Allergic Contact Dermatitis to TTSs
TTSs are ideally suited to produce sensitization because they simulate Kligman's maximization procedure, which requires occlusion, irritation, and repeated placement of the allergen at the same skin location. The prevalence of allergic contact dermatitis from TTSs is unknown. Sensitization may develop owing to the active pharmaceutical agent, adhesive, or other components ( Table 2 ). Figures 3 and 4 depict areas on a woman with allergic contact dermatitis from a component of a reservoir TTS.
Positive patch test reaction to the central portion of a reservoir patch. The ingredient common to both reservoir patches in Figure 3 and Figure 4 was hydroxypropyl cellulose.
Clonidine. Clonidine is a centrally acting antihypertensive that can be successfully delivered transdermally. Clonidine patches are generally left in place for 7 days, which is a longer application period than is required by most other TTSs and may explain the relatively high incidence of allergic contact dermatitis from clonidine TTS. Although clonidine itself is a very weak sensitizer, it is the main sensitizer in the clonidine TTS, and patch tests with the nonactive components of the clonidine TTS have rarely produced reactions.
Groth and colleagues observed 29 patients who applied clonidine TTSs to their upper outer arms; 11 (38%) of these patients experienced a local skin reaction. Patch testing with all components of the clonidine TTS was performed on 7 of these 11 patients, and 6 of these 7 were found to be allergic to clonidine. Horning and colleagues conducted a 2-year prospective study with 20 patients to determine the efficacy and safety of a clonidine TTS. Five (25%) of the patients had positive patch-test reactions to clonidine; 2 of these 5 patients were able to tolerate an oral challenge with clonidine.
In 1985, Maibach reported a series of trials performed to determine both the irritation and sensitization potential of clonidine and clonidine TTSs. The irritation study was conducted with two groups of 28 subjects. Group 1 had daily applications of clonidine 3% in petrolatum (pet), petrolatum, a Catapres-TTS (Alza Corp., Palo Alto, CA), and a placebo TTS. Group 2 had daily applications of petrolatum, clonidine 1% pet, clonidine 3% pet, clonidine 9% pet, and clonidine 3% with 0.03% LUE 92 (a contaminant reduction product consisting of two molecules of clonidine and one molecule of acetaldehyde) in petrolatum. The test materials were left in place for 24 hours and were then re-applied daily for 5 days; the last application was left in place over a weekend. The sites were evaluated at each removal, for a total of 21 days. Ten days after the 21-day irritancy study was completed, the patients were patch-tested with the same materials. Patch-test results were uniformly negative: none of the subjects were sensitized to the test materials.
Subsequently, Maibach performed a second set of experiments. In this second study, group 1 consisted of 103 subjects who received thrice-weekly applications of clonidine 9% pet and plain petrolatum. Group 2 consisted of 92 subjects who received thrice-weekly applications of a clonidine TTS and a placebo TTS. The applied material was left in place for 7 days. Three weeks later, the subjects were challenged with placement of the test materials at a separate site for 72 hours. Weekly applications at the original site were performed for another 2 weeks. The subjects were then rechallenged with the test materials and were evaluated at 24 hours and again at 48 hours after application. At the end of the study, both groups were cross-challenged with the other group's test materials. Group 1 subjects were found to have negative reactions at all evaluations as well as after cross-challenge with the clonidine TTS. In group 2, however, 4 patients (4.3%) demonstrated sensitization to clonidine. The fact that allergic contact dermatitis was observed only in the group tested with the clonidine TTS and not in the group tested with clonidine in petrolatum suggests that some factor in the TTS system enhances sensitization, possibly owing to enhanced penetration.
