Clonidine

CLONIDINE — clonidine patch
Physicians Total Care, Inc.

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

DESCRIPTION

Clonidine Transdermal System is a transdermal system (patch) providing 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:

Chemical Structure

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 ScaleChemical StructureCross-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.

CLINICAL PHARMACOLOGY

Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent.

Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15%-20%) of cardiac output in the supine position with no change in the peripheral resistance; at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance.

During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic responses to exercise.

Tolerance to the antihypertensive effect may develop in some patients, necessitating a reevaluation of therapy.

Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated.

Clonidine acutely stimulates the release of growth hormone in children as well as adults but does not produce a chronic elevation of growth hormone with long-term use.

Pharmacokinetics: The plasma half-life of clonidine is 12.7 ± 7 hours. Following oral administration, about 40-60% of the absorbed dose is recovered in the urine as unchanged drug within 24 hours. The remainder of the absorbed dose is metabolized in the liver.

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

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

WARNINGS

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.

PRECAUTIONS

General: In patients who have developed localized contact sensitization to Clonidine Transdermal System continuation of Clonidine Transdermal System or substitution of oral clonidine hydrochloride therapy may be associated with development of a generalized skin rash.

In patients who develop an allergic reaction to Clonidine Transdermal System, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

Clonidine Transdermal System should be used with caution in patients with severe coronary insufficiency, conduction disturbances: recent myocardial infarction, cerebrovascular disease, or chronic renal failure.

In rare instances, loss of blood pressure control has been reported in patients using clonidine transdermal systems according to the instructions for use.

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.

Information for Patients: Patients should be cautioned against interruption of Clonidine Transdermal System therapy without their physician’s advice.

Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. They should also be informed that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs.

Patients should be instructed to consult their physicians promptly about the possible need to remove the patch if they observe moderate to severe localized erythema and/or vesicle formation at the site of application or generalized skin rash.

If a patient experiences isolated, mild localized skin irritation before completing 7 days of use, the system may be removed and replaced with a new system applied to a fresh skin site.

If the system should begin to loosen from the skin after application, the patient should be instructed to place the adhesive cover directly over the system to ensure adhesion during its 7-day use.

Used Clonidine Transdermal System patches contain a substantial amount of their initial drug content which may be harmful to infants and children if accidentally applied or ingested. THEREFORE, PATIENTS SHOULD BE CAUTIONED TO KEEP BOTH USED AND UNUSED CLONIDINE TRANSDERMAL SYSTEM PATCHES OUT OF THE REACH OF CHILDREN. After use, Clonidine Transdermal System should be folded in half with the adhesive sides together and discarded away from children’s reach.

Instructions for use, storage and disposal of the system are provided at the end of this monograph. These instructions are also included in each box of Clonidine Transdermal System.

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.

Due to a potential for additive effects such as bradycardia and AV block, caution is warranted 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.

Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (See Toxicology).

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 to 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the AMES test for mutagenicity or mouse micronucleus test for clastogenicity.

Fertility of male and female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times the MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m2 basis).

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