrences of an AE, the subject was presented only once in the respective subject count. Treatment-emergent AEs are defined as AEs that started after the first dose of study treatment. Percentages are based on the number of subjects in the Safety Population in each treatment group

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ƒ Conclusion Study 18254 was conducted in order to evaluate the potential systemic exposure of Differin Gel applied in a maximal use manner. There were no restrictions to applied amount of formulation compared to the target amount of 2 grams applied in previous pharmacokinetic studies.

Measurements of the dose applied and surface area treated demonstrated that the amount of drug product applied (mean: 1.95 g, range: 1.21 to 2.92 g) was sufficient to cover the entire treated area of the face, shoulder, upper chest and upper back (1865 cm², range: 1387 to 2894 cm²).

The repeated application of Differin Gel resulted in quantifiable systemic exposure (>0.02 ng/mL at a minimum of one time point) in all subjects enrolled in this study. There was no drug accumulation over the treatment period after day 15.

The most exposed subject was a male of 16 years of age who received a dose of 1.89 g of formulation on an area of 1899 cm². This subject had an AUC0-24h of 2.897 ng.h/mL and a Cmax of 0.171 ng/mL. For this subject, the calculated elimination half-life was 15 hours.

This study also demonstrated that there was no significant difference of systemic exposure to adapalene across genders and age groups (adolescent vs adult subjects).

5.4.4 Conclusion of Maximal Use Clinical Pharmacokinetic Studies While quantitatively different, reflecting the different analytical methods used, the results of all maximal use studies are consistent. Systemic exposure after topical application of Differin Gel is extremely low. The data collected demonstrate that systemic exposure to adapalene is similar in adolescent and adult subjects receiving daily topical application of Differin Gel, even under maximal use conditions and in the presence of benzoyl peroxide. The importance of these data is further described in Section 5.5 that follows.

5.5 Teratogenicity and Fetotoxicity Vitamin A (retinol) and vitamin A derivatives, such as retinoic acid, are essential for proper embryo-fetal development in humans and animals. Vitamin A deficiency during pregnancy causes specific developmental abnormalities to the cardiovascular, ocular, urogenital and central nervous (CNS) systems, and can affect embryonic growth and survival.

Excess Vitamin A and retinoid exposure during pregnancy can also disrupt normal embryonic development in a wide range of experimental animals, targeting cardiovascular, CNS, craniofacial and skeletal development. For example, in rodents, treatment with excess retinoids during pregnancy results in embryolethality, as well as cardiovascular and sensory organ malformations early in organogenesis. Additionally, craniofacial, urogenital and skeletal defects are observed when systemic retinoid exposure occurs later in organogenesis. In rabbits, common retinoid-induced malformations include ectopic organs, hindlimb torsion, omphalocele and tail defects. At threshold embryotoxic doses of retinoids, an increase in supernumerary ribs is a commonly observed non-adverse fetal finding in several animal models. In humans, administration of systemic retinoids has been associated with developmental abnormalities to the

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CNS (hydrocephalus, hypoplastic or malformed cerebellar or cerebral cortices), craniofacial region (cleft palate, external ear defects), heart, thymus and limbs.16

5.5.1 Receptor-binding Properties of Adapalene Adapalene is a synthetic polyaromatic compound that structurally differs from naturally occurring retinol and its derivatives. Adapalene is a derivative of naphthoic acid, not retinoic acid and, consequently, the ability for adapalene to interact with DNA also differs. Retinoids act within the nucleus of the cell where they bind to specific nuclear receptors (retinoic acid receptors or RARs) in order to interact with the cell’s DNA and cause changes in gene expression. The cell’s nuclear material is contained within the nuclear envelope, which restricts access of most molecules in the cytoplasm to the DNA. However, cellular retinoic acid binding protein-II (CRABP-II) is present in certain cells and facilitates the transfer of retinoids to the nucleus. Once within the nucleus, retinoids bind to one the RARs, of which there are three major types: RARĮ, RARȕ, and RARȖ.11 Each of the RARs interacts with a different set of genes. Retinoic acid, tretinoin, isotretinoin, and etretinate bind to CRABP-II, which facilitates their access to the cell nucleus.

In contrast, the chemical structure of adapalene differs from earlier generation retinoids such as retinoic acid, tretinoin, isotretinoin and etretinate due to the adamantyl substituent group which interferes with adapalene’s ability to bind to CRABP-II. Thus, compared with other therapeutic retinoids adapalene has diminished access to the cell nucleus. This is important because tissues with CRABP-II are sensitive to high levels of retinoic acid which may cause defects in the development of those tissues. Within the nucleus, adapalene exhibits selective high affinity binding for the nuclear retinoic acid receptors, RARȕ and RARȖ but has a very low affinity for RARĮ; consequently, adapalene’s ability to induce changes in gene expression also differs from other retinoids.26 These differences in basic pharmacology suggest that adapalene effects after systemic exposure may be less as compared with other retinoids.

5.5.2 Nonclinical Reproductive Toxicity Studies with Adapalene The nonclinical reproductive and developmental toxicity of adapalene was evaluated in the rat and rabbit in dermal and oral studies. Pivotal studies in the rat included an oral 2-generation reproductive function and fertility study, an oral embryo-fetal development study, a dermal embryo-fetal development study and an oral pre-/postnatal development study. In the rabbit, a pivotal dermal embryo-fetal development study and a non-pivotal oral embryo-fetal development study were conducted. Several non-pivotal dose-range finding studies were also conducted in the rat. Oral adapalene was used to establish the full exposure related risk while topical studies were performed to more closely reflect the therapeutic scenario.

To investigate fertility and reproductive functions in the rat, adapalene was administered orally at doses of 1.5, 5, and 20 mg/kg/day to male rats for 71 days before mating and to female rats from 15 days prior to mating and throughout gestation and lactation. No adverse effects were observed upon reproductive performance and fertility. In this fertility study, there was an increase in the number of fetuses with supernumerary ribs at 5 mg/kg/day and higher. At the highest dose (20 mg/kg/day), there was also a slight reduction in pubic bone ossification. These minor variations

Page 47 NDA20380    NONPRESCRIPTIONADAPALENE0.1% BRIEFINGDOCUMENTFORAPRIL15,2016    TOPICALGEL NONPRESCRIPTIONDRUGSADVISORYCOMMITTEE in skeletal development and rib number had no demonstrable adverse effect on offspring survival, development and subsequent reproductive performance; as such they were not considered adverse. The No Observed Adverse Effect Level (NOAEL) was defined as the highest dose at which no which adverse malformations were observed. Plasma concentrations at these doses were used to define exposures that were safe with respect to teratogenicity risk. The No Observable Effect Level (NOEL) for adult toxicity, reproduction parameters, offspring development in both the F1 and F2 generations and for fetal development in F2 fetuses was 20 mg/kg/day. The NOAEL for fetal development for F1 fetuses was 20 mg/kg/day.

A rat oral peri- / post-natal development study at lower doses (up to 15 mg/kg/day) and over shorter dosing periods (from Day 6 of gestation to Day 20 of lactation) confirmed the absence of adverse effects upon mating performance and fertility of F0 females, growth and development of the F1 generation, and F2 fetuses up to the highest dose tested of 15 mg/kg/day, being the NOAEL for all parameters in this study.

Oral embryo-fetal toxicity studies performed either in the rat or the rabbit at high dose levels (25 mg/kg/day and 60 mg/kg/day respectively) gave several observations consistent with teratogenic effects expected for systemic retinoids including effects on bones, the urinary tract, and the palate. The oral dose of 5 mg/kg/day was established as the NOAEL both in the rat and the rabbit.

In embryo-fetal studies by the dermal route using gel formulations up to a concentration of 0.3% adapalene (corresponding to 6 mg/kg/day), only minor variations were observed, including lumbar supernumerary ribs in both species and cervical supernumerary ribs in the rat, incomplete ossification of heads of long-bones (that can be considered as a delay in development) and bone variations (inter-parietal bone reduced, fissured or absent and 27th pre-sacral vertebrae) only seen in the rabbit. The main issue to consider is the relevance and the significance of these minor observations seen only at the highest dose of 6 mg/kg/day (corresponding to 2 mL/kg of 0.3% adapalene gel) by the cutaneous route in both species.

Supernumerary ribs are the most common anomaly reported in laboratory animal developmental toxicity studies. Spontaneous incidences for lumbar ribs in several species are well documented and reach 28% in rats, 62% in mice and 78% in rabbits.33 In adult humans, cervical ribs are observed at up to 1.2% and lumbar ribs at up to 2%. Cervical ribs are a rare finding in the rat with incidences below 1%, but they are present in the mouse at up to 13%.

The rabbit differs to a large degree from rodent species with lower incidences of cervical ribs. Furthermore, ribs can be divided into rudimentary ribs (in general considered as less than 1/2 the length of the 13th rib) and extra ribs (more than 1/2 the length of the 13th rib). This distinction is very important because rudimentary ribs have been reported to subside during post-natal development34 and thus are considered to have little or no impact on normal development. Another observation reported in developmental toxicity studies with retinoids is reduced ossification and, indeed, this was true for the studies with high exposure to adapalene. This corresponds to a delay in ossification that can resolve during post-natal development and is thought to have no major consequences for survival and general development.

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In the oral fertility and oral pre- and post-natal studies performed with adapalene in the rat up to 20 mg/kg/day, these minor variations in skeletal development and rib number had no demonstrable adverse effect on offspring survival, development and subsequent reproductive performance. This clearly indicated that such minimal variations observed in the two dermal teratology studies can be considered as non-adverse. Thus, the highest dose level of 6 mg/kg/day (2 mL/kg of 0.3% gel) is the NOAEL for fetus development as well as the NOEL for maternal toxicity in rats and in rabbits.

Conclusion of Nonclinical Reproductive Toxicity Studies

Extensive nonclinical reproductive toxicity studies were conducted and NOAELs were defined. No teratogenic effects were observed in rats treated with oral doses up to 5.0 mg adapalene/kg/day, equivalent to up to 25 times (mg/m2 /day) the maximal use topical dose of 2 grams as determined in maximal use pharmacokinetic studies (see Section 5.4). Teratogenic changes were observed in rats and rabbits when treated with oral doses of • 25 mg adapalene/kg/day representing 123 and 246 times the maximal use topical dose, respectively. These malformations were not seen in topical studies in rats and rabbits at doses equivalent to 25 to 59 times the maximal use topical dose.

5.5.3 Calculation of Safety Margin

To fully characterize teratogenic risk based on systemic exposure, data obtained in nonclinical reproductive toxicity studies are used in conjunction with exposure data obtained in human pharmacokinetic studies to establish a margin of safety. The safety margin is the ratio of the lowest systemic exposure (AUC) in animal studies at the no observed adverse effect level (NOAEL) for teratogenicity in the most sensitive animal species (in the case of adapalene, the rat) to the highest human systemic exposure (AUC) determined under maximized conditions in subjects with moderate to severe acne. Enrollment of a more severe acne population was important due to potential increased systemic exposure of damaged/inflamed skin.

In a separate 10-day topical pharmacokinetic study with adapalene 6 mg/kg/day (2 mL/kg of adapalene 0.3% gel) in female rats, an AUC(0-24h) of 204 ng.h/mL and a Cmax of 14.47 ng/mL were determined. In female rabbits under the same conditions, an AUC of 1036 ng.h/mL and a Cmax of 48.47 were determined. As the lowest systemic exposure expressed as the AUC at the NOAEL was determined in the rat, the AUC(0-24h) of 204 ng.h/mL is selected to calculate the safety margin for Differin Gel.

It should be noted that this estimate is conservative as the observed NOAEL doses were well below the doses that actually demonstrated risk, and the human exposure estimate is based on an extreme outlier.

Using this approach, based on the human exposure defined in the two earliest pharmacokinetic studies, 18115 and 18097, safety margins ranged from 59 to 102 in adults as presented in Table 19.

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Using data from the most recent maximal use PK study, Study 18254, the safety margin for Differin Gel in adolescent and adult subjects with acne vulgaris was 70 for the most exposed subject. This margin increases to 234 if the mean systemic exposure at steady state is used. It is also important to note that the margin of exposure would be even higher under normal use situations when realistic therapeutic doses are used (versus the maximal exposure in the PK studies).

In summary, large margins of safety exist to ensure safe use of Differin Gel in a nonprescription environment.

