clonidine 0.3 mg/day patch generic catapres-tts-3

Uses

Hypertension

Clonidine hydrochloride and transdermal clonidine are used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Although other antihypertensive drug classes (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics) are preferred for the initial management of hypertension in adults, centrally acting agents such as clonidine may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs.

Although many hypertensive patients may be controlled by clonidine alone, the drug may be more effective when used with a diuretic. Clonidine hydrochloride has been used in conjunction with thiazide diuretics, chlorthalidone, or furosemide, producing a greater reduction in blood pressure than is obtained with either drug alone. Use of a diuretic may aid in overcoming tolerance to clonidine and permit reduction of clonidine dosage.

Clonidine may be useful in some patients who are unable to tolerate other adrenergic blocking agents because of severe postural hypotension. However, the possibility that geriatric patients may not tolerate the adverse cognitive effects of central α₂-adrenergic agonists such as clonidine should be considered. Clonidine hydrochloride has been used with other hypotensive agents such as hydralazine, reserpine, or methyldopa, permitting a reduction in the dosage of each drug and, in some patients, minimizing adverse effects while maintaining blood pressure control. As when clonidine is used alone, satisfactory results are obtained in both supine and standing patients during combined drug therapy; marked fluctuations in blood pressure because of postural changes usually do not occur during combined therapy. As with other hypotensive agents, treatment with clonidine is not curative; upon withdrawal of the drug, blood pressure returns to pretreatment levels or greater. (See Cautions: Withdrawal Effects.)

Transdermal clonidine has been effective in many patients for the management of mild to moderate hypertension when used alone or in combination with an oral thiazide diuretic and has also been successfully substituted for oral clonidine hydrochloride in some patients with mild to moderate hypertension whose therapy included the oral form of the drug. The role of transdermal clonidine relative to oral clonidine hydrochloride remains to be more fully evaluated; transdermal clonidine therapy may prove to be convenient in some patients (e.g., those in whom compliance with a daily dosing regimen may be a problem), but adverse dermatologic reactions may occur frequently.

For additional information on overall principles and expert recommendations for treatment of hypertension,

Hypertensive Crises

Oral loading-dose regimens of clonidine hydrochloride have been effective in rapidly reducing blood pressure in patients with severe hypertension in whom reduction of blood pressure was considered urgent, but not requiring emergency treatment. Hypertensive urgencies are those situations in which there is a severe elevation in blood pressure without progressive target organ damage. Hypertensive urgencies can be managed by intensification or reinstitution (e.g., following noncompliance) of the current antihypertensive regimen or with oral doses of short-acting antihypertensive agents such as clonidine hydrochloride followed by several hours of observation; however, there is no evidence suggesting that failure to aggressively reduce blood pressure in these patients is associated with any short-term risk. In fact, overly aggressive management of severe elevations in blood pressure not associated with impending or progressing organ damage can sometimes lead to cumulative hypotensive effects. Excessive falls in blood pressure should be avoided since they may precipitate renal, cerebral, or coronary ischemia.

Clonidine hydrochloride also has been used IV in the management of acute hypertensive crisis and in hypertensive episodes during labor, as well as IM or subcutaneously in the management of late-onset toxemia of pregnancy, with satisfactory results; however, an injectable dosage form is not currently available in the US. When the drug is administered IV, it must be injected very slowly in order to minimize the possible hypertension that may precede its hypotensive effect.

Pain

Clonidine hydrochloride administered by epidural infusion is used as adjunctive therapy in combination with opiates in the management of severe cancer pain that is not relieved by opiate analgesics alone. Epidural administration of analgesics should be considered only when maximum tolerated doses of opiate and adjunct analgesics administered by other routes (e.g., oral, transdermal, subcutaneous, IV) fail to relieve pain.(See Cautions: Precautions and Contraindications.) Consistent with the drug's mechanism of action, epidural clonidine is more likely to be effective in patients with neuropathic pain rather than somatic or visceral pain.

In a double-blind, placebo-controlled, randomized study, cancer patients with severe intractable pain below the cervical dermatomes not controlled by oral, epidural, or IV opiate analgesics received epidural morphine with either clonidine hydrochloride 30 mcg/hour by continuous epidural infusion or placebo for 14 days. Pain relief, measured by a decrease in use of epidural morphine or a decrease in visual analog pain score, was reported in 45 or 21% of patients receiving epidural clonidine or placebo, respectively. In this study, substantial analgesic effects of clonidine appeared to be restricted to patients with neuropathic pain, characterized as localized, burning, shooting, or electric-like pain in a dermatomal or peripheral nerve distribution.

