Long-term experience with transdermal clonidine

Research Paper Clinical Autonomic Research 3, 385-390 (1993)

THE long-term safety and efficacy of transdermal cloni- dine (C-TTS) w a s evaluated in 102 patients with mild to moderate hypertension over a mean treatment period of 4.9 + 1.4 years. C-TTS size 1 was used by 29.4%, C-TTS size 2 by 35.3%; in 35.3% of the patients a diuretic agent was given in addition. The baseline blood pressure of 168/100 m m H g was reduced to 150/85 m m H g at the end of titration and remained stable during long-term treat- ment. After 5 years seated blood pressure was 147/ 83 mmHg. Systemic side-effects, e.g. 4.9% dry mouth, were reported mainly during the first month.

Transient local side-effects occurred main ly between weeks 4-26, thereafter the inc idence clearly d imin i shed and did not cause any withdrawal due to skin reactions from 1 year up to 6.5 years. Overall the long-term transder- mal c lonidine treatment was h igh ly accepted by the pa- tients, was effective and was wel l tolerated.

Key words: Transdermal, Clonidine, Hypertension, Long- term treatment

Long-term (5 year) experience with transdermal clonidine in the t reatment of mild to moderate hypertension

J. B r e i d t h a r d t 1"cA, H. S c h u m a c h e r z and L. M e h l b u r g e r a

~General practitioner and principal investigator, Tangstedter LandstraBe 77, 22415 Hamburg, Germany; 2Medical Data Services-Biometrics Boehringer Ingelheim Deutschland GmbH, Germany; 3Medical Department Boehringer Ingelheim KG, Germany.

CACorresponding Author

Introduction The transdermal application of drugs with

controlled release therapeutic systems offers several advantages over oral dose regimes. By reducing the dose frequency together with the h igh patient acceptance it may improve compliance. By providing constant plasma levels transdermal therapy is able to reduce side-effects which might be related to plasma level peaks and fluctuations. 1,2 On the other hand continuous long-term treatment with transdermal nitroglycercin systems have been associated with tachyphylaxis and skin reactions have been encountered with the transdermal route. 3-5 Clonidine TTS is so far the only once a week transdermal system introduced for the treatment of hypertension. Efficacy and safety of the clonidine TTS is well documented. 6 Compared with oral clonidine treatment the systemic side-effects such as dry mouth and sedation appear to be reduced. >9 Compliance, still a problem especially in the treatment of mild to moderate hypertension, was improved compared with standard drugs) °<3 A loss of efficacy was not observed in long-term treatment. 14-18

However, studies with treatment periods be- tween 2-3 months and some up to 1 year have shown that skin reactions may be a limiting factor for the chronic transdermal clonidine treatment in some patients. 6'17

The aim of our study was to follow-up the safety and efficacy of treatment with transdermal clonidine over a long period of 5 years.

Subjects and Methods One hundred and two white patients (49 male,

53 female; median age 55 years, age range 24-76

© Rapid Communications of Oxford Ltd.

years) with mild to moderate essential hypertension who completed 1-1½ year successful transdermal clonidine treatment entered these follow-up ob- servations. Successful means that blood pressure was controlled (untreated baseline diastolic blood pressure between 90-110 mmHg reduced to _<90 mmHg or reduced at least by 10 mmHg if baseline was _> 100 mmHg) and no contact allergy or other serious adverse event was present.

Prior to transdermal clonidine, 32 (31.4%) patients were treated with oral antihypertensives.

Twenty-five patients received a matrix controlled type of transdermal clonidine system with equi- valent release properties for the first year, whereas 77 patients received the membrane controlled cloni- dine TTS from the beginning.

Patients were excluded if they had significant concurrent illnesses, bradycardia, psychic diseases, alcohol, opiate or drug abuse, concomitant medication which interfere with the antihyperten- sive effect of clonidine, and known skin allergies. Women with child-bearing potential were also excluded. Informed consent was obtained from all patients.

Design: The study was designed as open consecutive follow-up trials with a duration of 1 year each.

During long-term treatment regular visits were performed at 3-monthly intervals. During each visit blood pressure was measured after 5 min sitting and 5 min standing twice using a mercury sphygmoman- ometer and heart rate was likewise recorded. The diastolic pressure was measured using Korotkoff sounds phase V. If the patients reported adverse events following open questions concerning com- plaints since the last visit these events were assessed in detail.

Clinical Autonomic Research. vol 3.1993 385

J. Brddthardt, H. Schumacher and L. Mehlburger

The skin at the application site was examined at each visit for appearance, intensity and location of any skin reactions.

The adhesion of the patch was evaluated at each visit. Every 12 months blood and urine were analysed and an ECG performed.

The patches were applied at weekly intervals on the inner and outer upper arm, chest and back.

