Chemical Leukoderma: A Rare Adverse Effect of the Rotigotine Patch

Rotigotine, marketed as NEUPRO (UCB Inc., Smyrna, GA), is a nonergot dopamine agonist (DA) available as a transdermal therapeutic system (TTS).1 It was approved in 2007 for Parkinson's disease (PD)2 and in 2008 for restless leg syndrome.3 It has high affinity for the D3/D2/D1 receptors.1 The TTS gives rotigotine the advantage of direct entry into the systemic circulation, bypassing the intestinal absorption and the first pass liver metabolism with stable plasma concentration, leading to uniform symptomatic control. It is available in 6 different strengths in the market, ranging from 1 to 8 mg in each 24-hour patch. It is a well-tolerated medication, and mild-to-moderate application site reaction (ASR), nausea, and somnolence are the most common side effects. The ASRs were reported as localized erythema, edema, or pruritus with a dose-dependent reaction.2-5 We describe a case of application site depigmentation caused by the rotigotine patch and discuss the probable mechanism for this side effect. A 76-year-old Nigerian woman had been attending clinic for PD since 2012. She had developed wearing off and peak dose levodopa (l-dopa) dyskinesia at higher doses. She was initially maintained on l-dopa and rasagiline; however, because of motor fluctuations, she was started on the rotigotine patch in October 2015, with slow dose escalation from a 2-mg 24-hour patch to a 4-mg 24-hour patch. She reported good improvement in fluctuations. She discarded the patch every 24 hours and rotated the area of application, never using the same area within 14 days. She returned to the clinic in March 2016 and reported white skin patches at the application sites unrelated to the drug dose. Once the patch was applied, there was mild irritation/itchiness at the application site, which would be erythematous and slightly swollen the next day upon removal of the patch. The subsequent day, the area would become depigmented, leaving behind a white patch, with slow repigmentation occurring over the next 3 or 4 months. She had good motor improvement with no tremors, Grade 1 cogwheel rigidity, bradykinesia, and mild dyskinesia. There were areas of depigmentation and various stages of hypopigmentation with geometric configurations similar to those of the rotigotine patches across the arms, chest, abdomen, back, and thigh where the patches were applied (Fig. 1A–E). She had no known history of thyroid dysfunction, pernicious anemia, gastric carcinoma, Addison's disease, or diabetes mellitus (or any history suggestive of it). She had no prior history of cutaneous disorders and a negative family history for the same. Dermatology diagnosed it as chemical leukoderma, because the lesions did not spread beyond the patch contact area. Given the good motor response to rotigotine, the patient did not want to stop the patches and was continued on them after clearance from dermatology. She realized that applying Vitamin E or baby oil to the affected areas immediately after removing the patch reduced the depigmentation. Triamcinolone applied to the affected areas resulted in early repigmentation. She continues to use Rotigotine patches. Previously reported ASRs to the rotigotine patch have been limited to erythema, swelling, or pruritus.2-5 The causal chemical ingredient is uncertain. The patch has 3 layers—a backing film, a self-adhesive drug matrix layer, and a protective liner. The adhesive matrix layer in contact with the skin contains the active component rotigotine and the inactive components ascorbyl palmitate, povidone, silicone adhesive, sodium metabisulfite, and dl-α-tocopherol. Allergy to any of these components may lead to a skin reaction. Contact dermatitis is a known side effect of metabisulfite. A study of metabisulfite-related allergic contact dermatitis indicated that, among individuals with nonoccupational exposure, reactions were mostly secondary to topical medications with metabisulfite as a preservative, such as ketoconazole.6 A report of allergic contact dermatitis in the form of erythematous lesions with vesicles secondary to the rotigotine patch found that the offending chemical was rotigotine, as evident by the patch test.7 We did not identify any case reports of depigmentation related to rotigotine in our literature search. Chemical leukoderma is an acquired, hypopigmented dermatosis that results from repeated, cutaneous application of an agent that destroys epidermal melanocytes.8 The occurrence with repeated exposure to a suspected depigmenting agent helps to differentiate it from vitiligo. A study on vitiligo and the cytotoxic effects of different monoamines on melanocytes indicated that dopamine reduced melanocyte viability primarily by inducing apoptosis through auto-oxidation in a dose-dependent manner.9 Also, rotigotine has antagonist activity at the α-2 adrenergic receptor,1 and melanocytes exhibit the same receptor family.9 A possible hypothesis is that rotigotine absorbed through the skin results in apoptosis of the epidermal melanocytes, leaving behind well-demarcated depigmented lesions. The initial reaction of erythema and mild swelling caused by the patch in our patient may suggest an inflammatory state. Vitamin E is a known antioxidant and is also a proven adjuvant therapy in patients who have vitiligo that produces better repigmentation results,10 probably by counteracting oxidative free radicals. This could explain the benefit experienced by our patient from Vitamin E and baby oil, which essentially has Vitamin E. In conclusion, we report the rare side effect of chemical leukoderma caused by the rotigotine patch. Further studies are needed to elucidate the mechanisms that lead to this unusual skin reaction to rotigotine. Author Roles: 1. Case Report: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique. N.P.: 1A, 3A P.C.: 1A, 3B Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: The authors report no sources of funding and no conflicts of interest. Financial Disclosures for the previous 12 months: Pratap Chand is a member the Teva Neuroscience, US World Meds, and Acadia Pharmaceuticals Speakers' Bureaus. Neha Prakash reports no sources of funding and no conflicts of interest.