Chemical Leukoderma Associated with Methylphenidate Transdermal System: Data From the US Food and Drug Administration Adverse Event Reporting System

Abstract

Objective

To identify and characterize cases of chemical leukoderma, an underrecognized adverse event, associated with the methylphenidate transdermal system (MTS) reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS).

Study design

We searched the Food and Drug Administration Adverse Event Reporting System for reports of chemical leukoderma associated with MTS, received by the Food and Drug Administration from April 6, 2006 to December 23, 2014.

Results

We identified 51 cases of chemical leukoderma reported with the use of MTS. The median age was 11 years; 43 cases reported leukoderma at or near the application site only, and 7 reported leukoderma at other parts of the body in addition to the application site; 1 case did not provide enough information to confirm the affected site. The time to onset ranged from 2 months to 4 years after the initiation of MTS. MTS was discontinued in 31 cases. Thirteen patients were prescribed treatment for repigmentation. Three cases reported continued spread of leukoderma after MTS was discontinued. Nineteen cases were diagnosed as vitiligo, including 5 cases reporting histologic features consistent with vitiligo. Leukoderma was persistent in all cases. The median follow-up interval after the discontinuation of MTS in 23 cases was 14 months.

Conclusions

As outlined in recent changes to the prescribing information for MTS, health care professionals need to be aware of the potential risk of chemical leukoderma caused by MTS, especially given that chemical leukoderma is often misdiagnosed as idiopathic vitiligo. MTS should be discontinued at the earliest sign of pigment loss and other treatment options considered.

Chemical leukoderma is an acquired depigmentation or hypopigmentation caused by repeated application of or exposure to a specific chemical that is toxic to epidermal melanocytes. This condition was first described by Oliver et al¹ as occupational leukoderma when rubber gloves that contained monobenzyl ether of hydroxyquinone caused skin depigmentation at the site of contact. Over the years, this condition has also been termed occupational vitiligo, occupational leukoderma, contact leukoderma, and chemical depigmentation until Hogan^2–6 first used the term chemical leukoderma in 1992. Ghosh and Mukhopadhyay⁷ published a definitive article in 2009 using the term chemical leukoderma, and this is now the more widely accepted term.

Chemical leukoderma is often misdiagnosed as idiopathic vitiligo. The histologic findings are similar in chemical leukoderma and vitiligo; the main finding is a scarcity or absence of melanocytes. As a result, the diagnosis is made usually on clinical grounds. The diagnosis of chemical leukoderma must include 3 of the following 4 criteria: (1) acquired vitiligo-like depigmented lesions, (2) history of repeated exposure to a specific chemical compound, (3) patterned vitiligo-like macules conforming to site of exposure, and (4) confetti macules. Occasionally, there may be distant spread of the depigmented lesions in addition to the site of contact.⁸

A wide variety of chemical products have been identified as causes, including monobenzyl ether of hydroquinone, adhesives, insecticides, and industrial chemicals. Prevention is the most important aspect of management, and further exposure to the offending agent must be avoided once the diagnosis is suspected. The depigmentation is generally persistent and may occasionally progress even after contact with the offending agent is discontinued.⁹ Spontaneous recovery may occur, but is not the norm, and treatment, as for vitiligo, is usually required.

Daytrana (methylphenidate transdermal system [MTS]; Noven Pharmaceuticals, Inc, Miami, Florida) is a patch indicated for the treatment of attention deficit-hyperactivity disorder (ADHD). MTS is an extended-release formulation administered once daily. MTS is currently the only ADHD medication available as a patch in the US, which offers an additional treatment option in young patients who cannot swallow pills.

Some of the most commonly reported adverse reactions in clinical trials with MTS included the well-known adverse reactions that occur with orally administered methylphenidate. In clinical trials, the majority of the subjects, in both the treatment and placebo groups experienced erythema at the application site. However, a higher proportion of subjects in the active methylphenidate group had dermal application site reactions, and there was generally a higher level of severity of application site reactions in the methylphenidate group. Methylphenidate is a chemical irritant. Discoloration, hyperpigmentation, and hypopigmentation are among some of the application site reactions reported postmarketing that are included in the current prescribing information.¹⁰ Reports of vitiligo associated with MTS stimulated a review of all cases of application site hypopigmentation or depigmentation.

