Clonidine Transdermal System USP, 0.1 mg/day

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

DOSAGE AND ADMINISTRATION Apply Clonidine Transdermal System, USP 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, USP 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, USP dosage should be titrated according to individual therapeutic requirements, starting with Clonidine Transdermal System USP, 0.1 mg/day. If after one or two weeks the desired reduction in blood pressure is not achieved, increase the dosage by adding another Clonidine Transdermal System USP, 0.1 mg/day or changing to a larger system. An increase in dosage above two Clonidine Transdermal Systems USP, 0.3 mg/day is usually not associated with additional efficacy. When substituting Clonidine Transdermal System, USP for oral clonidine or for other antihypertensive drugs, physicians should be aware that the antihypertensive effect of Clonidine Transdermal System, USP may not commence until 2‐3 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.

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

ADVERSE REACTIONS 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. Musculosk …

Drug Interactions 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 ).

System Structure and Components Clonidine Transdermal System, USP is a multi-layered film, 0.2 mm thick, containing clonidine as the active agent. The system areas are 3.5 cm 2 (Clonidine Transdermal System USP, 0.1 mg/day), 7.0 cm 2 (Clonidine Transdermal System USP, 0.2 mg/day) and 10.5 cm 2 (Clonidine Transdermal System USP, 0.3 mg/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. Proceeding from the visible surface towards the surface attached to the skin, there are four consecutive layers: 1) a backing layer of pigmented polyester and aluminum film; 2) a drug reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide; 3) a microporous polypropylene membrane that controls the rate of delivery of clonidine from the system to the skin surface; 4) an adhesive formulation of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide. Prior to use, a protective slit release liner of polyester that covers the adhesive layer is removed. Cross Section of the System: cross-section-table

Release Rate Concept Clonidine Transdermal System, USP, is programmed to release clonidine 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 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 in the adhesive layer saturates the skin site 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 Clonidine Transdermal System, USP, 0.1 mg/day. The 3.5, 7.0, and 10.5 cm 2 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, USP 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.

Pharmacokinetics Clonidine transdermal system delivers clonidine at an approximately constant rate for 7 days. The absolute bioavailability of clonidine from the clonidine transdermal system dosage form is approximately 60%. Steady-state clonidine plasma levels are obtained within 3 days after transdermal application to the upper outer arm and increase linearly with increasing size of the transdermal patch. Mean steady-state plasma concentrations with the 3.5 cm 2 , 7.0 cm 2 and 10.5 cm 2 systems are approximately 0.4 ng/mL, 0.8 ng/mL, and 1.1 ng/mL, respectively. Similar clonidine steady-state concentrations are reached after application to the chest. Steady-state clonidine plasma levels remain constant after removal of one system and application of a new system of the same size. Following intravenous administration clonidine displays biphasic disposition with a distribution half-life of about 20 minutes and an elimination half-life ranging from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Clonidine has a total clearance of 177 mL/min and a renal clearance of 102 mL/min. The apparent volume of distribution (V z ) of clonidine is 197 L (2.9 L/ …

DESCRIPTION Clonidine Transdermal System, USP provides continuous systemic delivery of clonidine for 7 days at an approximately constant rate. Clonidine 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: System Structure and Components Clonidine Transdermal System, USP is a multi-layered film, 0.2 mm thick, containing clonidine as the active agent. The system areas are 3.5 cm 2 (Clonidine Transdermal System USP, 0.1 mg/day), 7.0 cm 2 (Clonidine Transdermal System USP, 0.2 mg/day) and 10.5 cm 2 (Clonidine Transdermal System USP, 0.3 mg/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. Proceeding from the visible surface towards the surface attached to the skin, there are four consecutive layers: 1) a backing layer of pigmented polyester and aluminum film; 2) a drug reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide; 3) a microporous polypropylene membrane that controls the rate of delivery of clonidine from the system to the skin surface; 4) an adhesive formulation of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide. Prior to use, a protective slit release liner of polyester that covers the adhesive layer is removed. Cross Section of the System: cross-section-table Release Rate Concept Clonidine Transdermal System, USP, is programmed to release clonidine 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 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 in the adhesive layer saturates the skin site 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 Clonidine Transdermal System, USP, 0.1 mg/day. The 3.5, 7.0, and 10.5 cm 2 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, USP 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. clonidine structure

OVERDOSAGE Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children. If symptoms of poisoning occur following dermal exposure, remove all clonidine transdermal systems. After their removal, the plasma clonidine levels will persist for about 8 hours, then decline slowly over a period of several days. Rare cases of clonidine transdermal system poisoning due to accidental or deliberate mouthing or ingestion of the patch have been reported, many of them involving children. There is no specific antidote for clonidine overdosage. Ipecac syrup‐induced vomiting and gastric lavage would not be expected to remove significant amounts of clonidine following dermal exposure. If the patch is ingested, whole bowel irrigation may be considered and the administration of activated charcoal and/or cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine‐induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Dialysis is not likely to significantly enhance the elimination of clonidine. The largest overdose reported to date, involved a 28‐year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/mL after 1 hour, 190 ng/mL after 1.5 hours, 370 ng/mL after 2 hours, and 120 ng/mL after 5.5 and 6.5 hours. In mice and rats, the oral LD 50 of clonidine is 206 and 465 mg/kg, respectively.

HOW SUPPLIED Clonidine Transdermal System USP, 0.1 mg/day, Clonidine Transdermal System USP, 0.2 mg/day, and Clonidine Transdermal System USP, 0.3 mg/day are supplied as 4 pouched systems and 4 adhesive covers per carton. See chart below. Programmed Delivery Clonidine in vivo Per Day Over 1 Week Clonidine Content Size Code Clonidine Transdermal System USP, 0.1 mg/day NDC 52817-610-04 0.1 mg 2.5 mg 3.5 cm 2 BI-31 Clonidine Transdermal System USP, 0.2 mg/day NDC 52817-611-04 0.2 mg 5.0 mg 7.0 cm 2 BI-32 Clonidine Transdermal System USP, 0.3 mg/day NDC 52817-612-04 0.3 mg 7.5 mg 10.5 cm 2 BI-33