Table 19: Systemic Exposure Reported in Clinical Pharmacokinetic Studies

Formulation Study Subjects N n Subject with Highest Exposure Safety Margina No. (Quantifiable AUC1-24h (ng.h/mL) Cmax at steady (ng/mL) state) Epiduo (FDC) Study Adapalene 0.1%/Benzoyl Adults 12 1 1.99 0.13-0.21 102 Peroxide 2.5% Gel 18097 Adapalene 0.1% gel Adults 12 2 2.65 0.16 77 monadb Differin Studies Adapalene 4 (at Day 1) to 18115f Adults 25 3.47 0.20-0.31 59 0.1% Gel 7 (at Day 15) Adapalene 18254 Adults 6 5c-6 2.90d 0.17d 70 e 0.1% Gel Adolescents (meanrSD=0.87±0.43) (234 ) (12-17 years 18 17-18c old) a The safety margin is the ratio of the lowest systemic exposure in animal studies at the NOAEL for teratology in the most sensitive animal species (AUC0-24h: 204 ng.hr/mL in the rat) divided by the highest human systemic exposure under maximized conditions (in subjects with moderate to severe acne) b Adapalene monad is adapalene formulated in the Adapalene 0.1%/Benzoyl Peroxide 2.5% gel vehicle. c One subject was not quantifiable at Day 15 d LOQ = 0.02 ng/mL for Study 18254 and LOQ = 0.1 ng/mL for all other studies e Value was based on the mean systemic exposure at steady state f Adapalene 0.3% Gel was also evaluated in this study

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5.5.4 Exposure During Pregnancy Galderma has screened the company's global reporting database for adapalene exposure during pregnancy. As described in Table 20 there have been 336 cases of topical adapalene use during pregnancy identified in clinical trials (60 cases) or post-marketing (276 cases) surveillance including four (4) that occurred in the Actual Use study.

The largest number of exposures during pregnancy in Galderma studies occurred in a 12-month trial conducted in support of the registration of Differin Gel in Japan. In this study there were 14 pregnancies reported. Pregnancy outcomes included normal delivery for 9 subjects, premature delivery for 2 subjects, miscarriage for 1 subject, intra-uterine death for 1 subject, and elective abortion for 1 subject. None of the (11) babies born had any malformation or illness.

There were no pregnancies reported in the original controlled-studies to support approval of the NDA for Differin Gel or the recent maximal use pharmacokinetic study (Study 18254).

Table 20: Distribution of Pregnancy Outcomes According to the Time of Inclusion in the Pharmacovigilance Database and to Sources of Notification

Prospectivea Cases Retrospectiveb Cases Outcome / Source Post-Marketing Clinical Trial Post-Marketing Clinical Trial Surveillance Surveillance Ongoing 27 1 0 0 Lost to Follow-up 126 12c 0 0 Healthy baby 83 26 0 0 Elective abortion 2 2c 5 10 Miscarriage 4 3 12 4 Other abnormal outcomes 2 1 15 1 Totals 244 45 32 15 a Prospective means to watch for outcomes during the study period. b Retrospective means to look backwards and examine exposure to suspected risk or protection factors c Includes cases reported in the Actual Use Study. 3 subjects were lost to follow-up and 1 elective abortion was reported.

Malformations that are characteristic of retinoid embryopathy from oral tretinoin and isotretinoin include: small/malformed/missing external ears; short lower jaw; cleft palate; defects of the outflow tract of heart; ocular anomalies involving retina and/or optic nerve; hydrocephalus; and thymus defects.16,27 To look for potential retinoid-induced malformations, the cases of malformation during exposure to adapalene were carefully examined. The observed anomalies were very different from one another and no specific pattern was identified: Fallot tetralogy, unilateral kidney agenesis, anophthalmia with agenesis of optic chiasma, Aarskog syndrome (a monogenic X-linked recessive disorder), multiple malformations, VACTERL association, and functional defects. The potential causative role of adapalene was considered questionable or was excluded in all. In some cases other explanations were identified and in others the information was too scarce to lead to any conclusion.

It is highly likely that not all exposed pregnancies were identified, and that the notification process was biased towards adverse outcomes: normal pregnancies are less likely to be reported

Page 51 NDA20380    NONPRESCRIPTIONADAPALENE0.1% BRIEFINGDOCUMENTFORAPRIL15,2016    TOPICALGEL NONPRESCRIPTIONDRUGSADVISORYCOMMITTEE than those resulting in an adverse outcome. To attempt to address this, outcome rates were calculated from the prospectively identified cases; that is to say the population included only those in whom the pregnancy outcome was not known at the time of notification of exposure during pregnancy. There were 123 such cases available from the 289 identified prospective exposures, taking into account the 138 lost to follow-up and 28 ongoing and the time of reporting as described in Table 21.

Table 21: Outcomes of Prospectively Identified Pregnancies

Pregnancy Outcome Post-marketing Clinical Trials Total Rate (%) Surveillance Elective abortion 2 2 4 3.3 Miscarriage 4 3 7 5.7 Among births 85 27 112 Healthy birth 83 26 109 97.3 Malformation 2 0 2 1.8 Other abnormal outcome (abruption placenta and 0 1 1 0.8 fetal death) Total 91 32 123

While these rates have to be compared with other datasets only with caution, several observations can be made. Major structural or genetic birth defects affect approximately 3% of births in the United States.28 In the prospectively identified cases of adapalene-exposure during pregnancy, malformations occurred in 1.8% of the full-term infants and there was no identifiable pattern of malformations (hydrops fetalis and Fallot tetralogy). Further these malformations are not reportedly associated with teratogenicity induced by oral retinoid therapy.16, 27

The rate of 5.7% for miscarriages is consistent with the reported rate of approximately 6% in the United States.29

Although these data are limited and not sufficient to draw a strong conclusion when taken in isolation, the outcomes reported are supportive of the lack of reproductive toxicity of adapalene resulting from the preclinical and pharmacokinetic programs.

5.5.5 Evaluation of Additional Data Sources

In addition to the data collected by Galderma described previously, external sources of data related to adapalene use during pregnancy were also searched in early 2015 including the FDA Adverse Event Reporting System (FAERS) database, VigiBase (WHO database) and published literature. The majority of cases identified were already included in Galderma’s database summarized previously. Eight (8) new cases of exposure to adapalene during pregnancy, not in Galderma’s database, were identified in the FDA and/or WHO databases and three (3) included information related to malformations following exposure of the mother to adapalene. Further evaluation revealed that the malformations may have been regarding the mother, not the neonate,

Page 52 NDA20380    NONPRESCRIPTIONADAPALENE0.1% BRIEFINGDOCUMENTFORAPRIL15,2016    TOPICALGEL NONPRESCRIPTIONDRUGSADVISORYCOMMITTEE other suspect concomitant medications were used or the malformations reported were not known to be associated with teratogenicity induced by oral retinoids.

A literature review, searching for adapalene and cases of potential human teratogenicity, was conducted in July, 2015 and identified one new article with detailed clinical findings. The focus of this publication was an evaluation of human data regarding the outcomes of topical retinoid- exposed pregnancies for the purpose of counseling pregnant women who had experienced exposure with an objective of determining whether exposure to topical retinoids is an increased risk for adverse pregnancy outcomes. In this publication, a search was described, using MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from inception to December, 2014 and a meta-analysis was conducted. The selection, review and quality assessment of the studies were carried out by two independent reviewers according to predetermined inclusion criteria. Odds ratios (OR) were calculated by the random effects method.30

This meta-analysis, which included a total of 654 pregnant women who were exposed to topical retinoids and 1375 unexposed control pregnant women, did not detect significant increases in rates of major congenital malformations (odds ratio [OR], 1.22; 95% confidence interval [Cl], 0.65-2.29), spontaneous abortions (OR, 1.02; 95% CI, 0.64-1.63), stillbirth (OR, 2.06; 95% CI, 0.43-9.86), elective termination of pregnancy (OR, 1.89; 95% CI 0.52-6.80), low birth weight (OR, 1.01; 95% CI, 0.31- 3.27) or prematurity (OR, 0.69; 95% CI, 0.39-1.23). No significant heterogeneity was detected among the studies for the evaluated outcomes. This meta-analysis included only 24 subjects exposed to adapalene and noted one major malformation in adapalene- exposed subjects (anophtalmia) not known to be associated with systemic retinoid therapy.

The conclusion of the systematic review and meta-analysis was that notable increases in the risk of major congenital malformations, spontaneous abortions, low birth weight and prematurity after inadvertent exposure to topical retinoids during the first trimester of pregnancy were excluded. The findings are also consistent with the data on exposure to topical adapalene during pregnancy described previously in this document. Although the statistical power was not adequate to justify the recommended use of topical retinoids during pregnancy, the author concluded that the findings could be used to reassure women who had been exposed to topical retinoids during their pregnancy.

5.5.6 Summary of Teratogenic Risk

Due to differences in molecular structure, members of the retinoid class exhibit varying biologic activity and the teratogenic effects of retinoids are exposure related. The pharmacology, animal and clinical pharmacokinetic studies described herein establish a clinically important safety margin for Differin Gel, even under maximal use conditions. This safety margin is supported by the absence of a human teratogenicity signals despite the extensive marketed drug use. Although the current OTC pregnant and breastfeeding mother’s warning is required only for drugs intended for systemic absorption, which would not include topical Differin Gel, Galderma has proposed to include this same warning (“if pregnant or breastfeeding, ask a health professional before use”) in the Differin Gel nonprescription label. This well-established language appears on many OTC medications today.

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5.6 Other Safety Considerations

5.6.1 Potential Off-Label Use Differin Gel has only been approved and marketed as a prescription medication for the treatment of acne and there are no additional indications for adapalene approved globally. Topical retinoids, including adapalene, have been studied for the treatment of fine lines, wrinkles, photoaging and other dermatoses such as hyperpigmentation. Topical tretinoin, also a retinoid, is approved by the FDA as an adjunctive agent for use in the palliation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin. Salicylic acid and BPO, currently approved OTC acne medications, have also been studied and used to treat a variety of non-acne dermatoses.

5.6.1.1 Post-Marketing Surveillance

Post-marketing surveillance data obtained from adverse event reporting are collected and reviewed annually to monitor use of adapalene-containing drugs. During the review period of August, 2013 to July, 2014, thirty-four (34) cases of off-label use were identified, which is consistent with usage identified in prior years which has shown an average rate of less than 50 reported cases per year. The most common off-label use was lightening of the skin and included eight (8) cases that were described as brightening (chemical peeling, lightening acne marks) and exfoliation of skin.

5.6.1.2 Clinical Studies Involving Use of Adapalene for Conditions Other than Acne

Two clinical studies of note have been identified that evaluated adapalene for conditions other than acne. One study evaluated adapalene use for the treatment of actinic keratosis and lentigines and enrolled 90 subjects, with 83 completing nine (9) months of treatment with either adapalene 0.1% gel, adapalene 0.3% gel or vehicle.17 In addition, a 6-month open-label study was also conducted that evaluated the safety and efficacy of adapalene 0.3% gel in the treatment of cutaneous photoaging.18 In this study 40 subjects were enrolled and 35 subjects completed 6 months of treatment.

No new safety risks were identified in these clinical studies and the commonly reported side effects aligned to those reported for acne treatment including dry skin, erythema, skin irritation and skin discomfort.17-18

5.6.1.3 Actual Use Study Results An actual use study was conducted to understand how Differin Gel would be used in an unsupervised OTC environment and was one of the studies required by FDA to support the proposed Rx-to-OTC switch of the drug. The results of this study, described further in Section 6.2, provide additional insights into the usage of Differin Gel by consumers.

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5.6.1.4 Summary of Off-Label Use Safety Considerations Nonprescription Differin Gel will only be labeled to treat acne. Consumer study results described herein have shown that people understand the indication for Differin Gel and how to use it, as expected for an existing, well-established OTC condition such as acne. Although off- label use can occur with any OTC drug, the risks of it occurring with adapalene are low, and the clinical sequelae of any off-label use are also low as any adverse events associated with such use would be dermatologic and generally mild, similar to those that can occur during acne treatment.

5.6.2 Concomitant Use with Other Acne Medications and Topical Products Studies have shown that adapalene concentrates in the epidermis and within hair follicles, resulting in very low percutaneous absorption.11 Due to this low systemic absorption of adapalene following topical administration, Galderma did not perform drug-drug interaction studies in support of the approved NDAs for adapalene-containing products previously described.

In addition, no drug interactions of clinical relevance have been identified throughout the more than 20-years of clinical investigations and marketing of adapalene-containing drugs. Consumers undergoing treatment for acne, either under the care of physicians or self-diagnosing, typically use multiple products such as facial washes, medicated or non-medicated, and moisturizers. BPO is approved for use with adapalene in a fixed-dose prescription drug with a safety profile that has been demonstrated in controlled clinically studies. Thus, there are no safety concerns about co-use of adapalene and BPO products in the OTC setting.

