Other
Clonidine Transdermal System 0.1 mg/day
Clonidine Transdermal System 0.2 mg/day
Clonidine Transdermal System 0.3 mg/day
Clonidine Transdermal System
Formulated to deliver in vivo 0.1, 0.2, or
0.3 mg clonidine per day, for one week.
Rx only
Prescribing Information
System Structure and Components: Clonidine Transdermal System is a multi-laminate patch, 0.3 mm thick, containing clonidine as the active agent. The patch surface areas are 10.8 cm2 (Clonidine Transdermal System 0.1 mg/day), 21.6 cm2 (Clonidine Transdermal System 0.2 mg/day), and 32.4 cm2 (Clonidine Transdermal System 0.3 mg/day). The composition per unit area is the same for all three doses.
Proceeding from the outer printed backing layer towards the surface applied to the skin, the system comprises: 1) a backing layer of polyethylene/aluminum/polyester film; 2) a drug reservoir layer of clonidine, isopropyl palmitate, and amine-compatible silicone adhesive; 3) an ethylene vinyl acetate (EVA) membrane that controls the rate of clonidine delivery from the system to the skin; 4) an amine-compatible silicone adhesive layer (ADHESIVE LAYER B); 5) an acrylate adhesive layer (ADHESIVE LAYER C) that attaches to the skin; and 6) a protective release liner of siliconized polyester that is removed prior to use.
Cross-sectional view of the Clonidine Transdermal System.
Not to scale.
Cross-sectional View Of The Clonidine Transdermal System (Not to Scale)
Release Rate Concept: Clonidine Transdermal System is designed to deliver clonidine through the skin at an approximately constant rate for 7 days. Saturated clonidine in the reservoir layer provides a concentration gradient between the system and the skin. Clonidine diffuses from the higher concentration in the system to the lower concentration in the skin. The rate of delivery from the system is primarily controlled by passage of clonidine through the EVA membrane.
When a patch is applied to the skin (after removal of the protective release liner), clonidine dissolved in adhesive layers B & C is delivered to the skin. The EVA membrane then becomes the principal factor controlling clonidine delivery from the system by regulating clonidine release from the reservoir. A constant clonidine driving force is maintained by the drug reservoir layer, which contains a uniform dispersion of clonidine crystals. Clonidine is delivered through the skin and into the systemic circulation via the capillaries beneath the skin. Therapeutic plasma clonidine levels are achieved 2 to 3 days after initial application of Clonidine Transdermal System to the skin.
The 10.8, 21.6, and 32.4 cm2 systems deliver 0.1, 0 2, and 0.3 mg of clonidine per day, respectively. To ensure constant release of drug for 7 days, the total drug content of the system is higher 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. If the Clonidine Transdermal System is removed and not replaced with a new system, therapeutic plasma clonidine levels will persist for about 8 hours and then decline slowly over several days. Over this time period, blood pressure returns gradually to pretreatment levels.
Withdrawal: Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with Clonidine Transdermal System, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology.
An excessive rise in blood pressure following discontinuation of Clonidine Transdermal System therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of Clonidine Transdermal System.
Perioperative Use: Clonidine Transdermal System therapy should not be interrupted during the surgical period. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. Physicians considering starting Clonidine Transdermal System therapy during the perioperative period must be aware that therapeutic plasma clonidine levels are not achieved until 2 to 3 days after initial application of Clonidine Transdermal System (See DOSAGE AND ADMINISTRATION).
Defibrillation or Cardioversion: The transdermal clonidine systems should be removed before attempting defibrillation or cardioversion because of the potential for altered electrical-conductivity which may increase the risk of arcing, a phenomenon associated with the use of defibrillators.
Toxicology: In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid.
In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged.
In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.
MRI: Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because the Clonidine Transdermal Patch contains aluminum, it is recommended to remove the system before undergoing an MRI.
Clinical trial experience with transdermal systems containing clonidine: Most systemic adverse effects during transdermal system therapy containing clonidine have been mild and have tended to diminish with continued therapy. In a 3-month multiclinic trial of clonidine transdermal therapy in 101 hypertensive patients, the systemic adverse reactions were, dry mouth (25 patients) and drowsiness (12), fatigue (6), headache (5), lethargy and sedation (3 each), insomnia, dizziness, impotence/sexual dysfunction, dry throat (2 each) and constipation, nausea, change in taste and nervousness (1 each).
In the above mentioned 3-month controlled clinical trial, as well as other uncontrolled clinical trials, the most frequent adverse reactions were dermatological and are described below.
In the 3-month trial, 51 of the 101 patients had localized skin reactions such as erythema (26 patients) and/or pruritus, particularly after using an adhesive cover throughout the 7-day dosage interval. Allergic contact sensitization to clonidine transdermal therapy was observed in 5 patients. Other skin reactions were localized vesiculation (7 patients), hyperpigmentation (5), edema (3), excoriation (3), burning (3), papules (1), throbbing (1), blanching (1), and a generalized macular rash (1).
