Cutaneous Reactions to Transdermal Therapeutic Systems

Andrea L. Musel; Erin M. Warshaw

Dermatitis. 2006;17(3):109-122.

Abstract and Introduction

Transdermal therapeutic systems have been increasingly used in the past two decades. However, cutaneous side effects are fairly common and may result in poor patient compliance. This review article summarizes the spectrum of reactions due to transdermal therapeutic systems and provides a current list of known allergens.

Over the last decade, transdermal administration has become an increasingly popular method of drug delivery because its benefits include not only convenience for patients but also increased compliance. Transdermal therapeutic systems allow drugs to be delivered in a rate-controlled manner, avoiding first-pass metabolism and the fluctuating plasma concentrations encountered with oral medications.^[1] In most cases, there are fewer side effects than there are with oral delivery of drugs, but skin reactions are not uncommon and may compromise compliance. The purpose of this review is to provide information on the spectrum of reactions caused by transdermal therapeutic systems and to review known responsible allergens.

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Irritant Cutaneous Reactions to Transdermal Therapeutic Systems
Study	Study Type	TTS	Total No. of Patients	Time Period	Patients with Cutaneous Side Effects (n = No. of Patients)	Patients Discontinued Owing to Side Effects
Weber^[70]	O	Clonidine	101	12 wk	8	5
Fillingim^[78]	O	Clonidine	41	88 wk	15	2
Dick^[79]	O	Clonidine	15	8-20 wk	4	4
Vaillant^[80]	P	Nitroglycerin	33	1-103 wk	5	0
Kounis^[24]	NR	Nitroglycerin	320	NR	21 (6.5%)*	11 (3.4%)
Homick^[81]	DBX	Scopolamine	11	Four 72 h applications	≈3	NR
Place^[82]	RDB	Estradiol	124	8 wk	n NR; 20% of study weeks had SE reported	Active: 1 Placebo: 12
de Cetina^[83]	O	Estradiol	45	24 wk	35	10
Mulligan^[84]	DBPC	Nicotine	80	24 wk	Active: 11 Placebo: 5	NR
Abelin^[85]	RDBPC	Nicotine	Active:100 Placebo:99	12 wk	Active: erythema, 25; pruritus, 29 Placebo: erythema, 13; pruritus, 8	Active: 5
Rose^[86]	RDB	Nicotine	Active: 33 Placebo: 32	3 wk	Active: 32 (97%) with "at least a mild reaction," 2 with generalized rash Placebo: 6 (19%) with "at least a mild reaction"	Active: 3 (9.1%) Placebo: 17 (53.1%)
Abelin^[87]	RDBPC field study	Nicotine	Active: 156 Placebo: 155	12 wk	Active: intense erythema ± edema, 12; mild/moderate erythema, 25; pruritus, 29 Placebo: mild/moderate erythema, 14; pruritus, 8	9
Transdermal Nicotine Study Group^[66]	RDBPC	Nicotine	Active: 664 Placebo: 271	6-12 wk	Active: itching or burning, 332 (50%); erythema, 93 (14%) Placebo: itching or burning, 35 (13%)	NR
Hurt^[88]	RDBPC	Nicotine	Active: 31 Placebo: 31	6 wk	Active: vesicles, 2; erythema, 29 Placebo: erythema, 10	Active: 0 Placebo: 2
Kornitzer^[89]	DBPC	Nicotine	Active: 299 Placebo: 75	24 wk	Active: edema, 3; pruritus, 16; erythema, 19 Placebo: edema, 1; pruritus, 1; erythema, 2	NR
Daughton^[90]		Nicotine	Active: 110 Placebo: 55	4 wk	Active: 1 with TTS worn 24 h, 3 with TTS worn only while awake Placebo: 1	Active: 2^§ Placebo: 2
Jordan^[41]	O (ph 1), RDB (ph 2)	Nicotine	186	Phase 1: 6 wk Phase 2: 4 d	Phase 1: papules + pustules, < 5.5 (< 3%); erythema, 167; pruritus, 145 tingling, 2; soreness, 2; stinging, 1; burning, 18 Phase 2: papules + pustules, < 1.86 (< 1%); other than erythema, < 3.72 (< 2%)
Eichelberg^[42]	O	Nicotine	183	8 wk	Pruritus, 29; erythema, 18	6
Jordan^[12]	OX	Testosterone	60	4 wk	0% scrotal system; 12% nonscrotal system	NR
Ross^[13]	RPC X	Estradiol	72	16 wk	Matrix TTS, 6; Reservoir TTS, 35; Both, 17	Matrix: 26; reservoir, 4; both, 9
Gammaitoni^[91]	O	Lidocaine	20	3 d	Slight to moderate erythema, 18; edema, 1	NR
Gammaitoni^[92]	O	Lidocaine	20	3 d	Erythema, 13	0
Barbano^[93]	O	Lidocaine	56	3-8 wk	Burning, 5; papular rash, 1; photosensitivity reaction, 1	2
Meier^[94]	RPC X	Lidocaine	40	3 wk	Active: rash, 10; pruritus, 4; vesicobullous rash, 1 Placebo: rash, 11; pruritus, 5; vesicobullous rash, 1	Active: 1 Placebo: 0