Methods

We searched the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for postmarketing reports of chemical leukoderma associated with MTS received by the FDA from April 6, 2006 (US approval date) to December 23, 2014. FAERS is a computerized repository of spontaneous adverse event reports submitted by product manufacturers, consumers, and health care professionals from US and non-US sites.¹¹ The database is designed to support the FDA’s postmarketing safety surveillance program for drug and therapeutic biologic products. Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology.¹² MedDRA is the international medical terminology developed by the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

To identify cases of chemical leukoderma, we searched the FAERS database using the following MedDRA Preferred Terms: application site discoloration, application site pallor, hypopigmentation of eyelid, leukoderma, pigmentation disorder, postinflammatory pigmentation change, skin depigmentation, skin discoloration, skin hypopigmentation, and vitiligo. We included cases describing leukoderma (skin hypopigmentation or depigmentation), at or near the application site of the MTS.

To evaluate the cases, we calculated a time to onset and follow-up interval. The time to onset of chemical leukoderma was calculated from the MTS initiation date to the finding or diagnosis of the loss of skin pigmentation, whichever was earlier. For cases that reported a discontinuation of MTS and no resolution of leukoderma, a follow-up interval was calculated to evaluate the persistence of chemical leukoderma after the discontinuation of MTS. The follow-up interval was calculated from the MTS discontinuation date to the latest date that the manufacturer or the FDA received the report. If the manufacturer submitted the report to the FDA, we calculated the follow-up interval using the latest date that the manufacturer received the report. If the FDA received the report directly from a consumer or health care professional, we calculated the follow-up interval using the latest date that the FDA received the report.

Results

We identified 51 cases that met our inclusion criteria; 43 patients had chemical leukoderma localized to the application site only; 7 patients had leukoderma in other parts of the body in addition to the application site; and the remaining case lacked sufficient information to determine whether there was distant spread in addition to the application site. Seven cases reported the finding of leukoderma when the application site did not tan. Although some cases described the leukoderma as the shape and size of the MTS, other cases reported the size of the leukoderma area was larger than the patch, measuring up to 8 inches in diameter. Nineteen cases were reported as vitiligo, 12 of whom were seen by a dermatologist, and 5 had skin biopsies reported as consistent with vitiligo. Four additional patients were evaluated by a dermatologist, of whom 1 had a skin biopsy; in these cases, it was not reported that the patients were diagnosed with vitiligo. Six cases reported that patients, aged 8 to 13 years old, suffered from “embarrassment,” “fear,” or “emotional trauma” as a result of the persistent leukoderma. In addition, these cases reported that leukoderma made participation in sports and other childhood activities difficult.

The characteristics of the 51 cases is presented in the Table. Of the 40 that reported an age, all but 1 case reported an age of 16 years or younger. The mean age was 11 years old. Of the 49 cases that reported the sex of the patient, 59% were male and 51% were female. The race was reported in only 21cases; all but one of the patients were Caucasian. All strengths of the MTS (10 mg, 15 mg, 20 mg, and 30 mg patches) were associated with chemical leukoderma in the 38 cases that reported a dose. Only 20 cases provided enough information to calculate a time to onset, which ranged from 2 months to 4 years after the initiation of MTS. Nineteen additional cases provided an estimate only for the time to onset.

Table.

