INFORMATION FOR HEALTH PROFESSIONALS
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Transdermal Therapeutic System No. 1 (Patch): 2.5mg/3.5cm², printed with Company symbol and BI 31.
Transdermal Therapeutic System No. 2 (Patch): 5mg/7.0cm², printed with Company symbol and BI 32.
Transdermal Therapeutic System No. 3 (Patch): 7.5mg/10.5cm², printed with Company symbol and BI 33.
The rate of release of clonidine and content of clonidine in each system is given in the table below:
| Programmed Delivery In vivo /day Over 1 week |
Clonidine content (mg) |
Size (cm²) | |
|---|---|---|---|
| CATAPRES-TTS-1 | 0.1mg | 2.5 | 3.5 |
| CATAPRES-TTS-2 | 0.2mg | 5.0 | 7.0 |
| CATAPRES-TTS-3 | 0.3mg | 7.5 | 10.5 |
The hypotensive effect of clonidine is produced mostly by its central effect of reducing sympathetic drive. In this respect clonidine differs from previously used anti-hypertensives. Clonidine does not deplete major catecholamine stores and clonidine is neither a ganglion nor an alpha- or beta-adrenergic receptor blocking agent. The specific and different mode of action of clonidine leads to additional benefits such as greatly reduced incidence of postural hypotension and only rarely an effect on libido.
The central action of clonidine appears to be due to direct central α2 adrenergic receptor stimulation, particularly the sympathetic cardio-accelerator and constrictor mechanisms in the bulbar structures of the central nervous system, leading to a decrease in the sympathetic outflow from the brain.
Clonidine, the active ingredient of CATAPRES, is active in very small doses (in the microgram range). Absorption from the gastrointestinal tract is virtually complete.
The plasma half-life of clonidine is between 10 and 20 hours. The half-life does not depend on the age or sex of the patient but is clearly prolonged in patients with severely impaired renal function.
The protein binding, found to be 30-40% in vitro, has no influence on the pharmacokinetics.
40-60% of the dose administered is excreted with the urine in unchanged form and 60-40% in the same manner in the form of metabolites. Approximately 10% of the total amount is excreted with the faeces.
The antihypertensive effect is reached at plasma levels between 0.2 and 1.5 ng/mL in patients with normal excretory function. A further rise in the plasma levels will not enhance the antihypertensive effect in patients with mild to moderate hypertension. However, in patients with severely impaired renal function, i.e. patients requiring dialysis, plasma levels up to 12 ng/mL may be necessary to reduce blood pressure.
CATAPRES-TTS is programmed to release clonidine at an approximately constant rate for 7 days. The energy source for drug release derives from the concentration gradient existing between a saturated solution of drug in the system and the much lower concentration prevailing in the skin. Clonidine flows in the direction of the lower concentration at a constant rate, limited by the rate-controlling membrane, so long as a saturated solution is maintained in the reservoir layer.
Following system application to intact skin, clonidine in the adhesive layer saturates the skin sites below the system. Clonidine from the drug reservoir then begins to flow through the rate-controlling membrane and the adhesive layer of the system into the systemic circulation via the capillaries beneath the skin. Therapeutic plasma clonidine levels are achieved 2 to 3 days after initial application of CATAPRES-TTS.
CATAPRES-TTS, by providing constant steady-state plasma levels, avoids the fluctuations in plasma levels associated with conventional oral CATAPRES. Thus CATAPRES-TTS may provide control of blood pressure at relatively lower clonidine plasma levels than with oral CATAPRES. Clinical experience indicates that in responders satisfactory blood pressure response can be achieved in 40% of cases with CATAPRES-TTS-1, 40% with Catapres-TTS-2 and 20% with CATAPRES-TTS-3. The 3.5, 7.0 and 10.5cm² systems respectively deliver 0.1, 0.2 and 0.3mg clonidine per day. To ensure constant release of clonidine over seven days, the total drug content of the system is greater than the total amount of drug delivered.
Application of a new system to a fresh skin site at weekly intervals continuously maintains therapeutic plasma concentrations of clonidine with very little perturbation in steady-state plasma levels. If the CATAPRES-TTS is removed and not replaced with a new system, the drug levels drop very slowly during the first 10 - 15 hours before showing the characteristic elimination function of the active ingredient clonidine with a half-life of 10 - 20 hours. Over this time period, blood pressure returns gradually to pre-treatment levels. If CATAPRES-TTS is left applied for more than 7 days, the system will continue to release therapeutic plasma levels of clonidine for a further 3-4 days, before declining slowly over several days. If the patient experiences localised skin irritation before completing 7 days of use, the system may be removed and replaced with a new one applied on a fresh skin site.