DB = double-blind; NR = not reported; O = open label; P = prospective; PC = placebo controlled; ph = phase; R = randomized; SE = side effects; TTS = transdermal therapeutic system; wk = weeks; X = crossover.
*Patch testing performed on at least 17 patients (exact number not reported).
Cutaneous side effects reported in bar graph only (not numerically in text).
Reported as a 3-month cumulative incidence rate.
^§Not reported whether due to cutaneous side effects.

Transdermal Therapeutic System Components and Recommended Patch-Test Concentrations
TTS Component	Recommended Patch-Test Concentrations
Adhesive components
Silicone adhesive	NR
Acrylic adhesive	NR
Polyisobutylene^[35]	1% benzene 2% benzene
Mineral oil^[87]	As is
Active ingredients
Estradiol-17ß^[59]	1% pet 5% pet
Clonidine^[1,95]	0.9% pet 9% pet
Fentanyl	NR
Flurbiprofen^[52]	2% pet
Hydroxyprogesterone^[33,34]	1% in 90% eth
Mesterlone^[34]	1% aq
Nicotine^[9,42,43]	10% aq
Nitroglycerin^[21,25,63]	0.2% pet 0.5% pet 1% pet 2% pet 3% pet 0.2% aq
Progesterone^[34]	1% in 90% eth 1% aq
Scopolamine^[29,59]	1% aq 1% pet 2% pet
Testosterone enanthate^[33,34]	1% in 90% eth 2.5% in oil
Testosterone propionate^[33,34]	1% aq 1% in 90% eth 2.5% in oil
Testosterone undecanoate^[31]	1% in 90% eth 4% in oil
Other components
Acrylate^[59]	0.1% pet 1% pet
Acrylic acid^[59]	0.1% pet
Anhydrous colloidal silicon dioxide	NR
Brown ink	NR
Carrageen^[42,59]	As is
Colloidal silicone fluid	NR
Copolymer foam	NR
Ethanol USP^{[54,55,56,59]}	10% aq 70-95% aq As is
Ethylene vinyl acetate copolymer	NR
Glycerin^[59]	1% aq 10% aq
Glyceryl monoleate^[59]	30% pet
Hydroxyethyl cellulose^[59]	10% aq
Hydroxypropyl cellulose^[35]	1% in 30% eth 2% in 30% eth
Isopropyl myristate^[52,59]	2% pet 5% pet 20% pet 10% eth
Lactose^[96]	As is
Laminated aluminized polyester film	NR
Lanolin^[59,96]	As is
Menthol^[52,59]	1% pet 2% pet 5% pet 8% pet
Methacrylates^[59]	2% pet 5% pet
Methyl laurate	NR
Mineral oil^[59]	As is
Pigmented film	NR
Peppermint oil^[52,59]	2% pet
Plasticizers	NR
Polyolefin	NR
Polyester	NR
Polyethylene glycol (stearate)^[58]	Polyethylene glycol (stearate)^[59]
Polyisobutylene	1% in benzene 2% in benzene
Polypropylene	NR
Polysorbate^[58]	80.5% pet
Polyvinyl alcohol	NR
Povidone^[59]	As is
Propylene glycol^[59]	2% pet
Rubber^[59]	As is
Silicone	NR
Sodium citrate^[59]	1% aq
Sorbitan sesquioleate^[52,59]	20% pet

aq = aqueous; eth = ethanol; NR = not reported; pet = petrolatum; TTS =transdermal therapeutic system; USP = United States Pharmacopeia

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Cutaneous Reactions to Transdermal Therapeutic Systems

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