The prescription label for Differin Gel includes the following information:

As DIFFERIN Gel has the potential to produce local irritation in some patients, concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices, or lime) should be approached with caution. Particular caution should be exercised in using preparations containing sulfur, resorcinol, or salicylic acid in combination with DIFFERIN Gel. If these preparations have been used, it is advisable not to start therapy with DIFFERIN Gel until the effects of such preparations in the skin have subsided.

Concomitant use with other acne medications could lead to increased irritation. This is also true of other approved topical OTC acne treatments and thus the currently approved OTC Topical Acne Drug Products monograph warning of “When using this product skin irritation and dryness is more likely to occur if you use another topical acne medication at the same time” was proposed by Galderma for the nonprescription label. The other specific agents mentioned in the prescription label (avoidance of medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices, or lime) are general recommendations for treating acne with topical medications. The same is also true for the recommendation to exercise caution when using sulfur, resorcinol or salicylic acid in combination with Differin Gel. No reports of drug interactions have been reported clinically, or noted during the post-marketing period, and Galderma has thus elected to

Page 55 NDA20380    NONPRESCRIPTIONADAPALENE0.1% BRIEFINGDOCUMENTFORAPRIL15,2016    TOPICALGEL NONPRESCRIPTIONDRUGSADVISORYCOMMITTEE align the proposed DFL to the current OTC Topical Acne Drug Products Monograph rather than include additional details regarding concomitant use that could potentially confuse the consumer.

5.6.3 Carcinogenesis and Mutagenesis Carcinogenicity studies with adapalene have been conducted in mice at topical doses of 0.3, 0.9, and 2.6 mg/kg/day. No treatment-related tumors were observed in the mouse even though the highest adapalene dose tested exceeded the maximal tolerated dose. Similarly, no signs of potential carcinogenicity were identified in rat studies. Carcinogenicity studies with adapalene have also been conducted in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day, approximately 4 to 75 times the maximal daily human topical dose. In these studies, positive linear trends were observed in the incidence of follicular cell adenomas and carcinomas in the thyroid glands of female rats, and in the incidence of benign and malignant pheochromocytomas in the adrenal medullas of male rats at high oral doses.

Galderma also conducted searches for cases of cancer following use of adapalene within the Galderma global adverse event database as well as the published literature, FDA FAERS and WHO databases. Four (4) cases were identified with no association to adapalene use suspected.

The data collected in both animal studies and post-marketing surveillance support the conclusion that topical Differin Gel is not a carcinogen.

Adapalene also did not exhibit mutagenic or genotoxic effects in vitro (Ames test, Chinese hamster ovary cell assay, mouse lymphoma TK assay) and in vivo (mouse micronucleus test).

5.6.4 Phototoxicity Differin Gel was neither phototoxic nor photoallergenic in guinea pigs after skin exposure to UV irradiation. In addition, other adapalene formulations were also tested and found neither phototoxic nor photoallergenic in guinea pigs after skin exposure to UV irradiation. No phototoxic or photoallergenic reactions were recorded in clinical phototoxicity studies or other clinical studies including long-term studies. Adapalene, unlike some topical retinoids, is photochemically stable and non-phototoxic. Studies have also found that adapalene did not have enhancing effects on UVB erythema and thus no increased sunburn risk.32 Adapalene can also be used in combination with BPO due to higher stability against oxidation.25 Consistent with the prescription labeling, the nonprescription label warns that exposure to excessive sunlight or UV irradiation should be avoided as part of general skin care advice for consumers with acne.

5.6.5 Lactation Clinical pharmacokinetic studies have demonstrated that systemic availability of topical adapalene is minimal, however, it is not known whether Differin Gel is excreted in human milk.

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Galderma has proposed to include the codified (and thus FDA mandated) OTC pregnant and breastfeeding mother’s warning “if pregnant or breastfeeding, ask a health professional before use” in the Differin Gel nonprescription label. Although this OTC pregnant and breastfeeding mother’s warning is required only for drugs intended for systemic absorption, which would not include topical Differin Gel, Galderma has conservatively proposed to include this statement. This well-established language appears on many OTC medications today.

6 DEVELOPMENT OF NONPRESCRIPTION DIFFERIN GEL

Acne is a well-established OTC category. Currently approved nonprescription topical acne medications are applied in a similar manner to Differin Gel and have been used by consumers for decades. Thus, self-diagnosis and self-selection were not a focus during the OTC development program. Rather, the studies conducted focused on key differences between existing OTC acne medication labeling and that of Differin Gel, primarily in the directions for use including once- daily application. This is important because current nonprescription acne medications are labeled for use up to three-times daily. A comparison of the proposed Nonprescription DFL for Differin Gel and a DFL for a representative acne product labeled according to the OTC Topical Acne Drug Products Monograph is provided in Figure 5.

Figure 5: Proposed Nonprescription DFL for Differin Gel and DFL for a Representative Acne Product Labeled According to the OTC Topical Acne Drug Products Monograph

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To evaluate consumer understanding and behavior, the following consumer studies were conducted: x A Label Comprehension study to primarily evaluate novel labeling information in the proposed nonprescription Differin Gel label (Study 100544); x An Actual Use study to evaluate consumer behavior as they use the product over time in a simulated actual use environment (Study 100931); and x A Targeted Self-Selection study to provide information on the effectiveness of the codified (currently required by law) OTC warning statement for pregnant or breast- feeding women proposed for the Differin Gel label (Study 103439). This study was conducted despite the totality of the evidence supporting safety if used during pregnancy.

6.1 Label Comprehension Testing A pivotal Label Comprehension Study was conducted in accordance with the FDA Guidance for Industry: Label Comprehension Studies in Nonprescription Drug Products to assess consumer comprehension of key communication messages in the DFL. The DFL is required by FDA and is designed to use simple language and an easy-to-read format to help people compare and select OTC medicines and follow dosage instructions. As the proposed nonprescription Differin Gel OTC label includes some elements from the existing OTC Topical Acne Drug Products monograph, the label comprehension studies conducted focused primarily on differences in the labeling to ensure consumer understanding. An annotated version of the proposed Differin Gel DFL, showing the origin of statements included, is provided as Appendix 2. A copy of the current Prescribing Information is provided as Appendix 3.

Galderma developed and refined the DFL through a series of four (4) iterative label comprehension pre-tests with a total of 141 subjects. The DFL was then evaluated in the pivotal label comprehension study in 586 unique subjects, 12 years of age and older. There were two (2) populations: the General Population (Cohort 1, N=515) and the Low Health Literacy Population (Cohort 2, N=130). The Low Health Literacy group comprised 22.2% of all study subjects and included 59 subjects from the General Population plus 71 subjects enrolled via targeted recruitment. Literacy levels were assessed using the REALM test or REALM-Teen test.

The General Population (N=515) was comprised of 304 females (59.0%) and 211 males (41.0%). Subject ages were distributed among those who were 12 to 24 years of age (53.8%; n=277), 25 to 54 years of age (34.0%; n=175) and 55+ years of age (12.2%; n=63).

The Low Health Literacy Population (N=130) was comprised of 61 females (46.9%) and 69 males (53.1%). Subject ages were distributed among those who were 12 to 24 years of age (63.1%; n=82), 25 to 44 years of age (12.3%; n=16) and 45+ years of age (24.6%; n=32).

There were two (2) primary communication objectives related to important warnings and directions and 10 secondary objectives conveying important considerations regarding product use:

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Primary communication objectives:

1. Do not use: On damaged skin (cuts, abrasions, eczema, sunburned) 2. Directions: Use once daily

Secondary communication objectives:

Use of the medication:

3. For the treatment of acne, clears up acne pimples and acne blemishes, helps prevent new acne pimples and acne blemishes from forming

When using this product:

4. Avoid unnecessary sun exposure, including tanning beds, and use a sunscreen when going outdoors (only tested the “including tanning beds” portion of this warning since all other wording is currently used on OTC acne medications)

Irritation (redness, itching, dryness, or burning) is more likely to occur:

5. In the first few weeks of use 6. If using more than one topical acne medication at a time 7. Moisturizers may be used to relieve dry skin 8. During the early weeks of use your acne may appear to worsen before it improves. This is not a reason to stop using 9. Do not use wax to remove hair in the areas where the product has been applied

Stop use and ask a doctor:

10. If irritation becomes severe

Directions:

11. Ages 12 and older 12. Under 12 years of age, consult a physician

Label comprehension scores for the 2 primary communication objectives within the General Population exceeded the pre-specified 85% lower bound (LB) threshold. The 85% lower bound threshold was selected due to the fact that these are novel instructions (i.e. not in the OTC Topical Acne Drug Products monograph) and they gave important information about proper use. These endpoints do not represent serious safety concerns; however, increased irritation could occur if the product is used on damaged skin or more than once daily. Based on these factors, the threshold was set at a lower bound of 85%.

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The General Population subjects achieved 97.5% correct comprehension (502 of 515 subjects; LB 95.7%) for the objective “Do not use on damaged skin (cuts, abrasions, eczema, sunburned)” and 95.9% correct comprehension (494 of 515 subjects; LB 93.8%) for the objective “Directions: Use once daily”.

Among the General Population, correct scores for 8 of the 10 secondary communication objectives in this study ranged from 87.6% (451 of 515 subjects) to 100.0% (515 of 515 subjects). In accordance with the Guidance for Industry: Label Comprehension Studies for Nonprescription Drug Products (August 2010), no LB thresholds were set for the secondary objectives. Results for these 8 secondary objectives were as follows: x Objective: “Use of the medication: For the treatment of acne, clears up acne pimples and acne blemishes, helps prevent new acne pimples and acne blemishes from forming” (515 of 515 subjects, 100.0%) x Objective: “Directions: Ages 12 and older” (510 of 515 subjects; 99.0%) x Objective: “When using this product, do not use wax to remove hair in the areas where the product has been applied” (507 of 515 subjects; 98.4%) x Objective: “When using this product, avoid unnecessary sun exposure, including tanning beds, and use a sunscreen when going outdoors” (only tested the “including tanning beds” portion of this warning; all other wording is in the final OTC Topical Acne Drug Products monograph; 502 of 515 subjects; 97.5%) x Objective: “When using this product, moisturizers may be used to relieve dry skin” (493 of 515 subjects; 95.7%) x Objective: “Under 12 years of age, consult a physician” (483 of 515 subjects; 93.8%) x Objective: “When using this product, irritation (redness, itching, dryness, burning) is more likely to occur in the first few weeks of use” (481 of 515 subjects; 93.4%) x Objective: “When using this product, during the early weeks of use your acne may appear to worsen before it improves. This is not a reason to stop using” (451 of 515 subjects; 87.6%)

The lowest scoring secondary objectives were: x “Stop use and ask a doctor if irritation becomes severe” (GP 77.5%; n=399) and x “When using this product, irritation (redness, itching, dryness, burning) is more likely to occur if using more than one topical acne medication at a time” (GP 62.7%; n=323).

When acceptable verbatim responses are included, the point estimates for the correct scores increase to 87.0% and 84.7%, respectively. Although some lack of comprehension was identified this is unlikely to lead to increased clinical risk. It is important to note that these two statements are both taken from the OTC Topical Acne Drug Products monograph and appear on nonprescription acne medications today.

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Results for both primary and secondary objectives were very similar by literacy subgroups when the General Population scores were compared to the Total Population and when Normal Literacy scores were compared to Low Literacy scores (results provided in Appendices 4 and 5, respectively).

In adolescents 12 to 17 years of age, rates of comprehension were similar to those for the General Population (see Appendix 6).

In conclusion, the pivotal label comprehension study conducted demonstrated that the proposed labeling is generally well-understood, which is expected for an existing OTC condition such as acne. Key differences in the Differin Gel label, such as the direction to use the product once daily and avoid damaged skin, were well understood by both normal literacy and low literacy subgroups.

6.2 Actual Use Study An observational, single-arm, open-label, 6-week Actual Use study (Study 100931) was conducted to evaluate ongoing use behavior in subjects 12 years of age and older who self- reported having acne and who represented potential consumers of Differin Gel. The primary rationale for the actual use study was to evaluate frequency of use (as Differin Gel is a once-daily medication compare to current OTC acne medications which can be used up to three-times daily), what indications the product will be used for and how much drug will be used.

6.2.1 Study Design The study was conducted at 31 geographically dispersed pharmacies in the United States and was to have included approximately 1200 male and female subjects who self-reported acne. The cohort included a population of low literacy subjects. The REALM test or REALM-Teen test was used to determine literacy level.