Case characteristics of chemical leukoderma reported with MTS, received by FDA from April 6, 2006 to December 23, 2014 (N = 51)

Age (n = 40)*
Mean	11 y
Median	10.5y
Range	7–38 y
Sex (n = 49)
Male	29
Female	20
Race (n = 21)
Caucasian	20
Asian	1
Initial reporter
Consumer	21
Health care professional	27
Lawyer	3
Reported indication (n = 39)
ADD/ADHD	38
Narcolepsy†	1
Reported leukoderma-related MedDRA
PT‡
Application site discoloration	33
Vitiligo	19
Skin discoloration	2
Pigmentation disorder	1
Skin depigmentation	1
Skin hypopigmentation	1
Strength of patch (n = 38)§
10 mg	12
15 mg	4
20 mg	11
30 mg	12
Additional events reported at site of
Leukoderma(n = 19)‡
Inflammatory reaction	15
Area does not tan	7
Diagnosis (n = 16)‡
Dermatologist	16
Biopsy	6
Time to onset (n = 20)
Mean	17 mo
Median	10 mo
Range	2 mo–4 y
Drug outcome (n = 47)
Discontinued	31
Continued	16
Treatment (n = 13)‡
Topical corticosteroid	9
Topical calcineurin inhibitor	6
Phototherapy	2
Unspecified topical cream	1
Unspecified medication	1
Event resolution
No	51
Follow-up interval (n = 23)
Mean	17 mo
Median	14 mo
Range	0–5.5 y

ADD, attention-deficit disorder; PT, Preferred Term.

^*Of the 40 cases that reported an age, 39 patients were less than or equal to 16 years of age. One patient was greater than 16 years of age.

^†One case reported narcolepsy as the indication of MTS by a physician. This case also reported MTS as one of the concomitant medications with an indication of ADHD.

^‡Each case may have reported 1 or more characteristics in the category.

^§One case reported the use of a combination of a 10 mg and 20 mg patch (2 dose categories).

None of the cases reported resolution during follow-up, despite discontinuation of MTS or treatment for repigmentation. Thirty-one patients discontinued the use of MTS, and 16 patients reported continued use of the patch.It is unknown whether the MTS was continued or discontinued in 4 cases. Thirteen patients were prescribed treatment for repigmentation. Twelve patients received treatment with 1 or more of the following: topical corticosteroid, topical calcineurin inhibitor, and phototherapy; 1 patient was prescribed an unspecified medication. Of the 13 cases that reported treatment, MTS was discontinued in 10, but it was continued in 2 (1 additional case did not report the status of the patch). The median follow-up interval after the discontinuation of MTS provided in 23 cases was 14 months, with the longest period of observation up to 5.5 years in 1 case. The 8 additional cases that reported the discontinuation of MTS did not provide enough information for the date of discontinuation to calculate a follow-up interval.

In addition to leukoderma at the application site, 7 cases reported leukoderma in other parts of the body as follows: (1) eyelids; (2) fingers; (3) right foot; (4) buttocks, chest, back, and legs; (5) face, arms, and legs; (6) lower abdomen, chest, back, elbows, right foot, and leg; and (7) lower back and 1 side of the body toward the ribs. Three cases reported spread of leukoderma after the discontinuation of MTS, either near the application site or to other parts of the body distant from the application site. Presented here is an example of a case diagnosed as “vitiligo” by the physician based on the appearance of the skin discoloration. In our assessment, this case is more consistent with chemical leukoderma based on the depigmentation at the site of repeated exposure to MTS.

Case Report

An 11-year-old white female was treated with the MTS 20 mg once daily for ADHD. The patient experienced irritation on her left hip, and she eventually rotated Daytrana (Noven Pharmaceuticals, Inc) to the right hip. After treatment with the patch for more than 2 years, she had a loss of pigment “about the size of a quarter” at the application site on her right hip. The patient avoided the area as much as possible by placing the patch around the affected area. One year later, the loss of pigment increased to the size of a “50 cent” coin. Because of the concern of further spread of the leukoderma, the physician discontinued the MTS and prescribed methylphenidate extended-release oral suspension instead. Even after discontinuation of the patch, the leukoderma on her hip progressively increased in size. One year after discontinuing the patch, the leukoderma was the size of a “dollar bill” and the area did not tan (Figure). At the time of the latest follow-up with the reporter, a dermatologist diagnosed the loss of pigment as vitiligo, and the patient began a topical corticosteroid and topical calcineurin inhibitor as treatment.