CATAPRES-TTS is indicated for the treatment of mild to moderate hypertension. It can be used as monotherapy or concomitantly with other antihypertensive agents if required to enhance hypotensive effect.
CATAPRES-TTS dosage should be titrated according to individual patient's therapeutic requirements. Commence with one CATAPRES-TTS-1 applied weekly to a freshly cleaned, hairless area of the upper outer arm or chest. A new site should be used each week when applying new patches. If after two to four weeks the desired reduction in blood pressure is not achieved, increase the weekly dosage by changing to CATAPRES-TTS-2. If this dosage is still not satisfactory after 2-4 weeks therapy then increase the weekly dosage by changing to CATAPRES-TTS-3.
Most patients with mild to moderate hypertension will be controlled on one CATAPRES-TTS-3 or less. In more resistant cases where blood pressure is not satisfactorily controlled on one CATAPRES-TTS-3, it is recommended that a diuretic and/or other antihypertensive agents be added to enhance the hypotensive effect. In this way, the dose of each individual drug may be reduced and side effects minimised. Higher doses of up to two CATAPRES-TTS-3 a week have been utilised.
When substituting CATAPRES-TTS in patients on prior oral antihypertensive therapy, including oral CATAPRES, physicians should be aware that the antihypertensive effect of CATAPRES-TTS might not commence until 2-3 days after initial application. Therefore, gradual reduction of prior drug dosage over 5-6 days is advised.
Instructions on correct application of CATAPRES-TTS are provided on a separate patient leaflet.
Sick-sinus syndrome.
Known hypersensitivity to clonidine or to any other component of the adhesive layer of the system.
Depending on the dose given, CATAPRES-TTS can lower the heart and pulse rate and a reduction to or below 56 beats/minute (bradycardia) should be avoided. In patients with diseases affecting the rhythmic and AV conduction systems of the heart, arrhythmias have been observed after high doses of the active ingredient.
In the case of hypertensive crisis on account of phaeochromocytoma, a hypotensive effect cannot be expected but, where the phaeochromocytoma has not been detected, administration of CATAPRES-TTS will not provoke the crisis.
Physicians considering starting CATAPRES-TTS therapy during the perioperative period must be aware that therapeutic plasma clonidine levels are not achieved until 2 - 3 days after initial application of CATAPRES-TTS.
Although glomerular filtration rate and renal blood flow remain essentially unaltered on CATAPRES-TTS therapy, patients with renal insufficiency should be carefully monitored.
In patients who have developed localised contact sensitisation to CATAPRES-TTS, substitution of oral clonidine therapy may in rare instances be associated with development of a generalised skin rash.
As is recommended for all cardiovascular agents, termination of clonidine treatment should be performed gradually to avoid the possibility of adverse effects. Abrupt cessation of oral clonidine may occasionally result in a rapid rise in blood pressure to pre-treatment levels 24 - 48 hours later which is usually preceded by symptoms of sympathetic overactivity such as tremor, sweating, headache, etc. Prospective studies have demonstrated that blood pressure rising above pre-treatment levels i.e. overshoot, is unlikely to occur at oral dosages of under 1200 mcg daily. The gradual decrease of clonidine plasma levels after cessation of CATAPRES-TTS therapy minimises the risk of symptoms commonly associated with abrupt discontinuation of orally administered cardiovascular agents.
Because of different individual reactions, the ability to drive or operate machinery may be impaired. This must be taken into account particularly in the initial phase of treatment with CATAPRES-TTS, when changing products and in interaction with alcohol.
There is as yet, no experience with the use of CATAPRES-TTS in children under 12 years of age.
There are no well-controlled studies in pregnant women with CATAPRES-TTS but the long term experience with the active ingredient clonidine, show no undesirable or harmful effects during pregnancy in women. Nevertheless, CATAPRES-TTS should be used during pregnancy only when the benefit clearly justifies any possible risk to the foetus. Clonidine enters breast milk, and therefore use of CATAPRES-TTS during the lactating period must be carefully considered.
In the initial phase of treatment mild sedation or tiredness and dryness of the mouth have been observed in some patients which subside, however, as treatment continues.
Treatment with CATAPRES-TTS rarely leads to bradycardia or orthostatic complaints such as drowsiness and giddiness.
In isolated cases constipation, sleep disturbances, impotence or peripheral circulatory disturbances have been observed after oral use of clonidine.