The sample size was selected to allow for broad representation of the intended user population as well as to accommodate a range of behaviors that could be expected if the product were to obtain OTC status. In order to achieve 800 completed subjects, approximately 1200 subjects were to be enrolled in the study. The type 1 error rate is set at 5% (95% CI) resulting in the 85% lower bound threshold. The samples size of 800 achieves a 99% study power based on a 90% point- estimate. The study is overpowered to ensure adequate power based on the subjects who ultimately complete the actual use portion of the trial.

The primary objectives were:

x To evaluate the frequency of use (i.e., no more than once daily in the same location).

x To determine whether the product was used for acne only (i.e., not off-label use).

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The secondary objectives were:

x To evaluate if the product was used on the correct body areas (i.e., was not used on damaged skin and contact with eyes, lips, and mouth were avoided).

x To determine if pregnant or breastfeeding women stated they would ask a health professional before use as instructed in the warnings section of the Drug Fact Labels.

Other data collected included extent of exposure (amount of product used), use on eczematous skin, concomitant medications and adverse events.

Mass advertising (radio, television, newspaper, and/or community outreach) was used to recruit the study subjects. A simple and non-leading message was used in the advertising (e.g., “Do you have acne? People of all races and ages get acne.” If so, you may qualify for a study. Please call 1-800-XXX-XXXX.”). Consumers who were interested in participating in the study were to call the number in the advertisement for minimal screening; qualified subjects were referred to a participating pharmacy site.

Consistent with methods for actual use studies on OTC products, the advertising referenced the product indication (acne) with no other details. Once approved, this product will be located on the retail shelving with other OTC acne medications and will be labeled only for acne. Alternative recruitment methods were considered, such as recruiting any subjects interested in taking part in a clinical study for skin conditions, but these methods were deemed not to be appropriate to predict OTC use by consumers.

Upon arrival at the pharmacy site, the subjects signed a Health Insurance Portability and Accountability Act (HIPAA)/Confidentiality Agreement. The subjects were given the Differin Gel OTC package to review at their own pace and then were asked whether they would like to purchase the product (for $7.00) to use at home.

Subjects who answered “No” to the purchase decision question, or were ineligible to participate based on exclusion criteria (e.g., were pregnant) had their demographics recorded, provided a targeted medical history, underwent a clarification query and an end-of-study medical history then exited the study.

Subjects who answered “Yes” to the purchase decision question provided their informed consent (subjects 18 years of age and older) or assent (subjects 12-17 years of age). Female subjects of childbearing potential then self-administered a urine pregnancy test. The Central Medical Operations Group (CMOG), which is a centralized group of medical professionals trained in conducting research, obtained a medical history for each subject via telephone interview. Based on the inclusion/exclusion criteria, the obtained medical history, and the pregnancy test result (if applicable), the CMOG physician determined whether to allow the subjects to continue and approve dispensing of the study product. Approved subjects were enrolled and entered the Actual Use period of the study and a diary was dispensed.

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The diary was to be used to record when and on what part of the body the study product was used, as well as any changes in medical conditions or concomitant medications. It should be noted that subjects were not instructed as to how to apply the study product or for what condition the study product should be used, but rather took the product home to use as they normally would if it was an approved OTC product. Subjects were permitted to return to the pharmacy site to repurchase additional study product at any time during the Actual Use period.

One 45 gram tube is generally expected to last the six-week period but, to evaluate usage, a maximum purchase limit of two (2) tubes per visit and three (3) tubes total per subject was established. The diary was collected at the time of repurchase and a new diary was dispensed. Over the six-week treatment period, the subjects reported any AEs, which were then followed-up by the CMOG as necessary. At the completion of the Actual Use period, each subject came to the pharmacy site for a final visit, returned the study diary along with any used or unused study product, completed the final clarification query (if applicable), and marked a body chart to show where the study product had been applied. A follow-up pregnancy test was administered to female subjects of childbearing potential and all subjects were administered a final medical history questionnaire. Subjects were reimbursed for their time and expense, as well as the study product they purchased; however, no subject knew in advance that they would be reimbursed for their study product purchases. Any ongoing AEs were followed-up as necessary and any new AEs were identified prior to the subject exiting the study.

There were two primary endpoints in this study. One was the proportion of subjects who used the product no more than once daily in the same body area and the other was the proportion of subjects who used the product only for acne (i.e., not “off-label”). The rationale for these endpoints was to evaluate the potential for over-use of the study product (i.e., more than 1 use per day in the same area) or off-label use of the study product (i.e., use for a purpose other than the treatment of acne) in purchasers with acne. These endpoints, while important, do not represent significant safety concerns. Thus, the success thresholds for the primary endpoints were set at a lower bound of 85%, which would be observed at a point estimate of approximately 90% based on 800 subjects.

The secondary endpoints included the proportion of subjects who used the study product on the correct body area (i.e., did not use the study product on damaged skin and avoided contact with the eyes, lips, and mouth) and a determination of whether pregnant or breastfeeding women would state that they would ask a health professional before use. Consistent with other consumer studies, there were no success thresholds established for the secondary endpoints. In particular, the pregnancy/breastfeeding warning was set as a secondary endpoint for several reasons:

x A separate, targeted self-selection study was conducted in pregnant and breastfeeding women; x The warning tested in both the targeted self-selection study and the current actual use study is an established codified warning that is usually not tested in consumer studies because the FDA mandates its use by law; and x Preclinical and clinical data summarized above support the safety of topical adapalene if used during pregnancy.

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When applicable, a priori mitigations (considering an incorrect action a correct action) were applied to the primary and secondary outcome responses. These mitigations were applied for specific behaviors only if clinically reasonable. Examples include a subject changing behavior after a single incorrect use of the study product or an understanding that the subject applied the study product accidentally. A priori mitigating factors were developed and considered in the final overall scores for the primary and secondary endpoints.

Since it is not possible to anticipate all responses that may be given by subjects, not all mitigations can be identified a priori. Therefore, additional post-study mitigations were also identified based on an assessment of actual subject responses.

Tabular summaries of the intended study product uses, the corresponding actual uses that triggered mitigation, and the rationale for mitigation are presented for the primary and secondary endpoints in Table 22 (primary endpoints, a priori mitigations), Table 23 (secondary endpoints, a priori mitigations), and Table 24 (post-study mitigations).

For the primary and secondary endpoint assessments, the number and proportion of subjects who initially provided correct responses were tabulated, as were the numbers and percentages of subjects who had their incorrect responses mitigated based on a priori and post-study reviews. The number and percentage of subjects who had a final correct actual use was then computed by combining the number of subjects with initially correct behaviors, the number of subjects with a priori mitigations, and the number of subjects with post-study mitigations.

A summary of the study flow is presented in Table 25.

Table 22: A Priori Mitigations – Primary Endpoints

Intended Use Actual Use/Mitigation Trigger Rationale for Mitigation No more than once daily Used product > 1 time/day only Did not initially see/understand the warning, once but only used > 1 time/day on one occurrence. Subject was using the study product for a For acne only (i.e., not off- The study product was previously purpose previously approved/prescribed by a label) for another indication physician

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Table 23: A Priori Mitigations – Secondary Endpoints

Intended Use Actual Use/Mitigation Trigger Rationale for Mitigation Adolescent under the age of Subject within 12 months of Very close to age range specified for study 12 years selects to use the labeled age range (i.e., age 11) product use, with no safety risk product, but consults a physician prior to use Apply to correct body areas (do not use on damaged skin, Contact with eyes, lips, or mouth 1-2 occurrences that were accidental avoid contact with eyes, lips, was accidental and not intended (i.e., unintentional use in these areas) and mouth) Apply to correct body areas Subject reported eczema Subject had eczema, but not in the area where the (do not use on eczema) study product was applied Subject reported eczema in the Subject applied the product on the area where she area where the study product was typically gets eczema, but currently did not have applied an eczematous rash in that area Pregnant or breastfeeding Pregnant subject decided to Subject was not aware that she was pregnant until women will state that they purchase the product at Visit 1 after the self-administered pregnancy test at will ask a health professional Visit 1 before use as instructed in Subject used the product Subject was not aware that she was pregnant until the Warnings section of the throughout the study, but had a after the self-administered pregnancy test at drug facts label positive pregnancy test at Visit 2 Visit 2 Pregnant or breastfeeding subject Subject was previously prescribed the study decided to purchase the product product by a physician with instructions for use during pregnancy or while breastfeeding

Table 24: Poststudy Mitigations – Primary and Secondary Endpoints

Intended Use Actual Use/Mitigation Rationale for Mitigation Trigger No more than once daily in Used late at night or had a Misuse was not intentional; subject adjusted study the same location change in schedule product use based on work schedule and showering/preparation in the morning, which sometimes resulted in more than 1 application in a 24-hour period (e.g., applied after midnight and again in the morning) Re-read directions and Misuse was not intentional; subject re-read the changed behavior directions and changed behavior For acne only (i.e., not off- Acne in same area as Subject may have used the study product in the same label) another condition area as another condition, but the primary purpose was to treat acne, not to treat the other condition Used “near” an area noted Subject reported using study product to treat acne near Apply to correct body areas in the warning, but not the area restricted by the warning (e.g., near the corners (do not use on damaged skin, “on” the area of the mouth), but not on or in that area avoid contact with eyes, lips, Applied to “damaged Subject reported having damaged skin; upon further and mouth) skin”, but skin was not evaluation, it was determined that the damage was damaged dryness from study product use

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Table 25: Actual Use Study Flow

Procedures Screening Visit 1 Use Period Visit 2 / (Call Center) Day 0 Days 1-42 Study (±6 days) Close Out Day 43 (±7 days) Prescreening via Telephone Subject will respond to advertisement (1-800-#) X Call center will conduct minimal screening X Call center will refer potential subject to participating pharmacy site X Part 1 – Purchase Decision Site will assign subject number X Subject will review and sign HIPAA/Confidentiality Agreement X Subject will review DFL X Site will ask purchase decision and probe X Site will administer ICF/assent (PD = Yes) X Subject will self-administer an OTC urine pregnancy test (female of X childbearing potential only) (PD = Yes) HIPAA/Confidentiality Agreement, PD, ICF/assent, and Pg test X results will be reviewed by CMOG CMOG will collect demographics, medical history and X inclusion/exclusion criteria For subjects with PD = Yes, CMOG will review actual use exclusion X criteria For excluded subjects or PD = No, CMOG will ask clarification probe X Site will administer REALM/REALM-Teen test X Part 2 – Actual Use Site will explain diary to subject X Subject will pay for and receive study product X Subject will use study product for 6 weeks at home X Subject will repurchase study product (if desired) X Subject will record usage on a diary at home X Subject will report and CMOG will follow-up on AEs/SAEs X Subject will take follow-up OTC urine pregnancy test (females of X childbearing potential only) Subject completes body chart X CMOG will administer end-of-study medical history X CMOG will ask clarification probe X Site will conduct study drug accountability X Site will reimburse subjects for time, travel, and product purchase X X AE = adverse event; CMOG = Central medical Operations Group; DFL = Drug Facts Label; HIPAA = Health Insurance Portability and Accountability Act; ICF = Informed Consent Form; PD = purchase decision; Pg test = pregnancy test; REALM = Rapid Estimate of Adult Literacy in Medicine; REALM-Teen = Rapid Estimate of Adolescent Literacy in Medicine; SAE = serious adverse event

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6.2.2 Disposition of Subjects Of the 1277 subjects who were screened, 947 subjects comprised the safety population and 938 subjects completed the study. Subject disposition is provided in Table 26.

330 subjects of the 1277 subjects (25.8%) were excluded from the actual use/safety populations and the most common reasons for exclusion included: choosing not to purchase the study product (169 subjects [13.2%]), screen failure (104 subjects [8.1%]), and lost to follow-up (41 subjects [3.2%]).

In this population of “all comers” with acne, subjects of any age could enter the study. Although not eligible for participation in the Actual Use period of the study, any subject less than 12 years of age who arrived at the pharmacy site for Visit 1 was permitted to make a purchase decision. In total, seven (7) subjects less than 12 years of age attended Visit 1. Of those subjects, two (2) correctly stated that they either would not purchase the study product (one (1) subject) or would need to speak to a healthcare professional prior to using the study product (one (1) subject). The remaining five (5) subjects stated they would purchase the product.

Taking the difference in sample sizes into consideration, the proportions of subjects in the normal literacy and low literacy groups were similar in regard to exclusion from the actual use/safety populations, reasons for exclusion, and study completion.