Nitroglycerin. The use of nitroglycerin TTSs is a common therapy for angina pectoris. Case reports of sensitization to nitroglycerin itself have rarely been reported in the literature.[4,21,22,23] Kounis and colleagues conducted a study of continuous and intermittent use of nitroglycerin TTSs with 320 subjects, using three different commercially available brands to assess cutaneous reactions to nitroglycerin TTSs. System A (Pancoran; Novartis, Metamorphosi, Greece) consisted of glyceryl trinitrate, lactose, colloidal silicon dioxide and silicone medical fluid, ethylene vinyl acetate copolymer membrane, and silicone adhesive. System B (Nitrodisc, GD Searle, Chicago, IL) consisted of glyceryl trinitrate, glycerin, purified water, lactose, polyvinyl alcohol, povidone, sodium citrate, and medical-grade unwoven tape. System C (Nitrodyl, Schering-Plough; Lavipharm, Paiania, Greece) consisted of covering foil and adhesive film, which included a drug reservoir and release control system (individual components of this system were not reported). The nitroglycerin concentrations in these systems were not reported. Twenty-one (6.5%) of the patients experienced skin reactions; 17 of these patients were classified as having local irritant reactions, 4 patients (1.2%) developed localized and remote skin reactions, and 1 patient developed an anaphylactic reaction. Eleven patients (3.4%) discontinued TTS therapy because of a skin reaction. Of the 4 patients with local and remote skin findings, 3 were patch-tested and had positive reactions to both a nitroglycerin solution (0.2 mg/mL) and a nitroglycerin ointment (concentration not reported). The patient who experienced an anaphylactic reaction was not patch-tested.
Torres and colleagues reported on a woman with pruritus, burning, erythema, and edema at nitroglycerin TTS application sites. She was patch-tested with a standard series, the nitroglycerin TTS, a placebo TTS, and two concentrations of nitroglycerin (0.2% and 2.0% pet). She had positive reactions to the nitroglycerin TTS and to both concentrations of nitroglycerin. Her therapy was changed to sublingual nitroglycerin and oral isosorbide dinitrate, without difficulty.
Rosenfeld and White reported a man with cutaneous reactions to a nitroglycerin TTS and a nitroglycerin ointment, both of which were used therapeutically. He was patch-tested with lanolin, petrolatum, a saline placebo, a silicone adhesive, a nitroglycerin ointment (concentration not reported), and a nitroglycerin 0.2 mg/mL solution. He had positive reactions to both the nitroglycerin ointment and the nitroglycerin solution. The patient was successfully transitioned to oral isosorbide dinitrate and sublingual nitroglycerin, without cutaneous sequelae.
Topaz and Abraham reported on two men who presented with painful erythematous edematous crusting reactions in the region of nitroglycerin TTS application sites. They were patch-tested with lanolin, lactose, nitroglycerin 0.2mg/mL in water (aq), nitroglycerin 0.5mg/mL aq, nitroglycerin ointment (concentration not reported), white petrolatum, a silicone adhesive, and a saline placebo. Both patients had negative reactions to all test sites except those of the nitroglycerin solutions and the nitroglycerin ointment.
Machet and colleagues reported on a man who presented with a diffuse truncal erythematous pruritic eruption 5 months after placement of a nitroglycerin TTS. After switching brands of TTS, his dermatitis progressed to a generalized eczematous eruption, sparing only the face. Numerous erythematous plaques with vesicles were present at TTS application sites on the patient's back. The patient was patch-tested with a standard series, Nitroderm TTS (Novartis, East Hanover, NJ), Discotrine TTS (3M Sante, Cergy-Pontrose, France), and Lenitral nitroglycerin spray (Besins, Montrouge, France) (concentration not reported). Nitroglycerin was the only common component among the three preparations. Relevant positive reactions were limited to the three nitroglycerin-containing preparations, which suggests that the nitroglycerin itself was the responsible allergen.
Perez-Calderon and colleagues reported on a man who presented with generalized edema, erythema, vesicles, and lichenification and excoriations, all sparing only the palms and soles, which developed after the use of a nitroglycerin TTS. Patch testing showed positive reactions to Minitran TTS and Nitroderm TTS as well as to nitroglycerin 0.2 mg/mL aq and nitroglycerin 0.5 mg/mL in ethanol. Patch-test reactions to adhesives were negative. It was postulated that the length of exposure and TTS placement at various sites, as well as the excoriations, accounted for the propagation of dermatitis in this case. The patient was able to transition to oral nitroglycerin, without side effects.
