Transdermal Clonidine

Summary

Synopsis

The clonidine transdermal therapeutic system (TTS) is a cutaneous delivery device which provides therapeutically effective doses of clonidine at a constant rate over 7 days. In clinical trials it reduces blood pressure in patients with mild to moderate hypertension as effectively as oral clonidine but with greater stability of blood pressure control. Most patients find the transdermal system more convenient than oral treatments, and compliance may be improved. The side effects known to occur with orally administered clonidine, dry mouth and sedation in particular, are also produced with transdermal administration, but possibly at a lower incidence than during oral treatment. A proportion of patients experience adverse skin reactions with the transdermal system.

At this stage of its development, transdermal clonidine has not been adequately compared with other ‘standard’ antihypertensive treatments such as diuretics or β-adrenoceptor blocking drugs. However, despite the lack of such comparative studies, transdermal clonidine represents a worthwhile new approach to antihypertensive therapy, particularly in terms of patient convenience.

Pharmacodynamic Properties

Clonidine is a centrally acting α-adrenoceptor agonist which reduces sympathetic outflow and decreases blood pressure through a sustained reduction in total peripheral resistance. When transdermal clonidine systems are applied to normotensive volunteers both systolic and diastolic blood pressures decrease steadily until a maximum reduction is reached after 2 or more days. This is then maintained for at least 7 days, or until the system is removed, after which blood pressures return to pretreatment values over a period of 3 to 4 days.

In hypertensive patients, transdermal clonidine at doses of 0.1 to 0.3 mg/day reduces sitting systolic and diastolic blood pressures by up to 15% and 19%, respectively, and daily variations in blood pressure are considerably reduced in comparison to oral clonidine therapy. A sustained reduction in heart rate does not occur during treatment, although an initial decrease may occur when therapy is started.

Plasma noradrenaline (norepinephrine) concentrations are significantly reduced by up to 36% during transdermal clonidine treatment, and plasma renin activity was decreased in some studies. Although basal sympathetic activity is reduced, exercise-induced increases in blood pressure, heart rate, plasma noradrenaline concentrations and plasma renin activity are not significantly affected by the treatment.

Pharmacokinetic Properties

The transdermal system is designed to release clonidine at a constant rate over 7 days. Studies in volunteers demonstrated that plasma concentrations rise to a maximum after 3 to 4 days, and that this level can subsequently be maintained over long periods without significant fluctuation. Transdermal doses of approximately 0.1 to 0.5 mg/day produce mean plasma concentrations of 0.2 to 2.1 Mg/L, effectively spanning the theoretical ‘therapeutic window’ of 0.2 to 2.0 µg/L. However, the plasma concentration produced by a particular transdermal dose of clonidine varies considerably between individuals as a result of interindividual variation in renal clearance (between 2.6 and 10.8 L/h). The elimination half-life of transdermal clonidine is approximately 19 hours.

Therapeutic Trials

In non-comparative studies of transdermal clonidine as monotherapy in the treatment of mild to moderate hypertension, and 1 double-blind comparison with placebo, blood pressure was effectively controlled in at least 60 to 80% of patients, while a diuretic was the only additional requirement to achieve adequate control in some other patients. Treatment has been continued successfully for up to 2 years in a small number of patients, and increases in dose were not required in most such patients. A number of crossover comparisons have demonstrated that patients can be successfully transferred from oral to transdermal clonidine therapy without loss of blood pressure control, and in a short term, double-blind comparative study transdermal clonidine 0.1 to 0.3 mg/day was equivalent to propranolol 40 to 120mg twice daily in terms of efficacy and side effects.

Evaluation of the acceptability of this type of treatment showed that 87% of more than 2000 patients thought transdermal clonidine to be more convenient than previous oral treatments. In the same study, patient compliance was considered by the physicians to be better in 65% of patients when compared with oral treatments.

Side Effects

The major systemic side effects that occur with transdermal clonidine therapy are dry mouth and drowsiness. These are generally mild and transient, and usually appear during the first few weeks of treatment. Interestingly, drowsiness occurred almost as frequently with placebo as with transdermal clonidine, but dry mouth appears to be a ‘true’ drug-induced effect. The incidence of systemic side effects with transdermal therapy may be lower than with oral clonidine. However, a proportion of patients experience skin reactions to the clonidine TTS which range from mild erythema resulting from irritant action, to full allergic contact dermatitis. The former usually arises during the early stages of treatment and may be resolved by changing the site of application, while the latter has a later onset and requires treatment to be stopped. Importantly, the severe rebound hypertension that occurs in some patients on abrupt withdrawal of oral clonidine therapy does not appear to be a problem when discontinuing transdermal clonidine.

Dosage and Administration

The clonidine TTS should be applied to a hairless area of the upper arm or chest and then replaced at 7-day intervals using a different skin site. Treatment should be started at 0.1 mg/day (i.e. one 3.5 cm² clonidine TTS patch) and then, if necessary, increased at 1- or 2-weekly intervals until the blood pressure is satisfactorily reduced. The dose should not exceed 0.6 mg/day (i.e. two 10.5 cm² clonidine TTS patches).