According to the titrated dose the patients received one clonidine TTS-1 containing 2.5 mg clonidine/3.5 cm 2 corresponding to an oral dose of 0 . 1m g clonidine/day or one clonidine TTS-2 containing 5.0 mg clonidine/7.0 cm 2 corresponding to an oral dose of 0.2 mg clonidine/day.

I f necessary a diuretic of free choice was added. Dose adjustments were allowed following the clinical requirement, e.g. if the blood pressure was not controlled the dose should be increased. Patients who failed to respond to the maximum dose regime of clonidine TTS-2 in combination with a diuretic should be excluded from the study.

Statistical ana~sis: For evaluation of data descriptive statistics were applied. Intra-individual compar- isons of blood pressure and pulse were performed by paired t-tests.

Results

Treatment period: The mean treatment period was 4 .9- t -1 .4 years with a minimum of 1.5 and a maximum of 7.2 years of continuous transdermal clonidine treatment.

Based on the 102 patients enrolled this represents the experience of 498 patient-years.

The number of patients in the corresponding periods and their outcome can be followed in Table 1.

The percentages given in Fig. 2 refer to the total study populat ion included in the long-term follow-up (n = 102), not to the populat ion included in the two primary studies.

Dosage: During the 6 years the C-TTS dosage and the use of an additional diuretic varied in both directions (increase and decrease). 64.7% of the patients were on clonidine T T S monotherapy and in 35.7% of the patients a combination with an oral diuretic was used constantly or for a certain time. The maximum dosage per interval is shown in Table 2.

Blood pressure : In all dose groups, the mean systolic and diastolic blood pressure in the sitting position

Table 1. Duration of treatment

Number of patients

Period entered completed dropped out a lost to fo l low-up b

> 1-2 years 102 99 3 1 > 2-3 years 98 87 11 3 > 3 - 4 years 84 77 7 - > 4 - 5 years 77 75 2 15 > 5-6 years 60 57 3 6 ° > 6 years 18 18 - 3

During a fo l low-up study. b After completion of a fo l low-up study, no side-effects reported at the last visit. c 33 patients were switched to another transdermal clonidine system.

Table 2. Maximal dosage per interval

C-TTS- 1

Period n %

C-TTS-1 + C-TTS-2 C-TTS-2 +

n % n % n %

ND

n %

Total

n

6-12 weeks 57 55.9 - 12 weeks-1 year 61 59.8 1 > 1-2 years 55 53.9 2 > 2 - 3 years 51 52.0 1 > 3 - 4 years 37 44.0 8 > 4 - 5 years 41 53.2 - :>5-6 years 29 48.3 - > 6 years 12 66.7 -

1.0 2.0 1.0 9.5

34 29 41 24 22 22 20

6

33.3 28.4 40.2 24.5 26.2 28.6 33.3 33.3

11 7 4

2O 16 13

3

10.8 6.9 3.9

20.4 19.0 16.9

5.0

3.9

2.0 1.2 1.3

13.3

102 102 102

98 84 77 60 18

ND = no data. 4- = additional diuretic.

386 Clinical Autonomic Research. vol 3 ' 1993

Long-term experience with transdermal clonidine

Table 3. Systolic and diastolic blood pressure (mmHg, mean 4- SD) at baseline and during long-term treatment

Blood pressure Baseline End of week 12 End of year 2 End of year 5

S i t t i n g n = 1 0 2 n = 1 0 2 n = 1 0 0 n = 6 5

Systolic 168.3 _+ 13.7 148.8 4- 14.1 * 148.2 _+ 11.7* 147.4 4- 9.6* Diastolic 100.0 ± 5.4 84.9 4- 8.6* 82.8 4- 7.1 * 82.7 4- 7.2*

Standing n = 102 n = 102 n = 99 n = 64 Systolic 167.94-15.8 149.8_+16.3" 147.94-13.2" 147.2___10.5" Diastolic 100.0 4- 5.4 84.9 4- 8.6* 82.8 _+ 7.1 * 82.7 4- 7.2*

• p < 0.0001 for difference from baseline levels.

was reduced from 168 ___ 14/100___ 5 mmHg to 148___ 14/85___9mmHg after 12 weeks ( p < 0.0001). During long-term treatment there was a further mild blood pressure reduction to 147 ___ 10/ 83 ___ 7 mmHg (p < 0.01 for the difference in diastolic blood pressure after 5 years compared with week 12). The blood pressure mean values at different times are given in Table 3. The time course of blood pressure during the total treatment period is depicted in Fig. 1.

Response rate: Normal blood pressure (sitting DBP < 90 mmHg) was achieved by 57.8% patients at the end of titration and between 77% and 86% of the patients during long-term treatment. The above mentioned criteria for controlled blood pressure was fulfilled by 89-100% respectively.

