THE JOURNAL OF CLINICAL HYPERTENSION VOL. IV NO. II MARCH/APRIL 2002136

The clonidine transdermal therapeutic system isbeing used as a therapy for blood pressure treat-ment. Systemic side effects seem to be fewer thanwith oral clonidine. However, localized skin reac-tions occur frequently and the incidence increaseswith the dose and duration of use. Common signs

include erythema, scaling, vesiculation, excoria-tion, and induration. Allergic contact dermatitis isless frequent but common. Hyperpigmentationand depigmentation also occur. Pretreatment with0.5% hydrocortisone is associated with less skinirritation and higher blood levels. Although oralclonidine is no longer widely used in the manage-ment of hypertension, awareness of these reactionsto the transdermal delivery of this agent is impor-tant. (J Clin Hypertens. 2002;4:136–138) ©2002 Le Jacq Communications, Inc.

Transdermal Clonidine Skin Reactions

L. Michael Prisant, MD

From the Department of Medicine, Section ofCardiology, Hypertension Unit, Medical Collegeof Georgia, Augusta, GAAddress for correspondence:L. Michael Prisant, MD, 1120 15th Street, BBR-6515A, Section of Cardiology, Medical College ofGeorgia, Augusta, GA 30912-3105

Figure 2. A close-up view of erythematous squares onthe chest, showing varying stages of erythema and scal-ing in squares due to transdermal clonidine

Figure 1. Examine the arms and upper chest. What doyou notice?

Figure 3. Diagram of transdermal clonidine delivery system

I m a g e s i n H y p e r t e n s i o nL . M i c h a e l P r i s a n t , M D , S e c t i o n E d i t o r

Backing

Clonidine Reservoir

Rate Control Membrane

Skin Contact Adhesive

Peel Liner

0.2 mm

VOL. IV NO. II MARCH/APRIL 2002 THE JOURNAL OF CLINICAL HYPERTENSION 137

Transdermal clonidine was introduced in 1984as a transcutaneous antihypertensive drug

that can be delivered for up to 168 hours.1,2 Thetransdermal therapeutic system (TTS) for Cat-apres-TTS consists of a 0.2-mm adhesive patchwith a drug reservoir and a rate-controlling mem-brane. Figure 3 shows the design of the deliverysystem. The patient is advised to place the patchon the upper arm or torso and to rotate the site.3

The α2 stimulant in this delivery system, whichresults in decreased sympathetic nerve activity,seems to be better tolerated than oral clonidine interms of dry mouth and drowsiness.4,5 It takes 2−3 days to achieve initial therapeutic blood levels.6On discontinuation, rebound and/or overshoot hy-pertension is less likely to occur, due to the skindepot of clonidine, except in elderly patients.7,8

However, dermatologic reactions occur commonly(Figures 1 and 2 and Table). The patient maycomplain of pruritus, and the objective signs in-clude erythema, scaling, vesiculation, excoriation,and induration.

Several types of dermatologic reactions havebeen reported, including early erythema associatedwith pruritus, allergic contact dermatitis, and al-terations in skin pigmentation.3 Allergic dermatitisoccurs more commonly in whites than in blacks9

and in women than in men.10 One report11 indi-cated that the sensitization rate with clonidineTTS is 34% in white women, 18% in white men,14% in black women, and 8% in black men. De-pigmentation and hyperpigmentation have been

observed in African Americans.12 There is a rela-tionship between duration of patch use and therate of development of allergic dermatitis.13,14

In a single-blind study with a 2-week placebopatch run-in and a 12-week maintenance period,15

the rates of erythema and induration were 52% vs.11% and 24% vs. 0% for active drug vs. placebo,respectively. Fifteen percent of patients discontin-ued treatment due to severe skin reactions.8

Potential causes of the allergic contact dermatitiscould be from the active drug, the adhesive, the dif-fusion membrane, the solvent, or the enhancer.16

Most studies have indicated that the skin reactionsare related to the drug itself and not other fac-tors.13,17 Other transdermal delivery systems areused with nicotine, nitroglycerin, scopolamine,estradiol, and testosterone; cutaneous and allergicreactions are less frequent.16 Treatment with 0.5%hydrocortisone or over-the-counter antacids (mag-nesium-aluminum hydroxide suspension) has beenused to ameliorate skin reactions.18

REFERENCES1 Prisant LM, Bottini B, DiPiro JT, et al. Novel drug-delivery sys-

tems for hypertension. Am J Med. 1992;93:45S–55S.2 Elliott WJ, Prisant LM. Drug delivery systems for antihyperten-

sive agents. Blood Press Monit. 1997;2:53–60.3 Transdermal clonidine for hypertension. Med Lett Drugs Ther.

1985;27:95–96.4 Burris JF, Mroczek WJ. Transdermal administration of cloni-

dine: a new approach to antihypertensive therapy. Pharma-cotherapy. 1986;6:30–34.