Scopolamine. Used for the prevention of motion sickness, scopolamine can be delivered transdermally through a retroauricular TTS, which is typically worn for 72 hours. Gordon and colleagues described 16 (10%) of 164 naval crew members who presented with cutaneous reactions after using scopolamine TTSs to treat motion sickness. The patients presented with pruritus, erythema, and an edematous, vesicobullous, or eczematous reaction on the retroauricular skin confined to the TTS location. Placement of a TTS behind the contralateral ear produced identical reactions. These 16 men had negative patch-test reactions to the placebo TTS (which contained all ingredients except scopolamine), which suggests that scopolamine was the sensitizer.
There have also been several case reports of sensitivity to scopolamine. Fisher reported on a woman who had used a scopolamine TTS for 3 weeks to prevent motion sickness and who presented with a pruritic eruption under the TTS. She was patch-test positive to scopolamine 2% pet. Van der Willigen and colleagues described a man with a retroauricular skin reaction at the site of a scopolamine TTS application. He had been using scopolamine TTSs for 2 weeks. The patient was patch-tested with a standard series, scopolamine TTS, and scopolamine in concentrations of 0.25%, 0.5%, and 1.0% aq. Patch-test results were positive for the three scopolamine aqueous concentrations and for the scopolamine TTS. Similarly, Trozak reported on a patient who presented with an eczematous skin rash and pruritus at the site of the application of a scopolamine TTS, as well as nummular eczematous reactions at previous application sites. Patch-test reactions to scopolamine 1.8% pet were positive; reactions to the other components of the TTS and to tropicamide and atropine were negative. These findings suggest that the tropic acid residue, which is common to all three compounds, was not the antigenic portion of the molecule. No cross-sensitivity between scopolamine and atropine has been demonstrated although they differ structurally only in an oxygen bridge between atoms 6 and 7 at the organic base of scopolamine.[30,32] These findings suggest that the antigenic portion may be the oxygen bridge.
Testosterone. Testosterone TTSs are used for testosterone-deficient men and improve mood, fatigue, and sexual function. Irritant contact dermatitis is the most commonly reported skin reaction although there have been few case reports of allergic contact dermatitis from the testosterone component of the TTS. Buckley and colleagues reported on a man with Klinefelter's syndrome who presented with erythema and vesiculation at testosterone TTS application sites. He had positive patch-test reactions to testosterone propionate and negative reactions to other components of the TTS (methyl laurate, glyceryl monooleate, carbomer 1342, and polyethylene). Shouls and colleagues reported on a man with erythema, blistering, and induration at TTS application sites; this progressed to generalized erythema after 3 months of TTS use. The patient had positive patch-test reactions to testosterone enanthate and testosterone undecanoate.
Estradiol. Estradiol TTSs are used to treat menopausal symptoms. There are few case reports of allergy to the estradiol component of the TTS. Boehncke and Gall reported on a woman who had been taking oral estrogen and was switched to estradiol TTS. After the ninth application, she presented with pruritic erythema at the application site; the erythema then spread, resulting in generalized urticarial plaques. Patch testing with the TTS and with individual components of the TTS yielded positive reactions to estradiol-17β 1%, 2%, and 4% in 96% ethanol, as well as to the complete estradiol TTS. Oral estrogen was reinstated without cutaneous effects. Carmichael and Foulds reported on a woman with contact allergy to an Estraderm TTS (Novartis Pharmaceuticals). She was tested with the complete Estraderm TTS and to a placebo TTS that contained all ingredients except estradiol-17β. She reacted only to the Estraderm TTS, which suggests that estradiol-17β was the allergen.
Koch described a woman who presented with a pruritic, discoid, indurated, erythematous plaque at the site of an estradiol TTS application. This was followed by a bullous reaction. She was transitioned to an estradiol-containing gel, but subsequent eczematous reactions also occurred at the site of gel application. Patch testing was performed with a standard series and with the individual components of the TTS and gel. Positive reactions to estradiol 1% and to norethisterone acetate 1% in ethanol were found. Patch-test reactions to the other components of the TTS (carbopol, triethanolamine, and ethanol) and with the placebo TTS were negative. Panhans-Gross and colleagues reported on a woman who presented with a history of cutaneous reactions to many different brands of estradiol TTS. Patch-test results were positive for all three estradiol TTSs she had tried, as well as to estradiol 1%, 2%, and 4% in 96% ethanol. Patch-test results for other components of the system including 96% ethanol were negative.