Heart rate: The baseline pulse rate of 77.0 ___ 8.6 beats/min in the seated position was reduced by 3-5

beats/min during long-term transdermal clonidine treatment (p < 0.005).

Systemic side-effects: The systemic side-effects listed in Table 4 occurred mainly during the initial phase whereas the following years remained nearly symptom free.

Local side-effects: Only transient mild to moderate skin reactions, mainly erythema and itching under the patch were reported at least once in 52 (51%) patients. After a maximum between week 4 and 12 the incidence of skin reactions declined clearly despite continued transdermal treatment, see Fig. 2. Within the period of 2-4 years only 1-2% of the patients experienced transitory skin irritations.

After 4 years up to 6.5 years no skin reaction was reported. No patient had to be withdrawn from the study due to skin reactions in the period after 1 up to 6.5 years.

Blood pressure mmHg 190

180

170

160

150

140

1.30

120

110

100

9O

8O

I I I

o .3 6

t /

I I I i t t t-k-t-

i L I I I I I 1 I I I } 1 I I I L I I i I I i

12 18 24 30 36 42 48 54 60 66 72 78 months

FIG. 1. Time course of blood pressure during long-term treatment with clonidine ]q'S (mean values _+ SD).

Clinical Autonomic Research .vol 3 .1993 387

j. Breidthardt, H. Schumacher and L. Mehlburger

Table 4. Systemic side-effects (several answers are possible)

> 4 weeks week 1~- _< 6.5 years Total

Side-ef fect n n n %

Dry mouth 3 2 5 4,9 Tiredness 2 - 2 2.0 Dizziness 2 - 2 2.0 Bradycardia - 1 1 1,0 Headache, nausea 1 - 1 1.0 Nausea, vomi t ing 1 - 1 1.0 Nervousness 1 - 1 1.0

Total 10 3 11 10.7

Palienls with s%~n ma~ions

30

~S

20

15

10

5

0

12 18 24 30 56 42 46 54 80 eo 72 78

m~ths

FIG. 2. Frequency of skin reactions during long-term treatment with clonidine OS.

Safety data: NO clinically relevant changes of the laboratory data listed in Table 5 or in ECG were observed during long-term transdermal clonidine treatment. The number of patients in Table 5 varied i n the given range because the data of single parameters are missing in some cases.

Withdrawals: In the course of a follow-up study 26 (25.4%) patients were withdrawn from the study. In four cases (3.9%) due to insufficient efficacy, in two cases (2%) due to side-effects of which one was

because of dry mouth after 5 years and one after 4.2 years because of bradycardia (lowest reported value 64 beats/min) and temporary congestive heart failure, not related to clonidine TTS treatment according to the investigator.

Two cases (2%) classified as other medical reasons not related to clonidine TTS treatment were one patient with intercurrent endocardial infarction and bypass-op after 1.5 years and one case of suicide after 1.8 years. One patient rejected his consent and seven (6.9%) patients were lost to follow-up during the study. Ten (9.8%) patients terminated the study prematurely due to non medical reasons, e.g. moving to another town.

After completion of each 1 year follow-up study some patients or investigators did not continue, so an additional 25 (24.5%) patients were lost to follow-up. In no case were side-effects reported at their last visit.

Adhesiveness: The adhesiveness over 1 week of clonidine TTS and its overlay was good in more than 90% of the observations. Only in seven patients did the C-TTS peel off completely at least once. In one case five detachments were reported. This patient used an additional adhesive strip once, and on the other occasions applied a new patch.

Global assessment: A global assessment of efficacy and tolerance was performed by the investigators every 12 months. Effcacy was judged as good in 75.3-94.4% of the patients and satisfactory in 4.9-23.4%. Unsatisfactory efficacy was reported in 0-3.9% of the patients. Good tolerance was reported in 83.3-100% and satisfactory in 2.9-16.7% of the patients. Only one patient was withdrawn due to dry mouth, in whom the tolerance was judged as unsatisfactory. In general the patients expressed their preference for transdermal clonidine over any other oral treatment. Only seven patients preferred oral medication, two due to insufficient blood pressure control, five due to other non- medical reasons. Fourteen drop-outs or patients who did not continue treatment gave no preference statement.