6.2.3 Actual Use Results

6.2.3.1 Demographics and Baseline Characteristics Of the 947 subjects in the actual use population, most were female (67.9%), most were white (52.0%), and most were not Hispanic/Latino (88.1%) (see Table 27). The mean (standard deviation [SD]) age of the subjects was 29.9 (12.72) years (range: 12-73 years). Overall, 203 subjects were 12-17 years of age and 744 subjects were 18 years of age or older. A majority of the adult subjects in the actual use population either had some college or technical school training (30.1%) or graduated from college or technical school (24.3%); however, 17.4% had not completed any college or technical training (14.3% completed high school and 3.1% had not completed high school.) In the normal literacy group, the largest percentage of subjects had some college or technical school training (31.4%), while in the low literacy group, the largest percentage of subjects completed high school or a General Education Development program (32.0%).

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Table 26: Subject Disposition (All Entered Subjects)

Normal Low Category All Subjects Literacy Literacy All Subjects Entered 1277 1047 189

Actual Use Population/Safety Populationa 947 (74.2) 822 (78.5) 125 (66.1) Exclude from Actual Use Population/Safety Populationa 330 (25.8) 225 (21.5) 64 (33.9) Reason for Excluding from Actual Use Population/Safety Populationa Purchase Decision = No 169 (13.2) 119 (11.4) 35 (18.5) Actual Use Screen Failure 104 (8.1) 71 (6.8) 18 (9.5) Subject Withdrew Consent 1 (0.1) 1 (0.1) 0 Lost to Follow-up 41 (3.2) 30 (2.9) 11 (5.8) Adverse Event 1 (0.1) 1 (0.1) 0 Other 14 (1.1) 3 (0.3) 0

Completed Actual Use Periodb 938 (99.0) 813 (98.9) 125 (100) Discontinued from Actual Use Periodb 9 (1.0) 9 (1.1) 0 Reason for Discontinuation from Actual Use Periodb Adverse Event 8 (0.8) 8 (1.0) 0 Other 1 (0.1) 1 (0.1) 0 a Percentages are based on the number of enrolled subjects in each literacy group. b Percentages are based on the number of subjects in actual use/safety population in each literacy group. The count of all subjects entered into the study includes all subjects who had Visit 1 data. The actual use population included all subjects who had Visit 1 data, purchased the study product to take home, and used the study product at least once. The safety population included all subjects from the actual use population. Subjects without literacy data collected are included only in the “All Subjects” column. None of these subjects were included in the safety population.

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Table 27: Subject Demographics and Baseline Characteristics (Actual Use Population)

All Subjects Normal Literacy Low Literacy Variable (N = 947) (N = 822) (N = 125) Age (years) Mean (SD) 29.9 (12.72) 29.6 (12.47) 31.6 (14.21) Median 28.0 28.0 28.0 Min, Max 12,73 12,73 12,64

Age group, n (%) 12-17 years 203 (21.4) 181 (22.0) 22 (17.6) • 18 years 744 (78.6) 641 (78.0) 103 (82.4)

Sex, n (%) Male 304 (32.1) 244 (29.7) 60 (48.0) Female 643 (67.9) 578 (70.3) 65 (52.0)

Race, n (%) White 492 (52.0) 452 (55.0) 40 (32.0) Black or African American 321 (33.9) 259 (31.5) 62 (49.6) American Indian or Alaska Native 12 (1.3) 12 (1.5) 0 Asian 25 (2.6) 23 (2.8) 2 (1.6) Native Hawaiian or Other Pacific Islander 6 (0.6) 6 (0.7) 0 Other 88 (9.3) 67 (8.2) 21 (16.8) Refused 3 (0.3) 3 (0.4) 0

Ethnicity, n (%) Hispanic or Latino 113 (11.9) 89 (10.8) 24 (19.2) Not Hispanic or Latino 834 (88.1) 733 (89.2) 101 (80.8)

Education, Adults Only, n (%) 744 (78.6) 641 (78.0) 103 (82.4) Did Not Complete High School 29 (3.1) 18 (2.2) 11 (8.8) Completed High School/GED 135 (14.3) 95 (11.6) 40 (32.0) Some College/Technical School 285 (30.1) 258 (31.4) 27 (21.6) Graduated College/Technical School or More 230 (24.3) 207 (25.2) 23 (18.4) Postgraduate Studies 58 (6.1) 57 (6.9) 1 (0.8) Other 7 (0.7) 6 (0.7) 1 (0.8) GED = General Education Development; max = maximum; min = minimum; SD = standard deviation Percentages are based on the number of subjects in the actual use population in each column category.

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To be included in the Actual Use period of the study, all subjects must have made a positive purchase decision. Of the 947 subjects in the actual use population, 919 (97.0%) made the decision without asking the advice of a healthcare professional (Table 28). There were 28 subjects (3.0%) who did ask a healthcare professional before use; most of these subjects (20) asked a pharmacist and, with one (1) exception, were in the normal literacy group. The eight (8) subjects who did not ask a pharmacist asked a study doctor, physician’s assistant, or nurse (seven (7) subjects), or a personal health professional (1 subject). The three (3) most commonly asked questions of the pharmacist included information about the study product ingredient (9 of 20 subjects), whether the study product could be used with other medications (4 of 20 subjects), and possible side effects of the study product (2 of 20 subjects). The most commonly asked questions of the study doctor, physician’s assistant, or nurse included information about the study product ingredient (2 of 7 subjects) and possible side effects (2 of 7 subjects). The subject who asked a personal health professional asked for information about the study product ingredient.

Table 28: Purchase Decision Characteristics (Actual Use Population)

All Subjects Normal Literacy Low Literacy Purchase Decision (N = 947) (N = 822) (N = 125) Yes 919 (97.0) 795 (96.7) 124 (99.2) Asked a Health Professional 28 (3.0) 27 (3.3) 1 (0.8) Asked a Study Doctor, PA, or Nurse 7 (0.7) 6 (0.7) 1 (0.8) Information about the ingredient 2 2 0 Side Effects 2 2 0 OK to use with other acne medication/treatment 1 0 1 Safety 1 1 0 The “2” on the front of the box 1 1 0 Asked a Pharmacist 20 (2.1) 20 (2.4) 0 Information about the ingredient 9 9 0 Side Effects 2 2 0 OK to use with other acne medication/treatment 1 1 0 Safety 1 1 0 The “2” on the front of the box 1 1 0 Location/use on broken/damaged skin 1 1 0 OK to use with other medications 4 4 0 OK to use as antifungal 1 1 0 Asked a Personal Health Professional 1 (0.1) 1 (0.1) 0 Information about the ingredient 1 1 0 PA = physician’s assistant Percentages are based on the number of subjects in the actual use population in each column category.

Thirteen additional subjects asked a health professional at Visit 1, but did not enter into the actual use period of the study. Of these 13 subjects, six (6) talked with a study doctor, six (6) talked with a pharmacist, and one (1) talked with a personal health professional. Most of the questions posed by the subjects were related to drug-drug interactions (5 of 13 subjects), while additional questions included, among other things, inquiries about other medical conditions (1 of 13 subjects) and whether it was acceptable to use the study product if pregnant/breastfeeding (1 of 13 subjects).

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Health literacy was assessed using the REALM test in subjects 18 years of age and older, and the REALM-Teen test in subjects 12-17 years of age. Raw scores from the REALM test correspond to the health literacy levels shown in Table 29. For the REALM-Teen test, scores were expressed as grade-level estimates of reading skill and were then compared with the subject’s actual current grade level to determine if the assessed reading skills were below grade level, which would indicate lower literacy. Raw scores from the REALM-Teen test correspond to the health literacy levels shown in Table 30.

Table 29: Health Literacy Interpretation for the REALM Test

Raw Score Grade Range Equivalent Literacy Skills 0-60 7th/8th Grade and Below Low Literate 61-66 High School and Above Normal Literate

Table 30: Health Literacy Interpretation for the REALM-Teen Test

Raw Score Grade Range Equivalent Literacy Skills 0-37 3rd Grade and Below Will have a 5-fold greater likelihood of reading below grade level; may be at risk for school failure 38-47 4th Grade to 5th Grade 48-58 6th Grade to 7th Grade Will struggle with most patient education materials; may have skills to pass a General Education Development program 59-62 8th Grade to 9th Grade 63-66 10th Grade and Above Will be able to read most patient education materials

In this study, the mean (SD) REALM score for adults was 64.4 (1.35) in the normal literacy group (range: 61-66) and 52.5 (10.08) in the low literacy group (range: 10-60) (Table 31). The mean (SD) REALM-Teen score for subjects 12-17 years of age was 62.7 (3.71) in the normal literacy group (range: 42-66) and 51.3 (10.19) in the low literacy group (range: 27-62).

Table 31: REALM and REALM-Teen Test Scores (Actual Use Population)

All Subjects Normal Literacy Low Literacy Variable (N = 947) (N = 822) (N = 125) REALM Score, n 744 641 103 Mean (SD) 62.7 (5.68) 64.4 (1.35) 52.5 (10.08) Median 64.0 65.0 57.0 Min, Max 10, 66 61, 66 10, 60

REALM-Teen Score, n 203 181 22 Mean (SD) 61.4 (5.97) 62.7 (3.71) 51.3 (10.19) Median 63.0 64.0 53.5 Min, Max 27, 66 42, 66 27, 62 REALM = Rapid Estimate of Adult/Adolescent Literacy in Medicine; SD = standard deviation Percentages are based on the number of subjects in the actual use population in each column category.

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6.2.3.2 Primary Endpoints

6.2.3.2.1 Evaluation of once daily use Based on final actual use determinations, 844 of the 947 subjects (89.1%) in the actual use population used the study product no more than once daily in the same location (95% confidence interval [CI] = 87.0%, 91.0%) (Table 32). Since the lower limit of the 95% CI was > 85%, the endpoint result was considered successful.

The proportions of subjects in the normal literacy and low literacy groups who used the study product correctly were similar (89.1% and 89.6%, respectively). When considered by age, 90.6% of the subjects who were 12-17 years of age and 88.7% of the subjects who were • 18 years of age used the study product correctly. Thus, approximately 90% of the subjects used the study product no more than once daily in the same location, irrespective of literacy level or age.

Table 32: Analysis of Once Daily Use in the Same Location (Final Correct Actual Use, Actual Use Population)

Normal Category All Subjects Literacy Low Literacy 12-17 Years • 18 Years Statistics (N = 947) (N = 822) (N = 125) (N = 203) (N = 744) Subjects Who Used the Study Product No More Than Once Daily in the Same Locationa n (%) 844 (89.1) 732 (89.1) 112 (89.6) 184 (90.6) 660 (88.7) 95% CI (87.0, 91.0) (86.7, 91.1) (82.9, 94.3) (85.8, 94.3) (86.2, 90.9) CI = confidence interval a Final corrected actual use was calculated as the number of subjects who had an overall correct behavior for the primary use objectives (initial use behavior + a priori mitigation + poststudy mitigation) divided by the number of subjects in the population who used the product. The CIs are based on binomial 2-sided 95% Clopper-Pearson Exact CIs.

The correct actual use determination was based on a combination of the initial correct use behavior, the a priori mitigation, and the post-study mitigation. Of the 844 subjects who had a final correct actual use determination, 767 (90.9%) had an initially correct use, 61 (7.2%) had an a priori mitigation, and 16 (1.9%) had a post-study mitigation.

In all cases of a priori mitigations, the reason for mitigation was that the subjects used the study product more than once daily, but did so only one time (61 of 61 mitigations). The reasons for post-study mitigations were associated with a subject using the study product late at night or changing their daily schedule (12 of 16 mitigations), or changing their behavior after re-reading the packaging directions (4 of 16 mitigations).

The percentages of subjects who initially used the study product correctly were similar in the normal literacy and low literacy groups (90.4% and 93.8%, respectively). The percentages were also similar for subjects who were 12-17 years of age and for subjects who were • 18 years of age (90.8% and 90.9%, respectively).

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Subjects who had a final incorrect actual use determination most commonly used the study product each time they showered or washed their face (37 of 103 subjects [35.9%]), applied more product hoping to improve acne faster (29 of 103 subjects [28.2%]), or misused the product in order to treat acne that was considered by the subject to be more severe (22 of 103 subjects [21.4%]).

6.2.3.2.2 Evaluation of use exclusively in acne Based on final correct actual use determinations, 938 of 945 subjects (99.3%) in the actual use population used the study product only to treat acne (95% CI = 98.5%, 99.7%) (Table 33). Since the lower limit of the 95% CI was > 85%, the endpoint result was considered successful.

The proportions of subjects in the normal literacy and low literacy groups who used the study product correctly were similar (99.3% and 99.2%, respectively). When considered by age, 99.5% of the subjects who were 12-17 years of age and 99.2% of the subjects who were • 18 years of age used the study product correctly. Thus, nearly 100% of the subjects used the study product only for acne, irrespective of literacy level or age.