Lamb and Wilkinson reported on a 61-year-old woman with persistent hand and foot dermatitis who developed multiple contact allergies to topical steroids. She had a history of eczematous reactions to estradiol-17β and to norethisterone-containing TTSs. Patch testing was performed with a standard series, a shoe series, a corticosteroid series, and a sex steroid series. The patient had positive reactions to hydroxyprogesterone, progesterone, estradiol, betamethasone valerate, and clobetasol propionate, as well as numerous other steroids. This case demonstrated a potential cross-reaction between topical corticosteroids and sex steroids, and patients who develop contact allergies to sex steroids may be at risk of developing corticosteroid allergies.
Nicotine. Nicotine TTSs are used as aids in smoking cessation. Nicotine is not particularly antigenic, and nicotine allergy in smokers and tobacco workers is rare. However, allergic contact dermatitis from nicotine has been reported among nicotine TTS users. It is hypothesized that cutaneous exposure to nicotine allows the molecule to penetrate the epidermis, and binding of this hapten with skin proteins may form a neoantigen, which may induce sensitization. Jordan reported on a two-phase trial involving 186 subjects. Phase one was an open-label study and involved only active nicotine TTSs. Phase two was a 4-day randomized double-blind challenge. Three (1.6%) of the patients were sensitized as determined by positive reactions to rechallenge.
Several other studies have reported cutaneous reactions to nicotine. In a double-blind study involving 183 smokers, 29 (15.8%) complained of pruritus and 18 (10%) reported erythema. Of 7 patients who had a papulovesicular rash, 6 were patch-tested with a nicotine TTS, a placebo TTS (without nicotine), matrix material, gauze, and a standard series (lacquer, adhesives, and plastics); 5 of these patients had positive patch-test reactions to nicotine. Six patients (3.3%) dropped out of the study because of cutaneous reactions. Similarly, Vincenzi and colleagues reported on five patients with cutaneous reactions at nicotine TTS application sites. Six patients were patch-tested with a standard series, nicotine 1% and 10% aq, and carrageen (a thickening, stabilizing, or emulsifying agent used in pharmaceutical, industrial, and food products) as is and had positive reactions to nicotine 10% aq; one patient also had a positive reaction to nicotine 1% aq. Färm reported a woman with diffuse eczema at past nicotine TTS application sites and a papulovesicular rash in other areas. The patient was patch-tested with a nicotine TTS, a placebo TTS, and nicotine base in six different aqueous concentrations (0.1%, 0.3%, 1%, 3%, 10%, and 30%); she had positive patch-test reactions to nicotine in 3%, 10%, and 30% aqueous concentrations.
Fentanyl. Fentanyl is a potent opioid analgesic used to treat pain. Cutaneous reactions (involving papules, pustules, erythema, and pruritus) to fentanyl TTSs have been described.[45,46,47,48,49] There were two reports of diffuse cutaneous reactions thought to be due to fentanyl TTS, but patch testing was not performed on either of these patients.[50,51]
Contact dermatitis is associated not only with the active ingredients of transdermal systems but also with other components. Various adhesives and other components of the TTS reservoir, such as alcohol and anesthetics, have been shown to cause allergic contact dermatitis.
Peppermint and Menthol. Foti and colleagues described a man with eczematous contact dermatitis in the lumbar region where he had applied a flurbiprofen LAT patch for relief of back pain. Peppermint and menthol were added to the LAT patch for their anesthetic properties and to aid vasodilation and drug penetration. The patient was patch-tested with the LAT patch in toto, as well as with its components (flurbiprofen 2% pet, isopropyl myristate 5% pet, polysorbate 80.5% pet, sorbitan sesquioleate 20% pet, peppermint oil 2% pet, and menthol 1% pet). The patient had positive reactions to the patch in toto and to menthol and peppermint and a weak reaction to fragrance mix. Menthol is a rare sensitizer but has been shown to undergo metabolism to menthone, which may induce sensitization.
Hydroxypropyl Cellulose. Schwartz and Clendenning described a woman with pruritus, erythema, edema, and postinflammatory hyperpigmentation at sites where an estradiol TTS containing hydroxypropyl cellulose, estradiol, and alcohol had been applied. Patch tests with components of the system yielded positive results for hydroxypropyl cellulose in 70% ethanol and hydroxypropyl cellulose in mineral oil and negative results for 70% ethanol, mineral oil, and hydroxypropyl cellulose in water. Because the patient had a negative result for hydroxypropyl cellulose in water, it was thought that the vehicle was important for allergen penetration and potential sensitization.