Table 5. Laboratory data (mean 4- SD)

Baseline After 2 years After > 5 -6 years Parameter n = 1 0 0 - 1 0 2 n = 96 -97 n = 4 8 - 4 9

Haemoglobin (g/al l) 14.8 +_1.3 14.7 _ 1.4 15.5 _+ 1.5 Haematocrit (%) 44.9 _+ 4.5 45.1 __+ 3.9 46.3 _+ 3.8 Erythrocytes ( M i o / # l ) 4.9 _+ 0.6 4.9 + 0.6 5.2 _+ 0.6 Leucocytes (/~1) 6796 _+ 1587 6741 +_ 1728 6565 _+ 1178 Thrombocytes (#1) 205455 _+ 55732 207309 + 43580 220877 + 42210 Gamma-GT (U/ I ) 19.9 4- 9.5 17.5 _+ 5.7 18.1 4- 6.9 Creatinin (mg/ml ) 0.9 4- 0.1 0.8 4- 0.1 0.9 4- 0.1 Glucose (mg/ml ) 92.2 _+ 21.1 92.5 _+ 21.1 92.6 _+ 22.8 Bi l i rubin (mg/d l ) 0.8 -I- 0.2 0.7 4- 0.2 0.7 4- 0.2

388 Clinical Autonomic Research. vol 3 .1993

Long-term experience with transdermal clonidine

D i s c u s s i o n

Orally administered clonidine is a well-proven antihypertensive drug. 1~22 Its efficacy and safety in long-term treatment have been reported in studies lasting up to 10 years. 23'24 A series of studies with oral clonidine pretreatment or against standard drugs have shown that clonidine is equally effective when administered in a transdermal preparation. 6 The majority of the clonidine TTS studies were over treatment periods up to 3 months, some investigators reported long-term treatments of 1 or 2 years. 8'14<8

The aim of our study was a long-term follow-up of 102 patients who successfully completed short-term transdermal clonidine studies. This report is based on a mean treatment period of 5 years.

In the two primary studies to this follow-up observation, five (respectively 12%) of the patients dropped out due to skin reactions, two (respectively 6%) were withdrawn because of lack of efficacy and one (respectively 2%) because of systemic side- effects. 25'26 In this respect the patients of this follow-up study represent a positively selected population. Nevertheless the study demonstrates the potential and reports the experience with chronic transdermal clonidine treatment in general practice.

A reduction of diastolic blood pressure below 90 mmHg was achieved in 58-86% of the patients during long-term treatment. The mean blood pressure reduction of - 1 8 / - 1 5 m m H g at the end of the titration phase was maintained throughout the study and was - 2 1 / - 1 7 mmHg after 5 years. Four patients were withdrawn due to insufficient efficacy after 4 years. Except for single dose adjustments, either increase or decrease there was no trend towards higher dosages which could indicate tolerance development. This is also the case with oral clonidine long-term treatment. 23'24 The systemic side-effects of transdermal clonidine seemed to be reduced compared with oral cloni- dine. 7-9'19 Dry mouth and tiredness, the typical systemic side-effects of oral clonidine, were reported in only 5% and 2% of the patients, respectively. During long-term treatment systemic side-effects were negligible as these side-effects occurred pre- dominately during the initial phase and subsided later.

However as with other transdermal systems, dermatological side-effects at the application site were encountered with the use of clonidine TTS. 4'5 The development of contact dermatitis to clonidine TTS which causes termination of treatment is dependent on race, gender and time. So in the literature the incidence of drop-outs due to skin reactions varied between 5% and 30%.

The majority of contact dermatitis developed within the first 20 weeks, thereafter the incidence seemed to level Off. 27-29 The contact allergy is characterised by intensive reddening of the skin, infiltration and vesiculation as well as severe pruritus under the patch. A contact allergic reaction will reappear with every subsequent application, also on new sites. In the first time 51% of the patients of this long-term follow-up experienced at least once a transient mild to moderate skin reaction, mainly erythema and itching under the patch. These mild reactions can be classified as a not immunological transient skin irritation, because all reactions subside and did not reappear despite continued long-term clonidine TTS treatment. In practice this corresponds to a multiple 7 days local re-exposition test. The reason why these skin irritations were reported more freqently in the first 6 months and disappeared later on cannot be answered by this study. This phenomenon was also observed in the other long-term studies. 14'1s,18 Fillingim reported that during the first year 32% of his 41 patients experienced mild skin irritation and 10% contact allergies. In the second year only 6% of the 33 patients experienced skin irritations and none had contact dermatitis. 14 A major problem of chronic treatment is poor patient compliance. Dosing frequency and side-effects are important factors, 1° Once weekly transdermal clonidine offers advantages over oral preparations in terms of patient acceptance and compliance. In a large-scale trial 87% of 2419 patients felt that transdermal clonidine was more convenient than their previous oral antihypertensive therapy and the investigators judged the compliance to be improved in 64% of the patients. 27

This is in line with the recently published studies comparing transdermal clonidine with captopril, enalapril and diltiazem. In all of these studies the compliance of transdermal clonidine was clearly superior to the oral forms. ~>13

In conclusion, during our long-term study transdermal clonidine was a safe, effective and well- accepted formulation for the treatment of mild to moderate essential hypertension. The incidence of skin reactions levelled off during long-term treatment and did not limit the chronic treatment in this patient population.

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390 Clinical Autonomic Research.vol 3 .1993