Table 33: Analysis of Exclusive Use in Acne (Final Correct Actual Use, Actual Use Population)

Normal Category All Subjects Literacy Low Literacy 12-17 Years • 18 Years Statistics (N = 947) (N = 822) (N = 125) (N = 203) (N = 744) Subjects Who Used the Study Product Only for Acnea n/m (%)b 938/945c (99.3) 814/820 (99.3) 124/125 (99.2) 202/203 (99.5) 736/742 (99.2) 95% CI (98.5, 99.7) (98.4, 99.7) (95.6, 100) (97.3, 100) (98.2, 99.7) CI = confidence interval a Final corrected actual use was calculated as the number of subjects who had an overall correct behavior for the primary use objectives (initial use behavior + a priori mitigation + post-study mitigation) divided by the number of subjects in the population who used the product. b m is the number of subjects in the population who used the study product and had a non-missing assessment. c 2 subjects did not complete all procedures at Visit 2 thus 945 subject responses were available for some endpoints The CIs are based on binomial 2-sided 95% Clopper-Pearson Exact CIs.

Of the 938 subjects who had a final correct actual use determination, 933 (99.5%) were initially assessed as correct use, zero (0) had an a priori mitigation, and five (5) (0.5%) had a post-study mitigation. All five (5) post-study mitigations were associated with subjects applying the study product in the same area as acne in order to treat the acne, but also having a separate condition in the same area, such as rosacea they were not intending to treat.

The percentages of subjects who were initially assessed as using the study product correctly were similar in the normal literacy and low literacy groups (99.4% and 100%, respectively). The percentages were also similar for subjects who were 12-17 years of age and for subjects who were • 18 years of age (100% and 99.3%, respectively).

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Six of the seven (7) subjects who had a final incorrect actual use determination used the study product to treat something other than acne (eczema [2 subjects], and anti-aging, pore size reduction, psoriasis, and under-eye puffiness [1 subject each]) because they thought it would help. The remaining subject indicated she had “dark spots” and wanted to try the study product.

6.2.3.3 Secondary Endpoints

6.2.3.3.1 Use on correct body area Based on final correct actual use determinations, 921 of the 945 subjects (97.5%) in the actual use population used the study product on the correct body location (i.e., was not used on damaged skin and contact with eyes, lips, and mouth were avoided; 95% CI = 96.2%, 98.4%) (Table 34). The proportions of subjects in the normal literacy and low literacy groups who used the study product correctly were similar (97.4% and 97.6%, respectively). When considered by age, 95.6% of the subjects who were 12-17 years of age and 98.0% of the subjects who were • 18 years of age used the study product correctly. Thus, approximately 97% of the subjects used the study product on the correct body location, irrespective of literacy level or age.

Table 34: Analysis of Use on the Correct Body Area (Final Correct Actual Use, Actual Use Population)

Normal Category All Subjects Literacy Low Literacy 12-17 Years • 18 Years Statistics (N = 947) (N = 822) (N = 125) (N = 203) (N = 744) Subjects Who Used the Study Product on the Correct Body Areasa n/m (%) 921/945c (97.5) 799/820 (97.4) 122/125 (97.6) 194/203 (95.6) 727/742 (98.0) 95% CI (96.2, 98.4) (96.1, 98.4) (93.1, 99.5) (91.8, 98.0) (96.7, 98.9) CI = confidence interval a Final corrected actual use was calculated as the number of subjects who had an overall correct behavior for the primary use objectives (initial use behavior + a priori mitigation + post-study mitigation) divided by the number of subjects in the population who used the product. b m is the number of subjects in the population who used the study product and had a non-missing assessment. c 2 subjects did not complete all procedures at Visit 2 thus 945 subject responses were available for some endpoints The CIs are based on binomial 2-sided 95% Clopper-Pearson Exact CIs.

Of the 921 subjects who had a final correct actual use determination, 908 (98.6%) were initially assessed as correct use, nine (9) (1.0%) had an a priori mitigation, and four 4 (0.5%) had a post- study mitigation. Among the cases of a priori mitigations, nine (9) subjects had mitigations for applying the study product to the wrong body area only once (7 subjects) or twice (2 subjects). The reasons for post-study mitigations were associated with a subject using the study product near the area with acne, such as on the corners of the mouth (3 of 4 mitigations) or on dry skin (1 of 4 mitigations).

The percentages of subjects who initially used the study product correctly were similar in the normal literacy and low literacy groups (98.5% and 99.2%, respectively). The percentages were also similar for subjects who were 12-17 years of age and for subjects who were • 18 years of age (100% and 98.2%, respectively).

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6.2.3.3.2 Analysis of women who were pregnant or breastfeeding at purchase The proposed Differin Gel DFL and study product labeling includes the codified pregnancy/breastfeeding warning (21 CFR Part 201.63[a]), which states:

“If pregnant or breastfeeding, ask a health professional before use.”

This warning is included on the labeling of the numerous currently marketed OTC medications and is usually not tested in consumer studies since it has been considered a sufficient warning on nonprescription medications since 1999. Nevertheless, it was tested in this study to provide data regarding the potential use of the product by women who are pregnant or breastfeeding. A more comprehensive evaluation of this statement was conducted in the Targeted Self-Selection study described in Section 6.3 of this document.

Nearly half (43.9%) of the study population was comprised of women of childbearing potential. At Visit 1, six (6) women were pregnant and 10 women were breastfeeding. An analysis of the purchase decisions made by these 16 women is presented in Table 35. Within the table, the numbers and percentages of the women with initially correct purchase decisions, a priori mitigations, and overall correct and incorrect purchase decisions are shown. (Note that the number of women with overall correct purchase decisions is the sum of the women with initially correct purchase decisions and those mitigated as correct.) The analysis is presented for the 16 women in total, within categories of pregnant and breastfeeding women, and by literacy level and age category.

Of the six (6) women at Visit 1 who were pregnant, one (1) correctly stated she should ask a health professional before using the study product. Two of the women did not know they were pregnant until the pregnancy test was administered; these women were mitigated as correct since they could only act on the information they had at the time of their purchase decision. The remaining three (3) women did not specifically state (unprompted) that they would ask a health professional before using the study product; these women were scored as having an incorrect purchase decision. None of the pregnant women were permitted to enter the actual use period of the study.

Of the 10 women at Visit 1 who were breastfeeding, four (4) correctly stated they should ask a health professional before using the study product. Of the remaining six (6) women, one (1) was mitigated as correct, as she had been prescribed the study product in the past by her physician and was not taken off the study product while breastfeeding, and five (5) were scored as having an incorrect purchase decision, as they did not specifically state (unprompted) that they would ask a health professional before using the study product. None of the breastfeeding women were permitted to enter the actual use period of the study.

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Table 35: Analysis of Women Who Were Pregnant or Breastfeeding at Visit 1 (Purchase Decision)

Normal Low All Subjectsa Literacyb Literacyb 12-17 Years • 18 Years Category (N = 16) (N = 14) (N = 1) (N = 0) (N = 16) Statistics n (%) n (%) n (%) n (%) n (%) Pregnant or breastfeeding women who 16 14 1 0 16 tried to enter the study Initial Correct 5 (31.3) 5 (35.7) 0 0 5 (31.3) A Priori Mitigation 3 (18.8) 2 (14.3) 0 0 3 (18.8) Overall Correct 8 (50.0) 7 (50.0) 0 0 8 (50.0) Incorrect (did not give unprompted 8 (50.0) 7 (50.0) 1 (100.0) 0 8 (50.0) response)

Pregnant Women 6 4 1 0 6 Initial Correct 1 (16.7) 1 (25.0) 0 0 1 (16.7) A Priori Mitigation (did not know she 2 (33.3) 1 (25.0) 0 0 2 (33.3) was pregnant) Overall Correct 3 (50.0) 2 (50.0) 0 0 3 (50.0) Incorrect (did not give unprompted 3 (50.0) 2 (50.0) 1 (100.0) 0 3 (50.0) response)

Breastfeeding Women 10 10 0 0 10 Initial Correct 4 (40.0) 4 (40.0) 0 0 4 (40.0) A Priori Mitigation (previously 1 (10.0) 1 (10.0) 0 0 1 (10.0) prescribed) Overall Correct 5 (50.0) 5 (50.0) 0 0 5 (50.0) Incorrect (did not give unprompted 5 (50.0) 5 (50.0) 0 0 5 (50.0) response) a Includes only women who were pregnant or breastfeeding at Visit 1. b One subject did not take the REALM Test.

6.2.3.4 Amount of Product Purchased Subjects in the Actual Use study were permitted to purchase up to three 45 gram tubes of Differin Gel, with a maximum of two tubes at any one time. Based on normal use estimation of between 0.5 and 1 gram per day, one 45 gram tube of product was expected to last the duration of the study although this was not communicated to the study subjects. In this study 886 of 947 subjects (93.6%) purchased only one tube while 57 subjects (6%) purchased two (2) tubes and four (4) subjects (0.4%) purchased 3 tubes. These results demonstrate that the vast majority of acne consumers will purchase one 45 gram tube for use over a 6-week period.

6.2.3.5 Adverse Events Nearly all of the subjects (938 of 947 subjects [99.0%]) who were included in the actual use/safety population completed the six-week actual use period. The nine (9) subjects who discontinued did so primarily due to AEs (8 of the 9 subjects). These events included acne

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(3 subjects), skin exfoliation (2 subjects), dry skin (1 subject), erythema and pruritus (1 subject), and erythema and skin irritation (1 subject).

Overall, 471 of the 947 subjects (49.7%) in the actual use population experienced at least one (1) self-reported AE during the study (see Table 36). The largest percentage of subjects (88.3% [416 of 471]) reported AEs that were mild in severity. This was true within both literacy levels and both age categories. Five subjects reported severe adverse events. The specific events, which were reported by 1 subject each, included asthma, headache, migraine, sinusitis, and viral infection; none were considered related to study drug. All of the severe events were reported by subjects in the normal literacy group who were t18 years of age.

A majority of the subjects (57.7% [272 of 471]) who had AEs had AEs that were not considered by the CMOG to be related to the study drug. There were no SAEs reported during the study. Four subjects had positive pregnancy tests at the Study Close-Out visit and these pregnancies were reported as AEs (outcomes included in Section 5.5.4; Table 20).

Table 36: Overview of Treatment-Emergent Adverse Events (Actual Use Population)

All Subjects Normal Literacy Low Literacy 12-17 Years • 18 Years Category (N = 947) (N = 822) (N = 125) (N = 203) (N = 744) Any TEAE 471 (49.7) 422 (51.3) 49 (39.2) 114 (56.2) 357 (48.0)

TEAE by Highest Severity Mild 416 (43.9) 372 (45.3) 44 (35.2) 103 (50.7) 313 (42.1) Moderate 50 (5.3) 45 (5.5) 5 (4.0) 11 (5.4) 39 (5.2) Severe 5 (0.5) 5 (0.6) 0 0 5 (0.7)

TEAE by Highest Relationship Not Related 272 (28.7) 239 (29.1) 33 (26.4) 66 (32.5) 206 (27.7) Related 199 (21.0) 183 (22.3) 16 (12.8) 48 (23.6) 151 (20.3)

SAE 0 0 0 0 0

TEAE Leading to Study 8 (0.8) 8 (1.0) 0 3 (1.5) 5 (0.7) Discontinuation SAE = serious adverse event; TEAE = treatment-emergent adverse event A subject having the same AE more than once in the category over the course of the study was counted only once. The percentages are based on the number of subjects in the actual use population in each column category.

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A tabulation of the AEs reported by 1% or more of all subjects in the actual use population is shown in Table 37.