Polyisobutylene. Groth and colleagues observed 29 patients who were using clonidine TTSs. Patch testing was performed on 7 patients; 1 patient had a positive reaction to polyisobutylene.
Ethanol. Irritation due to ethanol is common, but ethanol allergy is rare and can be missed. Patients who are topically sensitized to ethanol may develop local and generalized dermatitis from the consumption of alcoholic beverages.[55,56] Cross-reactions with other aliphatic alcohols and acetone have been reported. Pecquet and colleagues reported on two patients who were using estradiol TTSs to treat disabling menstrual headaches and who presented with pruritic erythematous lesions at TTS application sites. Both patients were patch-tested, and positive results were obtained for ethanol, TTS with ethanol and no estradiol, TTS with ethanol and estradiol, and hydroxypropyl cellulose in ethanol (concentrations not reported). Occlusion may have promoted the sensitization.
Grebe and colleagues described a woman with erythema, induration, vesicles, itching, and burning at estradiol TTS application sites. The patient was not patch-tested, and she was transitioned to oral ethinylestradiol. Her rash progressed within 48 hours, and she experienced systemic symptoms (including facial edema, reddening, generalized pruritus, and a fine macular rash on her face and upper trunk) along with re-activation of the dermatitis at TTS application sites. Oral ethinylestradiol therapy was discontinued, and her reaction subsided within 48 hours. She was patch-tested with six items: a TTS without estradiol, a TTS without estradiol and ethanol, a TTS without a drug reservoir and with occlusive adhesive (3M, St. Paul, MN), a TTS without a drug reservoir and with non-occlusive adhesive (3M), a TTS without a drug reservoir and with non-occlusive adhesive (polyisobutylene), and a complete estradiol TTS. Patch-test reactions to the TTS without estradiol and to the complete estradiol TTS were positive, suggesting an allergy to ethanol. Further patch testing with 0.1 mL each of pure ethanol, pure isopropyl alcohol, pure N-propyl alcohol, and fluid aspirated from the estradiol TTS reservoir showed positive reactions to ethanol and the fluid from the estradiol TTS. The patient recalled drinking two alcoholic beverages the night before the onset of the systemic symptoms. Previously, she had no adverse reactions to alcoholic beverages. Rechallenge with oral ethanol again produced a systemic reaction, and oral ethinylestradiol was restarted, without side effects. Although patch testing with 100% alcohol has been reported, repeated testing with lower concentrations (such as 10%) is recommended.
Adhesives. Adhesives are necessary for adherence of a TTS to the skin. Several publications have implicated adhesives as allergens. McBurney and colleagues reported on 9 women who had discontinued their use of estradiol TTSs because of skin reactions and who were subsequently patch-tested; 4 patients had positive patch-test reactions to the adhesive, and 2 of these 4 patients also had positive reactions to the placebo TTS. The allergen common to these two systems was the adhesive. Fisher described a man who developed a pruritic eruption at the site of a nitroglycerin TTS; a similar reaction occurred at a second site upon application. Patch testing was performed with adhesive materials, foil backing, a nitroglycerin TTS, and a placebo TTS. The patient showed positive patch-test reactions to only the adhesive material. Kounis and colleagues performed a study of continuous and intermittent use of nitroglycerin TTSs on 320 patients, using three different commercially available brands to assess cutaneous reactions to nitroglycerin TTSs. Thirteen (4%) of the 320 patients had positive patch-test reactions to a silicone adhesive (specific name and concentration not reported).
Dwyer and Forsyth described a man who presented with inflammation and irritation at nicotine TTS application sites. The manufacturer of the TTS reported its ingredients to be the following: (1) nicotine; (2) copolymer of 2-ethylhexyl acrylate, hydroxyethyl acrylate, glycidyl methacrylate, and vinyl acetate; (3) copolymer of ethyl acrylate and methyl methacrylate; and (4) a neutral oil containing a mixture of triglycerides of saturated vegetable fatty acids. Patch tests were performed with a standard series, the inner and outer layers of the nicotine TTS, two preparations of nicotine (5% aq and 5% in ethanol), a plastics and glues series, and an antimicrobial series. Positive reactions were observed to both layers of the nicotine TTS, triethylene glycol dimethacrylate, ethylene glycol dimethacrylate, 1,4-butanediol dimethacrylate, 2-hydroxyethyl methacrylate, m-m-dimethylaminoethyl methacrylate, tetrahydrofurfuryl-2-methacrylate, and p-phenylenediamine.