Figure.

Chemical leukoderma on the patient’s right hip, almost 1 year after the discontinuation of MTS.

Discussion

These 51 cases are consistent with the criteria for chemical leukoderma: (1) acquired vitiligo-like depigmented lesions; (2) history of repeated exposure of the skin to a specific chemical compound (methylphenidate patch) at the site of leukoderma; and (3) patterned vitiligo-like macules/patches conforming to site of exposure. Confetti macules, usually seen with exposure to liquids or sprays, were not described in our case reports; instead, the chemical leukoderma generally conformed to the shape and size of the patch.¹³ Reports of the area of chemical leukoderma being larger than the patch are consistent with the rotation of the patch application site in the same general area. The fact that the cases in our series reported both local and distant spread in addition to the application site is consistent with chemical leukoderma syndrome as classified by Ghosh and Mukhopadhyay.^7,8 This classification system includes 4 stages. Chemical leukoderma syndrome ranges from chemical leukoderma confined to the site of contact only (stage I) to a distant spread of depigmented patches 1 year after the discontinuation of the offending agent (stage IV).⁷

As is often the case in chemical leukoderma, it was diagnosed as vitiligo in 19 cases. Vitiligo is an acquired skin depigmentation disorder that arises spontaneously and usually has a characteristic distribution pattern. Vitiligo is thought to be the result of an autoimmune reaction, in which the epidermal melanocytes are destroyed.^14,15 Distinguishing chemical leukoderma from vitiligo is a challenge. Chemical leukoderma is also characterized by melanocyte destruction, hence, the identical histologic findings of reduced or absent melanocytes in both vitiligo and chemical leukoderma. Precisely what causes melanocyte death in chemical leukoderma has not been elucidated, despite recent studies in animal models with other topical depigmenting agents.¹⁶ There are several differences between vitiligo and chemical leukoderma. Vitiligo may be associated with ocular abnormalities, such as uveitis and fundal pigment disorders, and an increased risk of autoimmune diseases; chemical leukoderma is not associated with such disorders. The Koebner phenomenon associated with vitiligo can result from the first exposure of skin trauma; this is in contrast to chemical leukoderma, in which melanocyte damage occurs as a result of a repeated exposure to a chemical agent.¹⁷ Chemical leukoderma should always be suspected in cases of apparent vitiligo with unusual clinical features. The 2 conditions can be distinguished by a careful history and physical examination, but not by biopsy. However, occasionally, vitiligo may coexist in patients with chemical leukoderma.⁷

To further evaluate the association between chemical leukoderma and MTS, we searched the medical literature for additional case reports or articles about this association. We identified 1 published case report not included in our case series. It described a 3-year history of chemical leukoderma in a 16-year-old white male who was treated with MTS for ADHD.¹⁸ The patient alternated the patch sites between both hips daily. Initially, he developed redness and itchiness at the application sites. Soon after, he developed well-defined, symmetrical 10 cm² areas of depigmentation on both hips. A biopsy of the skin, in an area bordering the normal and depigmented skin, showed a reduction in the density of melanocytes. The patient discontinued the patch and the loss of pigmentation was ongoing.

In addition, there are a few published case reports of chemical leukoderma associated with other topical medications.^19–21 The prescribing information for the clonidine transdermal patch includes the adverse event “localized hypopigmentation.”²²

Some of the more common cutaneous adverse events associated with transdermal drug delivery systems include application site irritation, transient erythema following patch removal, and allergic contact dermatitis.²³ In clinical trials for MTS, application site reactions, such as skin erythema, were most commonly reported.¹⁰ Fifteen cases in our case series reported an inflammatory reaction at the application site, suggesting contact dermatitis, prior to pigment loss. Medications can cause both contact dermatitis and chemical leukoderma in the same patient by different mechanisms.⁸ The label for MTS also includes a warning for contact sensitization, which should be suspected if a patient experiences erythema with a more intense local reaction. Patients sensitized to MTS may develop systemic sensitization or other systemic reactions, even with the intake of oral methylphenidate-containing products.¹⁰