Table 37: Adverse Events by System Organ Class and Preferred Term Occurring in • 1% of the Subjects Overall (Actual Use Population)

All Normal Low System Organ Class Subjects Literacy Literacy 12-17 Years • 18 Years

Preferred Term (N = 947) (N = 822) (N = 125) (N = 203) (N = 744) Any TEAE 471 (49.7) 422 (51.3) 49 (39.2) 114 (56.2) 357 (48.0) Skin and Subcutaneous Tissue Disorders 210 (22.2) 193 (23.5) 17 (13.6) 51 (25.1) 159 (21.4) Dry Skin 100 (10.6) 93 (11.3) 7 (5.6) 25 (12.3) 75 (10.1) Erythema 44 (4.6) 39 (4.7) 5 (4.0) 8 (3.9) 36 (4.8) Skin Exfoliation 38 (4.0) 36 (4.4) 2 (1.6) 9 (4.4) 29 (3.9) Skin Burning Sensation 37 (3.9) 35 (4.3) 2 (1.6) 15 (7.4) 22 (3.0) Acne 30 (3.2) 27 (3.3) 3 (2.4) 6 (3.0) 24 (3.2) Pruritus 19 (2.0) 14 (1.7) 5 (4.0) 4 (2.0) 15 (2.0) Skin Irritation 17 (1.8) 15 (1.8) 2 (1.6) 6 (3.0) 11 (1.5) Rash 14 (1.5) 14 (1.7) 0 2 (1.0) 12 (1.6) Skin Fragility 9 (1.0) 9 (1.1) 0 2 (1.0) 7 (0.9) Nervous System Disorders 179 (18.9) 164 (20.0) 15 (12.0) 39 (19.2) 140 (18.8) Headache 155 (16.4) 143 (17.4) 12 (9.6) 35 (17.2) 120 (16.1) Migraine 19 (2.0) 19 (2.3) 0 2 (1.0) 17 (2.3) Injury, Poisoning and Procedural 79 (8.3) 65 (7.9) 14 (11.2) 30 (14.8) 49 (6.6) Complications Sunburn 28 (3.0) 23 (2.8) 5 (4.0) 13 (6.4) 15 (2.0) Laceration 18 (1.9) 13 (1.6) 5 (4.0) 9 (4.4) 9 (1.2) Skin Abrasion 10 (1.1) 10 (1.2) 0 5 (2.5) 5 (0.7) Infections and Infestations 62 (6.5) 57 (6.9) 5 (4.0) 12 (5.9) 50 (6.7) Nasopharyngitis 34 (3.6) 30 (3.6) 4 (3.2) 7 (3.4) 27 (3.6) Gastrointestinal Disorders 49 (5.2) 48 (5.8) 1 (0.8) 16 (7.9) 33 (4.4) Abdominal Pain Upper 12 (1.3) 11 (1.3) 1 (0.8) 6 (3.0) 6 (0.8) Immune System Disorders 48 (5.1) 45 (5.5) 3 (2.4) 15 (7.4) 33 (4.4) Seasonal Allergy 36 (3.8) 34 (4.1) 2 (1.6) 10 (4.9) 26 (3.5) Musculoskeletal and Connective Tissue 43 (4.5) 42 (5.1) 1 (0.8) 11 (5.4) 32 (4.3) Disorders Back Pain 21 (2.2) 20 (2.4) 1 (0.8) 4 (2.0) 17 (2.3) Reproductive System and Breast Disorders 40 (4.2) 38 (4.6) 2 (1.6) 11 (5.4) 29 (3.9) Dysmenorrhoea 38 (4.0) 36 (4.4) 2 (1.6) 11 (5.4) 27 (3.6) Respiratory, Thoracic and Mediastinal 34 (3.6) 30 (3.6) 4 (3.2) 10 (4.9) 24 (3.2) Disorders Oropharyngeal Pain 10 (1.1) 10 (1.2) 0 2 (1.0) 8 (1.1) General Disorders and Administration Site 18 (1.9) 17 (2.1) 1 (0.8) 3 (1.5) 15 (2.0) Conditions Pain 9 (1.0) 8 (1.0) 1 (0.8) 1 (0.5) 8 (1.1) TEAE = treatment-emergent adverse event A subject having the same event (as determined by the coded preferred term) more than once over the course of the study was counted only once in the incidence calculation for that event. Similarly, if a subject had more than 1 event in a system organ class, the subject was counted only once for that system organ class. All percentages are based on the number of subjects in actual use population in each column category.

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6.2.3.6 Conclusion

In conclusion, Differin Gel, when applied once daily for six (6) weeks in the treatment of acne in an unsupervised setting was used appropriately. The drug was used as instructed by the label at an acceptable rate and there were no trends or potential safety concerns that would alter the known safety profile of the study product. The study results were consistent regardless of subgroup evaluated including age and literacy level.

6.3 Targeted Self-Selection Study As established previously, topical Differin Gel poses no risks to the fetus if used during pregnancy. However, a self-selection study was designed to determine if pregnant and breast- feeding subjects age 13 or older with self-reported acne could make a correct self-selection decision based on the codified (and thus FDA mandated) OTC pregnancy and breastfeeding mother’s warning “if pregnant or breastfeeding, ask a health professional before use”.

6.3.1 Study Design

The self-selection study was conducted in 293 unique pregnant and/or lactating subjects 13 years of age and older who self-reported having acne. To identify participant health literacy levels, the REALM test was administered to subjects ages 18 and older and the REALM-Teen test was administered to subjects 13-17 years of age. Following the REALM test, each subject was provided the Adapalene 0.1% Gel OTC package (Principal Display Panel and DFL) and given an opportunity to review it and answer questions either by an interviewer or on-line survey. Pregnancy was confirmed via urinary pregnancy test at the end of the interview for subjects who were 18 or older.

Recruitment and data collection were managed by 26 facilities (25 malls and 1 specialty site) across the United States. Female subjects were randomly approached in a retail mall setting and individuals meeting minimal screening criteria (e.g., age 18 and older, do not work in a healthcare field, etc.) were invited to a research facility for the self-selection interview. Female subjects who were 13-17 years old were invited to complete an online survey during regular interactions the teen had with the specialty site; they were given the opportunity to complete this survey independently and in a private room.

Primary Objective

The primary objective was to evaluate self-selection in a targeted population who have acne and who were also pregnant or breastfeeding.

Secondary Objective

The secondary objective of this study was to assess reasons for incorrect self-selection.

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6.3.2 Study Population

Two (2) cohorts with subjects 13 years of age and older were recruited and interviewed for this study: a General Population and a Low Health Literacy Population. A total of 293 unique subjects completed the study.

Literacy levels were assessed using the REALM or REALM-Teen tests. Of the 112 subjects in the Low Health Literacy Cohort, 61 subjects came from the General Population and an additional 51 subjects enrolled through targeted recruitment.

1) Cohort 1: General Population of Females, 13 years of age and older, pregnant or breastfeeding (GP; N=242) 2) Cohort 2: Low Health Literacy Population Females, 13 years of age and older, pregnant or breastfeeding (LL; N=112)

Most subjects in Cohorts 1 and 2 were breastfeeding only (62.4% in Cohort 1 and 58.9% in Cohort 2), 18 to 34 years of age, and Caucasian. Approximately one-third of subjects were pregnant only (33.1% in Cohort 1 and 34.8% in Cohort 2). Finally, 4.5% of subjects in Cohort 1 and 6.3% of subjects in Cohort 2 said they were both pregnant and breastfeeding. Nineteen percent (19.0%) of subjects in Cohort 1 and 22.3% of subjects in Cohort 2 were of Hispanic origin. There were two (2) subjects between the ages of 13 years and 17 years in Cohort 1.

6.3.3 Study Results Upon reading the warning concerning pregnancy/breastfeeding, subjects were asked if it was okay for them to use the medication or not and the reason for their response. A 95% endpoint was set based on the expectation that this labeling was familiar to consumers as it appears on OTC medications today. The final correct self-selection point estimate for the study population (Cohort 1) was 74.4% (n=180) and the LB of the 2-sided 95% confidence limit was 68.4%.

Those of Lower Health Literacy had similar, but lower, correct self-selection compared with the Normal Health Literate (i.e., 78.5% vs. 70.5% point estimate).

Final self-selection scores for females who were pregnant, females who were breastfeeding, and females who were both pregnant and breastfeeding were quite similar (i.e., 72.9% vs. 76.6% vs. 76.9%, respectively).

Conclusion

In this study, about three quarters (74%) of pregnant or breastfeeding women who self-reported acne stated that they would ask a health professional prior to using Differin Gel. The final correct self-selection point estimate (PE) for the general population was 74.4% (n=180) and the lower bound (LB) of a two-sided 95% confidence limit was 68.4%. The primary endpoint (95% correct) was therefore not met.

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The statement evaluated in this study is a standard warning that has long use with a large number of OTC products that are currently marketed. Although these study results support the fact that the currently codified (required by law) and used OTC warning statement proposed for the Differin Gel labeling is generally understood and followed, not all pregnant or breast-feeding women who would consider using Differin Gel or other medications with this warning may adhere to the labeled direction. However, as comprehensively reviewed previously, Differin Gel is not associated with fetal risk if used during pregnancy.

6.4 Conclusions of Differin Gel Nonprescription Development Program

The consumer behavior studies conducted by Galderma confirmed that consumers understand the proposed DFL and can use Differin Gel, according to the DFL in an unsupervised OTC environment, as expected for an existing, well-established OTC condition such as acne. Consumers demonstrated that they would use the product once daily, on the correct body areas and for the indication of acne. Importantly, consumers used the product once daily for the label indication with only rare exceptions. None of the scenarios of mis-comprehension or label non- heeding identified posed clinically relevant safety concerns.

6.5 Differin Gel Nonprescription DFL

The proposed DFL for nonprescription Differin Gel, developed from the prescription label, current OTC Topical Acne Drug Products monograph and consumer studies is provided in Figure 6. The proposed Differin Gel consumer leaflet is provided in Appendix 7.

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Figure 6: Proposed Differin Gel Nonprescription DFL

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7 BENEFIT AND RISK CONSIDERATIONS

7.1 Benefits of Nonprescription Differin Gel Acne can profoundly impact quality of life, often resulting in significant physical and psychological morbidity, such as permanent scarring, poor self-image, depression, and anxiety.1 Early, effective treatment of acne is essential to prevent later complications including scarring and psychosocial burden.9, 19

Additional nonprescription acne treatment options are needed to more completely address this multi-factorial condition. No currently available OTC acne medication addresses the formation of the microcomedo or the underlying sub-clinical inflammation that may be present, aspects physicians are able to target through the use of topical retinoid prescription medications. In fact, topical retinoids are recommended as a first-line treatment for acne by dermatologists. BPO, primarily due to antimicrobial properties, is also recommended as a first-line treatment for mild acne while salicylic acid, sulfur and resorcinol, the other currently approved OTC acne active ingredients, are not recommended.1

Importantly, the efficacy of Differin Gel has been observed in a broad range of patients and skin types.20, 21 Differin Gel is an appropriate choice for patients with dark skin, and has been shown to reduce the post-inflammatory hyperpigmentation that is typically associated with inflammatory acne lesions in this population.22 It is also of note that Differin Gel employs a simplified regimen due to its once-daily use, whereas current OTC acne medications are labeled for use up to three times per day. This once daily regimen has the potential to promote patient compliance, an important factor in successful treatment of acne in an OTC setting.

Nonprescription Differin Gel would provide broad access to a once-daily, safe and effective treatment for acne, a common condition that can adversely impact the quality of life of acne sufferers, often leading to self-consciousness, depression, lack of confidence, embarrassment, shame and social withdrawal.

7.2 Adverse Event Profile of Differin Gel With regard to safety, the adverse events most commonly reported during use of Differin Gel are dermatologic in nature and local to treatment, such as: dry skin, erythema, scaling, burning and itching. These adverse events are most commonly seen during the first month of therapy and decrease in frequency and severity thereafter, are reported as mild in the majority of cases and typically resolve without additional medical intervention.

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7.3 Teratogenicity The animal and clinical pharmacokinetic studies described herein indicate a clinically important safety margin for risk with topical use, under normal or maximal use conditions. Further, a review of the pregnancies reported following use with adapalene has shown no increase in fetal malformations.

Although the current OTC pregnant and breastfeeding mother’s warning is required only for drugs intended for systemic absorption, which would not include topical Differin Gel, Galderma has proposed to include this same warning (“if pregnant or breastfeeding, ask a health professional before use”) in the Differin Gel nonprescription label. This well-established language appears on many OTC medications today.

7.4 Potential Off-label Use Topical retinoids have been studied for the treatment of fine lines, wrinkles, photoaging and other dermatoses such as hyperpigmentation. When used to treat these conditions the drug is applied in a similar manner (topically) as when treating acne. It is thus not surprising that no new safety risks have been identified when considering potential off-label use as the common side effects reported align to those observed during acne treatment (dry skin, erythema, itching and burning).

Differin Gel has been, and will continue to be in the nonprescription setting, marketed as an acne medication only and there are no additional indications for adapalene approved globally. Salicylic acid and BPO, currently approved OTC acne medications, have also been studied and used to treat a variety of non-acne dermatoses and although it remains possible that Differin Gel could be used off-label, there are no differentiating safety risks reportedly associated with this usage.

7.5 Other Safety Considerations Additional safety aspects that have been carefully considered include drug interactions, concomitant use with other acne products, phototoxicity and photoallergic potential. As described in this document, there are no significant risks, in any of these areas that would arise by switching to nonprescription usage.