Pheochromocytoma

Clonidine is not indicated in patients with pheochromocytoma; however, unlike reserpine and guanethidine, it does not cause acute cardiovascular collapse in patients with this condition. Because of clonidine's ability to suppress plasma norepinephrine concentration in healthy individuals via stimulation of central α-adrenergic receptors, the drug has been used as an aid in the diagnosis of pheochromocytoma in hypertensive patients with suggestive symptoms and borderline catecholamine values; in patients with pheochromocytoma, plasma norepinephrine concentration is generally unchanged following administration of a single oral dose of clonidine, while patients with sympathetic hyperactivity exhibit a decrease in plasma norepinephrine concentration.

Vascular Headaches

Although clonidine has been used in the prophylaxis of migraine headaches, the efficacy of the drug for this condition is questionable. Results of most studies using α-adrenergic agents (e.g., clonidine) for prevention of migraine headaches indicate that these drugs have limited or no efficacy in most patients, and therefore, some experts state that such use is not recommended. For further information on management and classification of migraine headache,

Dysmenorrhea

Because clonidine reduces the responsiveness of blood vessels to vasodilators or vasoconstrictors, the drug has been used for the treatment of severe dysmenorrhea.

Vasomotor Symptoms Associated with Menopause

Clonidine has been used orally and transdermally for the management of vasomotor symptoms (e.g., hot flashes) associated with menopause. Although limited data indicate that the drug may improve the severity and frequency of vasomotor symptoms in some patients, albeit modestly, the required dosages (exceeding the equivalent of 0.1 mg daily administered orally) may result in increased and, sometimes, intolerable adverse effects. Therefore, some clinicians recommend the use of clonidine for management of vasomotor symptoms mainly in postmenopausal women in whom estrogen replacement therapy is contraindicated or in those with preexisting hypertension.

Opiate Dependence

Clonidine hydrochloride has been used safely and effectively for rapid detoxification in the management of opiate withdrawal in opiate-dependent individuals, in both inpatient and outpatient settings. The exact role of clonidine and its efficacy compared with other methods of detoxification (e.g., methadone) remain to be clearly determined. Clonidine appears to be most useful as a transitional treatment between opiate dependence and administration of the opiate antagonist naltrexone. Clonidine also may be especially useful when detoxification using methadone is inappropriate, unsuccessful, or unavailable.

Alcohol Dependence

Clonidine also has been used in conjunction with benzodiazepines for the management of alcohol withdrawal. Clonidine appears to be effective in reducing symptoms of the hyperadrenergic state associated with alcohol withdrawal, including elevated blood pressure, increased heart rate, tremor, sweating, and anxiety. However, clonidine has not been shown to prevent delirium or seizures, and the drug should be used only as an adjunct to benzodiazepines (not as monotherapy) for the treatment of alcohol withdrawal . Some clinicians state that the use of clonidine may be particularly helpful in patients with certain coexisting conditions (e.g., opiate withdrawal).

Smoking Cessation

Clonidine is used for the management of nicotine (tobacco) dependence. Nicotine dependence is a chronic relapsing disorder that requires ongoing assessment and often repeated intervention. Because effective nicotine dependence therapies are available, every patient should be offered effective treatment, and those who are unwilling to attempt cessation should be provided at least brief interventions designed to increase their motivation to stop tobacco use. The US Public Health Service (USPHS) guideline for the treatment of tobacco use and dependence currently recommends clonidine as a second-line drug for use under the supervision of a clinician. Second-line pharmacotherapy (e.g., clonidine, nortriptyline) is of a more limited role than first-line pharmacotherapy (i.e., bupropion [as extended-release tablets], nicotine polacrilex gum or lozenge, transdermal nicotine, nicotine nasal spray, nicotine oral inhaler, varenicline) in part because of more concerns about potential adverse effects. The use of second-line pharmacotherapy should be considered after first-line therapies have been used without success or are contraindicated. For additional information on smoking cessation, , and also consult the most current USPHS Clinical Practice Guideline on Treating Tobacco Use and Dependence available at http://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/index.html.

Glaucoma

Clonidine hydrochloride has been used topically to reduce intraocular pressure in the treatment of open-angle (chronic simple) and secondary glaucoma and hemorrhagic glaucoma associated with hypertension.