5 Weber MA, Drayer JI, Brewer DD, et al. Transdermal continu-ous antihypertensive therapy. Lancet. 1984;1:9–11.

6 Langley MS, Heel RC. Transdermal clonidine. A preliminary

Table. Adverse Skin Reactions With Transdermal Clonidine

AUTHOR (YEAR) N DURATION (WK) SKIN REACTION DERMATITIS

Boekhorst (1983)19 21 4–28 52% 14%Groth et al. (1983)20 29 4 ? 38%McMahon (1983)20 73 12 ? 6%Weber et al. (1984)5 20 12 10% 0%Weber et al. (1984)21 85 12 9% ?Schaller et al.(1985)22 7 4 43% 0%Burris and Mroczek (1986)4 25 4 64% 8%Hollifield (1986)10 2681 12 ? 15%Kellaway and Lubbe (1986)15 135 12 51% 15%Popli et al. (1986)23 30 5 ? 0%McChesney et al. (1987)24 28 12–36 39% 12%Horning et al. (1988)9 20 104 50% ?Fillingim et al. (1989)25 41 88 41% 5%Schmidt et al. (1989)8 22 12–20 50% 23%McMahon et al. (1990)26 39 8 33% 9%Burris et al. (1991)27 23 8 ? 13%Lueg et al. (1991)28 60 8 20% 2%Houston and Hays (1993)29 35 8 29% 9%Weidler et al. (1992)30 66 20 ? 5%

THE JOURNAL OF CLINICAL HYPERTENSION VOL. IV NO. II MARCH/APRIL 2002138

review of its pharmacodynamic properties and therapeutic effi-cacy. Drugs. 1988;35:123–142.

7 Metz S, Klein C, Morton N. Rebound hypertension after dis-continuation of transdermal clonidine therapy. Am J Med.1987;82:17–19.

8 Schmidt GR, Schuna AA, Goodfriend TL. Transdermal cloni-dine compared with hydrochlorothiazide as monotherapy in el-derly hypertensive males. J Clin Pharmacol. 1989;29:133–139.

9 Horning JR, Zawada ET Jr, Simmons JL, et al. Efficacy andsafety of two-year therapy with transdermal clonidine for es-sential hypertension. Chest. 1988;93:941–945.

10 Hollifield J. Clinical acceptability of transdermal clonidine: alarge-scale evaluation by practitioners. Am Heart J.1986;112:900–906.

11 Berardesca E, Maibach HI. Sensitive and ethnic skin. A needfor special skin-care agents? Dermatol Clin. 1991;9:89–92.

12 Doe N, Seth S, Hebert LA. Skin depigmentation related totransdermal clonidine therapy. Arch Intern Med.1995;155:2129.

13 Maibach H. Clonidine: irritant and allergic contact dermatitisassays. Contact Dermatitis. 1985;12:192–195.

14 Dick JB, Northridge DB, Lawson AA. Skin reactions to long-term transdermal clonidine. Lancet. 1987;1:516.

15 Kellaway GS, Lubbe WF. A community-based trial of transder-mal antihypertensive therapy with clonidine (Catapres-TTS). NZ Med J. 1986;99:711–714.

16 Carmichael AJ. Skin sensitivity and transdermal drug delivery.A review of the problem. Drug Saf. 1994;10:151–159.

17 Maibach HI. Oral substitution in patients sensitized by trans-dermal clonidine treatment. Contact Dermatitis. 1987;16:1–8.

18 Ito MK, O'Connor DT. Skin pretreatment and the use of trans-dermal clonidine. Am J Med. 1991;91:42S–49S.

19 Boekhorst JC. Allergic contact dermatitis with transdermalclonidine. Lancet. 1983;2:1031–1032.

20 Groth H, Vetter H, Knusel J, et al. Allergic skin reactions totransdermal clonidine. Lancet. 1983;2:850–851.

21 Weber MA, Drayer JI, McMahon FG, et al. Transdermal ad-ministration of clonidine for treatment of high BP. Arch InternMed. 1984;144:1211–1213.

22 Schaller MD, Nussberger J, Waeber B, et al. Transdermalclonidine therapy in hypertensive patients. Effects on office andambulatory recorded blood pressure values. JAMA.1985;253:233–235.

23 Popli S, Daugirdas JT, Neubauer JA, et al. Transdermal cloni-dine in mild hypertension. A randomized, double-blind, place-bo-controlled trial. Arch Intern Med. 1986;146:2140–2144.

24 McChesney JA, Ryan C, Shaw RE, et al. Transdermal cloni-dine for the treatment of essential hypertension. Compr Ther.1987;13:49–53.

25 Fillingim JM, Matzek KM, Hughes EM, et al. Long-term treat-ment with transdermal clonidine in mild hypertension. ClinTher. 1989;11:398–408.

26 McMahon FG, Jain AK, Vargas R, et al. A double-blind com-parison of transdermal clonidine and oral captopril in essentialhypertension. Clin Ther. 1990;12:88–100.

27 Burris JF, Papademetriou V, Wallin JD, et al. Therapeutic ad-herence in the elderly: transdermal clonidine compared to oralverapamil for hypertension. Am J Med. 1991;91:22S–28S.

28 Lueg MC, Herron J, Zellner S. Transdermal clonidine as an adjunct to sustained-release diltiazem in the treat-ment of mild-to-moderate hypertension. Clin Ther.1991;13:471–481.

29 Houston MC, Hays L. Transdermal clonidine as an adjunct tonifedipine-GITS therapy in patients with mild-to-moderate hy-pertension. Am Heart J. 1993;126:918–923.

30 Weidler D, Wallin JD, Cook E, et al. Transdermal clonidine asan adjunct to enalapril: an evaluation of efficacy and patientcompliance. J Clin Pharmacol. 1992;32:444–449.