In additional clinical experience, contact dermatitis resulting in treatment discontinuation was observed in 128 of 673 patients (about 19 in 100) after a mean duration of treatment of 37 weeks. The incidence of contact dermatitis was about 34 in 100 among white women, about 18 in 100 in white men, about 14 in 100 in black women, and approximately 8 in 100 in black men. Analysis of skin reaction data showed that the risk of having to discontinue clonidine transdermal treatment because of contact dermatitis was greatest between treatment weeks 6 and 26, although sensitivity may develop either earlier or later in treatment.
In a large-scale clinical acceptability and safety study by 451 physicians in a total of 3539 patients, other allergic reactions were recorded for which a causal relationship to clonidine transdermal treatment was not established: maculopapular rash (10 cases); urticaria (2 cases); and angioedema of the face (2 cases), which also affected the tongue in one of the patients.
Marketing Experience with transdermal systems containing clonidine: Other adverse effects reported since the drug has been marketed are listed below by body system. In this setting, an incidence or causal relationship cannot always be accurately determined. However, none of the events listed below occurred in a frequency greater than 0.5%.
Body as a Whole: Fever; malaise; weakness; and pallor, and withdrawal syndrome.
Cardiovascular: Congestive heart failure; cerebrovascular accident; electrocardiographic abnormalities (i.e., bradycardia, sick sinus syndrome disturbances and arrhythmias); chest pain; orthostatic symptoms; syncope; increases in blood pressure; sinus bradycardia and atrioventricular block with and without the use of concomitant digitalis; Raynaud's phenomenon; tachycardia; bradycardia; and palpitations.
Central and Peripheral Nervous System/Psychiatric: Delirium; mental depression; visual and auditory hallucinations; localized numbness; vivid dreams or nightmares; restlessness; anxiety; agitation; irritability; other behavioral changes; and drowsiness.
DermatologicaI: Angioneurotic edema; localized or generalized rash; hives; urticaria; contact dermatitis; pruritus; alopecia; and localized hypo or hyperpigmentation.
Gastrointestinal: Anorexia and vomiting.
Genitourinary: Difficult micturition; loss of libido; and decreased sexual activity.
Metabolic: Gynecomastia or breast enlargement and weight gain.
Musculoskeletal: Muscle or joint pain, and leg cramps.
Ophthalmological: Blurred vision; burning of the eyes and dryness of the eyes.
Adverse Events Associated with Oral Clonidine Therapy: Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The following less frequent adverse experiences have also been reported in patients receiving clonidine hydrochloride USP, but in many cases patients were receiving concomitant medication and a causal relationship has not been established.
Body as a Whole: Weakness, about 10 in 100 patients; fatigue, about 4 in 100; headache and withdrawal syndrome each about 1 in 100. Also reported were pallor; a weakly positive Coombs' test; increased sensitivity to alcohol; and fever.
Cardiovascular: Orthostatic symptoms, about 3 in 100 patients; palpitations and tachycardia, and bradycardia, each about 5 in 1000. Syncope, Raynaud's phenomenon, congestive heart failure, and electrocardiographic abnormalities (i.e., sinus node arrest, functional bradycardia, high degree AV block and arrhythmias) have been reported rarely. Rare cases of sinus bradycardia and AV block have been reported, both with and without the use of concomitant digitalis.
Central Nervous System: Nervousness and agitation, about 3 in 100 patients; mental depression, about 1 in 100 and insomnia, about 5 in 1000. Other behavioral changes, vivid dreams or nightmares, restlessness, anxiety, visual and auditory hallucinations and delirium have rarely been reported.
Dermatological: Rash, about 1 in 100 patients; pruritus, about 7 in 1000; hives, angioneurotic edema and urticaria, about 5 in 1000; alopecia, about 2 in 1000.
Gastrointestinal: Nausea and vomiting, about 5 in 100 patients; anorexia and malaise: each about 1 in 100; mild transient abnormalities in liver function tests, about 1 in 100; hepatitis, parotitis, constipation, pseudo-obstruction, and abdominal pain, rarely.
Genitourinary: Decreased sexual activity, impotence and loss of libido, about 3 in 100 patients; nocturia, about 1 in 100; difficulty in micturition, about 2 in 1000; urinary retention, about 1 in 1000.
Hematologic: Thrombocytopenia, rarely.
Metabolic: Weight gain, about 1 in 100 patients; gynecomastia, about 1 in 1000; transient elevation of blood glucose or serum creatine phosphokinase, rarely.
Musculoskeletal: Muscle or joint pain, about 6 in 1000 and leg cramps, about 3 in 1000.
Oro-otolaryngeal: Dryness of the nasal mucosa was rarely reported.
Ophthalmological: Dryness of the eyes, burning of the eyes and blurred vision were reported.
Renal Impairment: Dosage must be adjusted according to the degree of impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.