Attention Deficit Hyperactivity Disorder

Clonidine has been used for the treatment of attention deficit hyperactivity disorder (ADHD). Although pooled data from a retrospective analysis of studies in children with ADHD (with and without comorbid conditions [e.g., developmental delay, conduct or tic disorders]) indicate that the drug has produced a moderate reduction in symptoms of ADHD, stimulants (e.g., methylphenidate, amphetamines) remain the drugs of choice for the management of ADHD because of their greater efficacy compared with that of other drugs (e.g., clonidine). Clonidine generally has been shown to be more effective than placebo in the treatment of core symptoms of ADHD, but the magnitude of its effects is lower than with stimulants and efficacy has been established mainly in children with ADHD and comorbid conditions, especially sleep disturbances. However, because clonidine may improve motor tics in patients with Tourette's syndrome, some experts recommend its use as an adjunct to stimulant therapy in pediatric patients with ADHD whose comorbid tic disorder is not controlled by therapy with a stimulant alone. In pediatric patients without such comorbid psychiatric disorders, use of clonidine for the treatment of ADHD usually is not recommended, because of the current lack of evidence establishing safety and efficacy. For a more detailed discussion on the management of ADHD,

Other Uses

Because of its GI effects (see Pharmacology: Other Effects), clonidine hydrochloride has been used with some success in a limited number of patients for the management of diarrhea of various etiologies (e.g., narcotic bowel syndrome, idiopathic diarrhea associated with diabetes).

Dosage and Administration

Administration

Clonidine hydrochloride is administered orally or by epidural infusion, and clonidine is administered percutaneously by topical application of a transdermal system. To ensure overnight blood pressure control with oral administration, the last dose of the day should be administered immediately before retiring. If oral clonidine therapy is to be discontinued, dosage of the drug should be slowly reduced over a period of 2-4 days to avoid the possibility of precipitating the withdrawal syndrome. (See Cautions: Withdrawal Effects.)

Patients receiving transdermal clonidine therapy should be carefully instructed in the use of the transdermal system. To obtain optimum results, patients should also be given a copy of the patient instructions provided by the manufacturer. To expose the adhesive surface of the system, the clear plastic protective strip should be peeled and discarded prior to administration. The transdermal system is applied topically to a dry, hairless area of intact skin on the upper arm or chest by firmly pressing the system with the adhesive side touching the skin. If the system becomes loose during the period of use, an adhesive cover should be applied directly over the system to ensure good adhesion. If the patient develops isolated, mild localized skin irritation before completion of the intended period of use, the system may be removed and replaced with a new system at a different application site. To minimize and/or prevent potential skin irritation, each transdermal system should be applied at a different site (e.g., systems may be applied progressively across the arms and chest in one direction or the other).

Specialized techniques are required for continuous epidural administration of clonidine hydrochloride; the drug should be administered via this route only by qualified individuals familiar with the techniques of administration and patient management problems associated with this route of clonidine administration. Prior to the implantation of a permanent controlled infusion device, screening should be conducted to ensure adequate response to epidural therapy. Chronic epidural analgesia should only be used when adequate pain relief cannot be achieved with less invasive therapies.

The injection for epidural use concentrate containing 500 mcg/mL must be diluted prior to use in sodium chloride 0.9% injection to provide a final concentration of 100 mcg/mL.

For continuous epidural infusion of clonidine hydrochloride, a controlled-infusion device is used to administer the drug. Infusion of clonidine into the upper thoracic spinal segments may be associated with substantial decreases in blood pressure.(See Cautions: Cardiovascular Effects.) The manufacturer states that administration of epidural clonidine above the C4 dermatome is contraindicated because of inadequate safety data supporting such use. Careful monitoring of infusion pump function and inspection of catheter tubing for obstruction or dislodgement is recommended to reduce the risk of inadvertent abrupt withdrawal of epidural clonidine infusion. Clonidine hydrochloride injection for epidural infusion contains no preservatives, and partially used vials of the drug should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

Dosage

To avoid the possibility of precipitating the withdrawal syndrome, clonidine therapy should not be discontinued abruptly. (See Cautions: Withdrawal Effects.)

Hypertension

Dosage of clonidine and clonidine hydrochloride must be adjusted according to the patient's blood pressure response and tolerance. Adverse effects such as drowsiness and dry mouth may be minimized by increasing dosage gradually and/or by taking the larger portion of the daily dose at bedtime.