Very rarely after oral doses of clonidine, hypersensitivity reactions (allergies), perceptual disorders, transitory state of confusion, nightmares, gynaecomastia, pain in the parotid gland, depressive moods, drying out of nasal mucosa and reduced lacrymal flow have been reported.
As with other hypotensives, abrupt discontinuation of clonidine, the active ingredient of CATAPRES, in high doses (0.9 mg per day) may, in very isolated cases, cause rise in blood pressure, occasionally accompanied by nervousness, unrest, tachycardia, tremor, headache or nausea. Therefore, antihypertensives should not be discontinued or withdrawn abruptly, without replacement. This also applies the CATAPRES-TTS. Dangerous increase in blood pressure is unlikely following the discontinuation of CATAPRES-TTS because of the particular circumstances with regard to the transdermal use.
Treatment with CATAPRES-TTS may cause local side effects in the form of skin irritation. These include:
Particularly in the initial phase of treatment with CATAPRES-TTS frequently mild (non-allergic) local skin irritation with symptoms such as reddening of the skin and pruritis have been observed which disappear, as a rule, once the patch has been replaced during continued treatment.
In some patients contact-allergic skin reactions with intensive reddening and vesiculation as well as severe pruritis may occur under the matrix of the patch. With such a contact allergy the reactions will reappear with every subsequent application. This delayed allergic contact dermatitis has been commonly observed after 3 - 6 weeks of continuous treatment. Experience to date shows that the allergic contact dermatitis is a type 1V reaction (delayed type hypersensitivity, cell-mediated hypersensitivity). In normal cases, such a skin reaction is unpleasant but not dangerous and disappears completely after 1 - 2 weeks on discontinuation of therapy. In isolated cases, particularly when transdermal therapy is continued, despite these obvious skin reactions, the reactions may spread to other areas of the skin.
In patients with allergic contact dermatitis to CATAPRES-TTS, it is recommended that the transdermal therapy be discontinued and that oral antihypertensive treatment be continued with a different medication. If therapy is continued with oral forms of clonidine, all symptoms of allergic contact dermatitis can reappear.
In isolated cases hypo- and hyperpigmentation of the skin have been observed at the application site of CATAPRES-TTS. In extremely isolated cases angioneurotic oedema have been reported during application of the transdermal CATAPRES systems but its connection with the therapy is doubtful.
The concomitant use of other antihypertensive agents may enhance the blood pressure lowering effect of CATAPRES-TTS. These include diuretics, vasodilators and beta-receptor blockers.
Concomitant use of beta-receptor blockers and/or cardiac glycosides can further lower heart rate (bradycardia) or cause dysrhythmia (AV-block) in isolated cases.
It may be necessary to adjust the dosage of CATAPRES-TTS if tricyclic antidepressant agents are concurrently administered.
If therapy is to be discontinued in patients receiving beta-receptor blockers and CATAPRES-TTS concurrently, the beta-receptor blocker should be gradually discontinued several days before the cessation of CATAPRES-TTS therapy.
Although there is no experience from clinical trials, the effect of
tranquillizers or hypnotics, as well as that of alcohol, can theoretically be
potentiated by the active ingredient of CATAPRES-TTS.
Pallor, miosis, dryness of the mouth, sedation, somnolence, hypotension, orthostatic symptoms, bradycardia, possibly AV block, rare increase in blood pressure after high doses; in severe cases, respiratory depression with short phases of apnoea; rarely vomiting.
Remove CATAPRES-TTS.
In severe cases, symptomatic intensive treatment are necessary (e.g. plasma expander, cardiovascular agents, artificial respiration, external pacemaker). For an increase in heart rate atropine or something similar is recommended.
Store below 30°C.
Store in a safe place out of the reach of children.
Prescription Medicine.
Patch, TTS-1, 2 and 3, 4s.
CATAPRES-TTS® is a registered Trademark
Source Document BPI No.: 0172-00 dated 16.11.1992
CATAPRES-TTS is a multi-layered film, 0.2mm thick, containing clonidine as the active agent. System area is 3.5, 7.0 or 10.5cm² and the amount of drug released is directly proportionally to area. The composition per unit area of all three dosages is identical.
Proceeding from the visible surface towards the surface attached to the skin are four layers:
Cross Section of the System
| Backing | ||
|---|---|---|
| Clonidine Reservoir | ||
| Control Membrane | ||
| Adhesive | ||
| Protective Peel Strip | ||
Boehringer Ingelheim (N.Z.) Limited
P.O. Box 76-216
Manukau City
Auckland.
NEW ZEALAND
Telephone: (09) 262-1356
Facsimile: (09) 262-1462
3 June 1999