CLONIDINE

Clonidine transdermal system USP provides continuous systemic delivery of clonidine USP for 7 days at an approximately constant rate. Clonidine USP is a centrally acting alpha-agonist hypotensive agent. It is an imidazoline derivative with the chemical name 2, 6-dichloro-N-2-imidazolidinylidenebenzenamine and has the following chemical structure: C 9 H 9 Cl 2 N 3 M.W. 230.10 Chemical Structure System Structure and Components Clonidine transdermal system USP is a multi-layered film, 0.2 mm thick, containing clonidine USP as the active agent. The system areas are 4.33 cm 2 (clonidine USP 0.1 mg per day), 8.67 cm 2 (clonidine USP 0.2 mg per day) and 13 cm 2 (clonidine USP 0.3 mg per day) and the amount of drug released is directly proportional to the area (see Release Rate Concept ). The composition per unit area is the same for all three doses. The inactive ingredients are: aluminum, colloidal silicon dioxide, ethylene vinyl acetate copolymer, light mineral oil, microporous polypropylene membrane, pigmented polyethylene polyester film, polyisobutylene and silicon coated polyester film. Proceeding from the visible surface towards the surface attached to the skin, there are four consecutive layers: 1) a backing layer of polyester film; 2) a drug reservoir; 3) a microporous polypropylene membrane that controls the rate of delivery of clonidine USP from the system to the skin surface; 4) an adhesive formulation. Prior to use, a protective slit release liner of silicone coated polyester film that covers the adhesive layer is removed. Cross Section of the System: Figure Release Rate Concept Clonidine transdermal system USP is programmed to release clonidine USP at an approximately constant rate for 7 days. The energy for drug release is derived from the concentration gradient existing between a saturated solution of drug in the system and the much lower concentration prevailing in the skin. Clonidine USP 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 drug reservoir. Following system application to intact skin, clonidine USP in the adhesive layer saturates the skin site below the system. Clonidine USP 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 USP levels are achieved 2 to 3 days after initial application of clonidine transdermal system USP. The 4.33, 8.67 and 13 cm 2 systems deliver 0.1, 0.2, and 0.3 mg of clonidine USP 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 USP. If the clonidine transdermal system USP is removed and not replaced with a new system, therapeutic plasma clonidine USP 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.

Clonidine transdermal system is indicated in the treatment of hypertension. It may be employed alone or concomitantly with other antihypertensive agents.

Apply clonidine transdermal system once every 7 days to a hairless area of intact skin on the upper outer arm or chest. Each new application of clonidine transdermal system should be on a different skin site from the previous location. If the system loosens during 7 day wearing, the adhesive cover should be applied directly over the system to ensure good adhesion. There have been rare reports of the need for patch changes prior to 7 days to maintain blood pressure control. To initiate therapy, clonidine transdermal system dosage should be titrated according to individual therapeutic requirements, starting with clonidine transdermal system 0.1 mg. If after one or two weeks the desired reduction in blood pressure is not achieved, increase the dosage by adding another clonidine transdermal system 0.1 mg or changing to a larger system. An increase in dosage above two clonidine transdermal system 0.3 mg is usually not associated with additional efficacy. When substituting clonidine transdermal system for oral clonidine or for other antihypertensive drugs, physicians should be aware that the antihypertensive effect of clonidine transdermal system may not commence until 2 to 3 days after initial application. Therefore, gradual reduction of prior drug dosage is advised. Some or all previous antihypertensive treatment may have to be continued, particularly in patients with more severe forms of hypertension. Renal Impairment Patients with renal impairment may benefit from a lower initial dose. 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.

Clonidine transdermal system should not be used in patients with known hypersensitivity to clonidine or to any other component of the therapeutic system.

Clinical Trial Experience With Clonidine Transdermal System Most systemic adverse effects during clonidine transdermal system therapy have been mild and have tended to diminish with continued therapy. In a 3 month multi-clinic trial of clonidine transdermal system 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 system 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 system 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 system 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 Clonidine Transdermal System The following adverse reactions have been identified during post-approval use of clonidine transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to clonidine transdermal system. Body as a Whole: Fever; malaise; weakness; 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 AV 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; hallucinations (including visual and auditory); localized numbness; vivid dreams or nightmares; restlessness; anxiety; agitation; irritability; other behavioral changes; and drowsiness. Dermatological: Angioneurotic edema; localized or generalized rash; hives; urticaria; contact dermatitis; pruritus; alopecia; and localized hypo or hyper pigmentation. 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 tablets, but in many cases patients were receiving concomitant medication and a causal relationship has not been established. Body as a Whole: Fatigue; fever; headache; pallor; weakness; and withdrawal syndrome. Also reported were a weakly positive Coombs' test and increased sensitivity to alcohol. Cardiovascular: Bradycardia; congestive heart failure; electrocardiographic abnormalities (i.e., sinus node arrest; junctional bradycardia; high degree AV block and arrhythmias); orthostatic symptoms; palpitations; Raynaud's phenomenon; syncope; and tachycardia. Cases of sinus bradycardia and AV block have been reported, both with and without the use of concomitant digitalis. Central Nervous System: Agitation; anxiety; delirium; delusional perception; hallucinations (including visual and auditory); insomnia; mental depression; nervousness; other behavioral changes; paresthesia; restlessness; sleep disorder; and vivid dreams or nightmares. Dermatological: Alopecia; angioneurotic edema; hives; pruritus; rash; and urticaria. Gastrointestinal: Abdominal pain; anorexia; constipation; hepatitis; malaise; mild transient abnormalities in liver function tests; nausea; parotitis; pseudo-obstruction (including colonic pseudo-obstruction); salivary gland pain; and vomiting. Genitourinary: Decreased sexual activity; difficulty in micturition; erectile dysfunction; loss of libido; nocturia; and urinary retention. Hematologic: Thrombocytopenia. Metabolic: Gynecomastia; transient elevation of blood glucose or serum creatine phosphokinase; and weight gain. Musculoskeletal: Leg cramps and muscle or joint pain. Oro-otolaryngeal: Dryness of the nasal mucosa. Ophthalmological: Accommodation disorder; blurred vision; burning of the eyes; decreased lacrimation; and dryness of the eyes.

Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose. If a patient receiving clonidine is also taking neuroleptics, orthostatic regulation disturbances (e.g., orthostatic hypotension, dizziness, fatigue) may be induced or exacerbated. Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers, and beta-blockers. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil. Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (see Toxicology ).

STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.