Tolerance to the hypotensive effect of clonidine or clonidine hydrochloride may develop in some patients necessitating increased dosage or concomitant administration of a diuretic to enhance the hypotensive response to the drug.

Oral Dosage

For the management of hypertension, the usual initial oral dosage of clonidine hydrochloride in adults and children 12 years of age and older is 0.1 mg twice daily. Geriatric patients may benefit from a lower initial dosage of 0.05 mg twice daily. Most clinicians have reported satisfactory results with administration of the drug in 2 or 3 divided doses daily. Dosage may be increased by 0.1 mg at weekly intervals until the desired response is achieved. When clonidine hydrochloride is used alone, the usual oral maintenance dosage ranges from 0.05-0.4 mg twice daily. The manufacturers report 2.4 mg daily to be the maximum effective dosage in adults and children 12 years of age and older.

When combination therapy is required, the commercially available preparations containing clonidine hydrochloride in fixed combination with chlorthalidone should not be used initially. Dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation, the fixed combination may be used. Smaller than usual dosages of clonidine hydrochloride may be adequate in patients who are also receiving diuretics or other hypotensive drugs.

Transdermal Dosage

When transdermal clonidine therapy is used for the management of hypertension in adults and children 12 years of age and older, transdermal therapy is initiated with one system delivering 0.1 mg/24 hours applied once every 7 days. Because of interpatient variability in transdermal absorption, it is recommended that this initial dosage be used in all patients, including those who had been receiving oral clonidine hydrochloride therapy, and that dosage subsequently be titrated according to individual requirements; the relationship between the effective dosage of oral clonidine hydrochloride and that of transdermal clonidine is not predictable.

If the desired reduction in blood pressure is not achieved after 1 or 2 weeks with the initial dosage, dosage may be increased by using 2 systems delivering 0.1 mg/24 hours or a larger dosage system. Subsequent dosage adjustments may be made at weekly intervals. The usual dosage range for transdermal clonidine recommended by some experts is 0.1-0.3 mg/24 hours applied once every 7 days. Transdermal dosages exceeding 0.6 mg/24 hours (2 systems each delivering 0.3 mg/24 hours) are usually not associated with additional efficacy. In patients who develop localized skin irritation during the intended period of use (7 days), it may be necessary to move the transdermal system to a different site or replace it with another system at shorter intervals (e.g., every 3-5 days). Replacement of the transdermal system following a duration of less than 7 days may be required rarely to maintain blood pressure control.

When transdermal therapy is initiated in patients who have been receiving low dosages of oral clonidine hydrochloride, some clinicians recommend continuing the usual oral dosage the first day the initial transdermal system is applied. When transdermal clonidine therapy is administered to patients already receiving other hypotensive agents, dosage of the other hypotensive agents should be gradually reduced when transdermal therapy is initiated since the hypotensive effect of transdermal clonidine may not begin until 2-3 days after application of the initial system; the other hypotensive agents may have to be continued, particularly in patients with more severe hypertension.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of clonidine hydrochloride is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting clonidine hydrochloride dosage in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the .

Hypertensive Crises

For rapid reduction of blood pressure in patients with hypertensive urgencies, clonidine hydrochloride has been administered orally in an initial dose of 0.1-0.2 mg, followed by hourly doses of 0.05-0.2 mg until a total dose of 0.5-0.7 mg has been given or diastolic blood pressure has been controlled. Excessive falls in blood pressure should be avoided since they may precipitate renal, cerebral, or coronary ischemia. Thereafter, maintenance dosage of clonidine should be adjusted according to the patient's response and tolerance.

For rapid reduction of blood pressure in pediatric patients (1-17 years of age) with severe hypertension, some experts recommend an initial oral clonidine hydrochloride dose of 0.05-0.1 mg, which may be repeated up to a total dosage of 0.8 mg.

Pain

Adult Dosage

When used for the relief of severe, intractable cancer pain that is unresponsive to epidural or spinal opiate analgesia or other more conventional methods of analgesia, the recommended initial dosage of clonidine hydrochloride in adults is 30 mcg/hour, administered by continuous epidural infusion. The dosage may be adjusted based on clinical response and tolerance; however, clinical experience with infusion rates exceeding 40 mcg/hour is limited. Patients should be closely monitored, particularly during the first few days of epidural clonidine therapy.