One of the strengths of spontaneous postmarketing surveillance is the ability to detect adverse events not previously identified in clinical trials and adverse events with a low background rate. In our case series, chemical leukoderma occurred more than 2 months after the initiation of MTS and even up to 4 years. The study period in each of the clinical trials for the initial approval of MTS was 7 weeks. However, the limitations of a spontaneous reporting system include variable quality of reporting and substantial underreporting of adverse events. Despite the variable quality of reporting and possible missing data in the reports, we identified 51 cases that met our case definition for chemical leukoderma with enough information for assessment. Furthermore, because of underreporting of adverse events, we cannot calculate the true incidence rate of chemical leukoderma associated with MTS based on the number of FAERS reports. The number of cases is likely to be much higher than 51.

Our findings generated questions for further research that we cannot answer based on the FAERS cases or the current literature. From our analysis, we identified that the use of MTS may result in chemical leukoderma in some patients. However, the causative ingredient in MTS that causes chemical leukoderma remains unknown. The MTS consists of 3 layers: (1) a polyester/ethylene vinyl acetate laminate film backing, (2) an acrylic and silicone adhesive containing methylphenidate, and (3) a fluoropolymer-coated polyester protective liner.¹⁰ Without further studies, we do not know for certain whether it is the active ingredient, methylphenidate, the excipients, or the combination of the ingredients in MTS that contribute to chemical leukoderma. Controlled clinical trial data demonstrated that subjects treated with placebo patches and subjects treated with active methylphenidate patches both experienced a range of application site reactions (not including chemical leukoderma). However, these reactions occurred at a higher rate in the methylphenidate group and generally were more severe, compared with the placebo group. This suggests that methylphenidate and some components of the patch excipients both contribute to the dermal reactions; but the potential relationships to chemical leukoderma is unknown. In addition to the MTS, Noven Pharmaceuticals manufactures 2 additional patches, Minivelle (estradiol transdermal system, Noven Pharmaceuticals, Inc, Miami, Florida) and CombiPatch (estradiol/norethindrone acetate transdermal system, Noven Pharmaceuticals, Inc), also using an adhesive with acrylic and silicone.^24,25 At the time of this analysis, the FAERS database did not contain reports of chemical leukoderma associated with these 2 products. Therefore, it seems unlikely that the acrylic and silicone adhesives are the sole cause of the chemical leukoderma. The available information raises the possibility that methylphenidate or the combination of methylphenidate with the excipients in MTS via the transdermal route may be the cause of the chemical leukoderma. Current evidence from the FAERS database and the medical literature do not support an association between leukoderma and the oral methylphenidate products. Thus, further research is needed to identify which ingredient is the culprit of this adverse reaction. Through this publication, we hope to increase public awareness of this adverse reaction and generate further research to identify the role of methylphenidate, or its interaction with the excipients in MTS, in the onset of chemical leukoderma.

Our case series identified a strong association between MTS and chemical leukoderma that was the basis for regulatory action taken by the FDA.²⁶ As demonstrated in our case series, chemical leukoderma is not only physically disfiguring, but can cause significant emotional stress, especially in this young population using MTS. In June 2015, the FDA issued a Drug Safety Communication regarding this new information. In August 2015, the MTS prescribing information was updated with a warning for chemical leukoderma. Prescribers and other health care professionals need to be aware of the potential risk of chemical leukoderma associated with MTS, especially given that chemical leukoderma is often misdiagnosed as idiopathic vitiligo. It is important to convey this risk to patients and consider other available treatment options because the loss of pigmentation associated with MTS may be permanent. If a patient reports a loss of pigmentation, prescribers should promptly discontinue the patch and prescribe an alternative treatment.

Glossary

ADHD

Attention deficit-hyperactivity disorder

FAERS

FDA Adverse Event Reporting System

FDA

Food and Drug Administration

MedDRA

Medical Dictionary for Regulatory Activities

MTS

Methylphenidate transdermal system