Other safety considerations that are commonly considered when evaluating an Rx-to-OTC switch include the ability to self-diagnose and properly use the medication for the indicated condition, carcinogenicity, drug abuse and dependence. These aspects are not areas of concern for nonprescription Differin Gel.

7.6 Conclusion A comprehensive OTC development program was carried out to carefully evaluate nonprescription Differin Gel. The studies conducted demonstrate that Differin Gel is an acceptable candidate for broad nonprescription access without the oversight of a health care professional.

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Differin Gel is an ideal candidate for Rx-to-OTC switch and would fit well alongside current OTC acne medications based upon the following: 1. Adapalene has been available as a prescription drug in various dosage forms and strengths in the United States since 1996. Numerous clinical studies, coupled with vast post-market experience, have established an excellent safety profile for 'LIIHULQ*HO; 2. Differin Gel has been proven effective for the treatment of acne; 3. The drug is applied topically, similar to current OTC acne products, and requires no special handling or storage conditions; 4. Differin Gel has a different, dermatologist recommended, mechanism of action compared to current OTC medications and offers consumers another option for treating their acne; 5. Differin Gel meets all of the well-accepted criteria for evaluation of drugs for OTC use: ƒ The consumer must be able to recognize and diagnose the condition proposed to be treated x Consumers have self-treated their acne with topical OTC drugs for decades;

ƒ The consumer must be able to read and understand the product labeling to ensure proper usage x The proposed Differin Gel DFL is similar to current OTC acne labeling in many aspects and communicates key messages from the prescription label that consumer studies have demonstrated to be well understood;

ƒ The product must be effective when used as recommended x Numerous clinical studies have confirmed effectivenessDQG

ƒ ThedrugmustbesafeIRUVHOIXVH x Clinical pharmacokinetic studies confirm that the systemic exposure to topical adapalene is consistently very low, even under maximal use conditions, and large margins of safety exist to ensure that Differin Gel does not pose a risk of teratogenicity in a nonprescription environment; and x Adverse events are dermatologic in nature, local, transient, generally mild and become less frequent with continued treatment.

Galderma has provided data to demonstrate that consumers can safely and effectively use Differin Gel as directed in the proposed product labeling to treat their acne without healthcare professional supervision.

Nonprescription Differin Gel would provide broad access to a once-daily, safe and effective treatment for acne, a common condition that can adversely impact the quality of life of acne sufferers, often leading to self-consciousness, depression, lack of confidence, embarrassment, shame and social withdrawal.23

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8 LITERATURE REF ERENCES

1. Zaenglein et al. Guidelines on the Treatment of Acne. J AM Acad Dermatol. Published Online February, 2016. http://www.jaad.org/article/S0190-9622(15)02614-6/pdf 2. Dreno B, Poli F. Epidemiology of acne. Dermatology 2003;206(1):7-10. 3. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999;41(4):577-80. 4. Stathakis V, Kilkenny M, Marks R. Descriptive epidemiology of acne vulgaris in the community. Australas J Dermatol 1997;38(3):115-23. 5. Hay RJ, Johns NE, Williams HC, et al. The global burden of skin disease in 2010: an analysis of the prevalence and impact of skin conditions. J Invest Dermatol 2014;134(6):1527-34. 6. Webster GF. The pathophysiology of acne. Cutis 2005;76(2 Suppl):4-7. 7. Balkrishnan R, McMichael AJ, Hu JY, et al. Correlates of health-related quality of life in women with severe facial blemishes. Int J Dermatol 2006;45(2):111-5. 8. Barnes LE, Levender MM, Fleischer AB Jr, Feldman SR. Quality of life measures for acne patients. Dermatol Clin 2012;30(2):293-300. 9. Zaenglein, AL. Making the Case for Early Treatment of Acne. Clin Pediatr (Phila) 2010;49(1)54-59. 10. Medicated acne product market share data collected September, 2015 11. Czernielewski J, Michel S, Bouclier M, Baker M, Hensby JC. Adapalene biochemistry and the evolution of a new topical retinoid for treatment of acne. J Eur Acad Dermatol Venereol 2001;15 Suppl 3:5-12. 12. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad Dermatol 1997;36:S96-S103. 13. Advance Notice of Proposed Rulemaking; March 23, 1982 (47FR12430) 14. 21 CFR Part 333 Topical Antimicrobial Drug Products for Over-The-Counter Human Use, Subpart D – Topical Acne Drug Products 15. Ross SA, PJ McCaffery, UC Drager, LM De Luca (2000) Retinoids in embryonal development. Physiol Rev 80(3):1021-1054. 16. Soprano DR and KJ Soprano (1995) Retinoids as teratogens. Annu Rev Nutr 15:111-32. 17. Kang, et al. Assessment of Adapalene Gel for the Treatment of Actinic Keratoses and Lentigines: A Randomized Trial. J AM Acad Dermatol. July, 2003; 83-90. 18. Herane, et al. Clinical Ef¿cacy of Adapalene (Differin) 0.3% Gel in Chilean Women with Cutaneous Photoaging. J Dermatol Treat. 2012; 23: 57–64. 19. Gupta, et al. Psychiatric Aspects of the Treatment of Mild to Moderate Facial Acne. Intl J Dermatol. Dec, 1990. 29:10. 719-721. 20. Thiboutot D, Gollnick H, Bettoli V, et al. Global Alliance to Improve Outcomes in Acne. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol 2009;60(suppl 5):S1-S50. 21. Gollnick H, Cunliffe W, Berson D, et al; Global Alliance to Improve Outcomes in Acne. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol 2003;49(suppl 1):S1-S37. 22. Jacyk WK, Mpofu P. Adapalene gel 0.1% for topical treatment of acne vulgaris in African patients. Cutis 2001;68(4 Suppl):48-54.

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23. Alexis A, Daniels SR, Johnson N, Pompilus F, Burgess SM, Harper JC. Development of a new patient-reported outcome measure for facial acne: the Acne Symptom and Impact Scale (ASIS). J Drugs Dermatol. 2014;13(3):333-340. 24. Gollnick H, Schramm M. Topical therapy in acne. J Eur Acad Dermatol Venereol 1998;11 Suppl1:S8-12 25. Martin B, Meunier C, Montels D, Watts O. Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation. Br J Dermatol 1998;139 Suppl 52:8-11. 26. Ruberte E, Friederich V, Morriss-Kay G, Chambon P (Aug 1992). Differential distribution patterns of CRABP I and CRABP II transcripts during mouse embryogenesis. Development 115 (4): 973–987. 27. Lammer et al. Retinoic acid embryopathy. N Engl J Med. 1985 Oct 3;313(14):837-41. 28. Statistic Obtained from Center for Disease Control and Prevention Web-Site, accessed February 27, 2016, and is based upon data collected for Atlanta, Georgia from 1978 to 2005. 29. Gregory ECW, MacDorman MF, Martin JA. Trends in fetal and perinatal mortality in the United States, 2006–2012. NCHS data brief, no 169. Hyattsville, MD: National Center for Health Statistics. 2014. 30. Kaplan et al. Pregnancy Outcomes After Exposure to Topical Retinoids. British Journal of Dermatol (2015) 173, pp 1132-1141. 31. Nielsen research survey of acne sufferers (2015). 32. Cetiner et al. Phototoxic effects of topical azelaic acid, benzoyl peroxide and adapalene were not detected when applied immediately before UVB to normal skin. Eur J Derm 2004; 14:235-7. 33. Chernoff 2004 p437 Chernoff N, Rogers JM. Supernumerary ribs in developmental toxicity bioassays and in human populations: incidence and biological significance. J Toxicol Environ Health, Part B. 2004;7:437-49. 34. Foulon 2000 p205 Foulon O, Jaussely, C, Repetto M, Urtizberea M and Blacker AM. Postnatal evolution of supernumerary ribs in rats after a single administration of sodium salicylate. J Appl. Toxicol. 2000; 20:205-9.

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9 APPENDIX

Appendix 1 Topical Acne Drug Products Monograph Appendix 2 Annotated Drug Facts Label Appendix 3 Current Prescribing Information for Differin (adapalene) Gel, 0.1% Appendix 4 Label Comprehension Study: Analysis of Primary and Secondary Communication Objectives: General Population vs Total Study Population Appendix 5 Label Comprehension Study: Analysis of Primary and Secondary Communication Objectives: Normal Health Literacy Populations vs Low Health Literacy Population Appendix 6 Label Comprehension Study: Analysis of Primary and Secondary Communication Objectives: Teen Subjects vs. Adult Subjects of General Population Appendix 7 Proposed Differin Gel Consumer Leaflet

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Drug Facts Reference/Source

Active Ingredient Purpose Statement of identity (acne treatment) is $GDSDOHQH $FQHWUHDWPHQW identical to text included in the OTC Topical Acne Drug Products Monograph [21 CFR 333.350 (a)]

Uses Uses are identical to text included in the x )RUWKHWUHDWPHQWRIDFQH OTC Topical Acne Drug Products x &OHDUVXSDFQHSLPSOHVDQGDFQHEOHPLVKHV Monograph [21 CFR 333.350 (b)]

Warnings x )RUH[WHUQDOXVHRQO\ “For external use only” is identical to text  included in the OTC Topical Acne Drug  Products Monograph [21 CFR 333.350  (c)(i)]  Do not use Adapted from Prescribing Information and x RQGDPDJHGVNLQ FXWVDEUDVLRQVHF]HPD OTC Topical Acne Drug Products VXQEXUQHG  Monograph [21 CFR 333.350 (c)(2)(i)]  and FDA comments received  x ,ISUHJQDQWRUEUHDVWIHHGLQJDVNDKHDOWK Identical to text required for many current SURIHVVLRQDOEHIRUHXVH OTC drugs per 21 CFR 201.63(a).  Although this warning is only required for  drugs intended for systemic use, Galderma  is proposing to include this warning in the  DFL as an added precaution.  When using this product Adapted from Prescribing Information and x DYRLGXQQHFHVVDU\VXQH[SRVXUHLQFOXGLQJ OTC Topical Acne Drug Products WDQQLQJEHGVDQGXVHVXQVFUHHQZKHQJRLQJ Monograph [21 CFR 333.350 (c)(4)(ii)]. RXWGRRUV Adapalene has been shown to not have  phototoxic or photoallergic potential but  avoidance of sun is recommended during  acne treatment.  x LUULWDWLRQ UHGQHVVLWFKLQJGU\QHVVEXUQLQJ LV Adapted from: PRUHOLNHO\WRRFFXU o LQWKHILUVWIHZZHHNVRIXVH o Prescribing Information o LIXVLQJPRUHWKDQRQHWRSLFDODFQH o Prescribing Information and OTC PHGLFDWLRQDWDWLPH Topical Acne Drug Products  Monograph [21 CFR 333.350  (c)(1)(ii)]    

Page 94 x PRLVWXUL]HUVPD\EHXVHGWRUHOLHYHGU\VNLQ Adapted from Prescribing Information of  recent FDA-approved adapalene-  containing drugs including Differin Lotion  0.1% (NDA 22502) and Differin Gel 0.3%  (NDA 21753)  x DYRLGFRQWDFWZLWKH\HVOLSVDQGPRXWK,I Adapted from Prescribing information and FRQWDFWRFFXUVLPPHGLDWHO\IOXVKZLWKZDWHU OTC Topical Acne Drug Products  Monograph [21 CFR 333.350 (c)(3)]  x GXULQJWKHHDUO\ZHHNVRIXVH\RXUDFQHPD\ Adapted from Prescribing information DSSHDUWRZRUVHQEHIRUHLWLPSURYHVWKLVLVQRWD UHDVRQWRVWRSXVLQJWKHSURGXFW  x GRQRWZD[WRUHPRYHKDLULQDUHDVZKHUH Adapted from Prescribing Information of SURGXFWKDVEHHQDSSOLHG recent FDA-approved adapalene-  containing drugs including Differin Lotion 0.1% (NDA 22502) and Differin Gel 0.3% (NDA 21753)

Stop use and ask a doctor if Identical to text included in the OTC x LUULWDWLRQEHFRPHVVHYHUH Topical Acne Drug Products Monograph [21 CFR 333.350 (c)(4)(iii)] and also serves as a more consumer friendly equivalent of hypersensitivity statements in Prescribing Information

.HHSRXWRIUHDFKRIFKLOGUHQ,IVZDOORZHGJHW Required for all OTC drugs per 21 CFR PHGLFDOKHOSRUFRQWDFWD3RLVRQ&RQWURO&HQWHUULJKW 330.1(g) DZD\

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