Pediatric Dosage

The recommended initial dosage of epidural clonidine hydrochloride in pediatric patients is 0.5 mcg/kg of body weight per hour. The dosage of epidural clonidine in pediatric patients should be cautiously adjusted based on clinical response.

Pheochromocytoma

As an aid in the diagnosis of pheochromocytoma, clonidine hydrochloride has been administered orally as a single 0.3-mg dose. To conduct the test, patients should rest in the supine position for 30 minutes, after which time, 2 blood samples for baseline determination of catecholamine concentrations are drawn at 5-minute intervals. The 0. 3-mg dose is then administered and blood samples for catecholamine determinations are drawn at hourly intervals for 3 hours. In patients with pheochromocytoma, plasma norepinephrine concentrations generally remain unchanged following administration of clonidine, whereas plasma norepinephrine concentrations generally decrease in patients without pheochromocytoma.

Vascular Headache

The oral dosage of clonidine hydrochloride used in the prophylaxis of migraine is 0.025 mg 2-4 times a day or up to 0.15 mg daily in divided doses.

Dysmenorrhea

For the treatment of dysmenorrhea, 0.025 mg of clonidine hydrochloride has been administered orally twice daily for 14 days before and during menses.

Vasomotor Symptoms Associated with Menopause

Oral Dosage

Oral clonidine hydrochloride dosages of 0.025-0.2 mg twice daily have been employed in the management of vasomotor symptoms (e.g., hot flashes) associated with menopause.

Transdermal Dosage

While comparative efficacy of various transdermal clonidine dosages have not been established, patients in clinical studies have received one transdermal system delivering 0.1 mg/24 hours applied once every 7 days.

Opiate Dependence

For rapid detoxification in the management of opiate withdrawal in opiate-dependent individuals, various dosage regimens of oral clonidine hydrochloride have been used. Dosage must be carefully individualized according to the patient's response and tolerance, and patients must be closely monitored and supervised. Because of varying sensitivity to clonidine's sedative, hypotensive, and withdrawal-suppressing effects, it may be difficult or impossible to establish a dosage regimen that adequately suppresses withdrawal without producing intolerable adverse effects. Some clinicians administer an initial oral test dose of clonidine hydrochloride of 0.005 or 0.006 mg/kg; if signs and symptoms of withdrawal are suppressed, patients then receive an oral dosage of 0.017 mg/kg daily, given in 3 or 4 divided doses, generally for about 10 days. Alternatively, some clinicians have administered an initial oral dosage of 0.1 mg 3 or 4 times daily, with dosage adjusted by 0.1-0.2 mg per day according to the patient's response and tolerance. Dosage usually ranges from 0.3-1.2 mg daily. When clonidine hydrochloride therapy is discontinued, dosage has been reduced by decrements of 50% per day for 3 days and then discontinued, or reduced by 0.1-0.2 mg daily. Clinicians should consult published protocols for more specific information.

Alcohol Dependence

While dosages of clonidine hydrochloride in the management of alcohol dependence have not been established, oral dosages of 0.5 mg twice or 3 times daily have been shown to reduce tremor, heart rate, and blood pressure in patients with alcohol withdrawal.

Smoking Cessation

Optimum dosage of oral clonidine hydrochloride or transdermal clonidine for smoking cessation (nicotine [tobacco] dependence) has not been established, and various regimens have been employed.

Oral Dosage

For use in the cessation of smoking, the initial adult oral dosage of clonidine hydrochloride is typically 0.1 mg twice daily. Therapy with the drug is initiated on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior). Dosage may be increased each week by 0.1 mg daily, if needed. In clinical studies, oral dosages varied from 0.15-0.75 mg daily, without a clear relationship to achievement of cessation of smoking. The duration of oral therapy with clonidine hydrochloride also varied in these studies, ranging from 3-10 weeks.

Transdermal Dosage

When transdermal clonidine is used for the cessation of smoking, therapy is initiated typically in adults with one system delivering 0.1 mg/24 hours applied once every 7 days. Therapy with the drug is initiated on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior). Dosage may be increased at weekly intervals by 0.1 mg/24 hours, if needed. In clinical studies, the transdermal dosage varied from 0.1-0.2 mg/24 hours, without a clear relationship to achievement of cessation of smoking. The duration of transdermal clonidine therapy also varied in these studies, ranging from 3-10 weeks.

Glaucoma

In the treatment of glaucoma, clonidine hydrochloride has been applied topically in the form of 0.125%, 0.25%, or 0.5% ophthalmic solutions or as a 0.1% ophthalmic ointment. The 0.25% solution appears to provide maximum effectiveness with minimum adverse effects.