Other Components. Several investigators reported eliminating the active drug as the culprit but were unable to identify the offending allergen.[25,42,60,62] Another ingredient implicated in allergic contact dermatitis from TTSs is glycerin.
Di Landro and colleagues reported allergic contact dermatitis from a Nitroderm TTS in a patient who presented with erythematous vesicular lesions over the entire body but sparing the head and distal portions of the extremities. He was subsequently patch-tested with nitroglycerin at concentrations of 0.5%, 1%, 2%, and 3% in petrolatum and with a placebo TTS; the results were negative. His only positive reaction was to the complete Nitroderm TTS. The authors did not test individual components of the TTS, other than the nitroglycerin, but hypothesized that because no reaction was observed to the placebo TTS (which contained all the other ingredients except nitroglycerin), it may have been a neoantigen or the complex of chemicals in the TTS that provoked sensitization.
Corazza and colleagues described a woman who presented with erythematous vesiculation and pruritus at the site of application of a clonidine TTS. She was patch-tested with clonidine as well as the other individual components of the transdermal system and the entire system itself. She had a positive patch-test reaction only to the complete clonidine TTS system. During manufacture, clonidine and acetaldehyde can form a reactive condensation product (called LUE) that consists of two molecules of clonidine and one molecule of acetaldehyde. This neoantigen may have been the sensitizing agent in this case.[17,64]
Most patients are able to successfully transition to oral medication after failing transdermal therapy because of allergic contact dermatitis.[4,19,21,25,26,64,66,67,95] For the 31 patients patch-test-positive to clonidine who were orally challenged, 30 had no cutaneous or systemic effects.[19,95] One patient had a skin reaction consisting of localized erythema and edema at a previous clonidine TTS site after taking oral clonidine. None of the rechallenged patients experienced a systemic reaction. Nitroglycerin was tolerated by 4 out of 4 patch-test-positive patients who underwent oral challenge.[4,25,26,64] Nicotine caused no systemic or skin symptoms in 7 out of 7 patients who patch-tested positive for nicotine allergy and later resumed smoking. However, most drug manufacturers do not recommend oral challenge for patients topically sensitized to drugs.
A literature search found no reports of patients with contact allergy to nicotine who experienced a relapse of dermatitis or systemic skin reactions after stopping the TTS and restarting smoking. However, a case report discussed earlier in this paper reported a woman who began chewing nicotine-replacement gum after discontinuing nicotine TTS due to widespread cutaneous reaction, and positive patch testing to nicotine. Her cutaneous symptoms progressed despite treatment with topical corticosteroids. Her widespread dermatitis was possibly worsened by her continued nicotine intake. There were no local reactions in her mouth, however, and the patient continued to smoke after stopping the gum. Her skin lesions cleared two weeks after cessation of the nicotine gum, and the dermatitis did not return.
Dermatitis at the site of a TTS can cause decreased absorption of active medication. Carmichael and Foulds described a man who had irritation, redness, and induration at nitroglycerin TTS application sites. In addition, the patient experienced a worsening of his angina, which was postulated to be because of decreased drug delivery via the irritated skin. Similarly, White and Guidry described a woman who presented in the eleventh week of transdermal clonidine treatment with hypertension, nausea, light-headedness, and headache in conjunction with painful pruritus, edema, erythema, and vesiculation at the TTS site. Her symptoms were thought to be consistent with contact dermatitis and clonidine withdrawal syndrome. The authors proposed that the clonidine was not being absorbed, owing to cutaneous inflammation caused by the contact dermatitis reaction.
Dermatitis. 2006;17(3):109-122. © 2006 American Contact Dermatitis Society
Cite this: Cutaneous Reactions to Transdermal Therapeutic Systems - Medscape - Sep 01, 2006.