Attention Deficit Hyperactivity Disorder

For the management of attention deficit hyperactivity disorder (ADHD), the initial oral daily dosage of clonidine hydrochloride in pediatric patients is 0.05 mg given as a single dose at bedtime. Thereafter, dosages may be cautiously increased over a period of 2-4 weeks, in order to minimize development of adverse effects (e.g., sedation). Maintenance dosages of clonidine hydrochloride range from 0.05-0.4 mg daily (depending on tolerance and patient's weight). Usually, pediatric patients may receive the maximum tolerated dosages of clonidine hydrochloride for 2-8 weeks in order to assess treatment response, although it should be considered that onset of action of clonidine may be more variable than that associated with stimulants or antidepressants. The American Heart Association (AHA) states that ECG monitoring is not required in pediatric patients receiving clonidine for ADHD; however, several experts recommend weekly office visits during clonidine titration period to monitor both erect and supine blood pressure and heart rate.

Dosage in Renal Impairment

Smaller than usual dosages of clonidine or clonidine hydrochloride may be adequate in patients with renal impairment. Dosage should be adjusted according to the degree of renal impairment. Some clinicians suggest that adjustment of clonidine hydrochloride dosage is not necessary in patients with creatinine clearances of 10 mL/minute or greater, but those with lower clearances can receive 50-75% of the usual dosage. Supplemental doses after hemodialysis are not necessary.

Cautions

Adverse effects occurring most frequently during oral clonidine hydrochloride therapy are dry mouth, dizziness, drowsiness and sedation, and constipation; these adverse effects appear to be dose related. Headache, fatigue, and weakness also have been reported. Generally, these adverse effects are mild and tend to diminish with continued therapy or may be relieved by a reduction in dosage. Adverse effects occurring with transdermal clonidine generally appear to be similar to those occurring with oral therapy; however, systemic adverse effects with transdermal clonidine appear to be less severe and possibly may occur less frequently than with oral therapy. Most adverse systemic effects occurring during transdermal therapy have been mild and have tended to diminish with continued treatment. The most frequently occurring adverse effects during transdermal therapy have been dry mouth, drowsiness, and local adverse dermatologic effects. Adverse effects reported most frequently in patients with cancer receiving clonidine by epidural infusion in combination with epidural morphine in a controlled clinical trial included hypotension, postural hypotension, and dry mouth, which occurred in 45, 32, and 16% of patients, respectively.

Nervous System Effects

Drowsiness has been reported in about 33, 13, or 12% of patients receiving oral, epidural, or transdermal clonidine, respectively. In addition to drowsiness, sedation, dizziness, headache, fatigue, and weakness, other adverse nervous system effects of clonidine include lethargy, vivid dreams, nightmares, insomnia, behavioral changes, nervousness, restlessness, anxiety, agitation, irritability, mental depression, visual and auditory hallucinations, delirium, localized numbness, and cerebrovascular accidents.

Depression, which occurs often in patients with cancer, may be exacerbated by the use of epidural clonidine. Therefore, the manufacturer recommends that patients be monitored for signs and symptoms of depression (especially those with a history of affective disorders). Sedation and ventilatory abnormalities, usually mild, have been reported in patients receiving bolus epidural doses of clonidine that were substantially higher than the infusion rate recommended for the treatment of cancer pain. Tolerance to these effects may occur with chronic administration of the drug.

GI Effects

Dry mouth has been reported in about 40, 25, or 13% of patients receiving oral, transdermal, or epidural clonidine, respectively. Nausea and vomiting have occurred in about 5% of patients and anorexia and malaise in about 1% of patients receiving oral clonidine. In addition, parotid pain, parotitis, pseudo-obstruction, abdominal pain, and constipation have occurred rarely in patients receiving oral clonidine. Nausea and vomiting were reported in about 13 and 11%, respectively, of patients receiving clonidine by epidural infusion in combination with epidural morphine for the treatment of intractable cancer pain in a controlled clinical trial. Dry throat, constipation, nausea, dysgeusia, anorexia, and vomiting have been reported in patients receiving transdermal clonidine.

Cardiovascular Effects

Orthostatic symptoms have occurred in about 3% of patients receiving oral clonidine; palpitation and tachycardia, and bradycardia have occurred in about 0.5% of patients receiving oral drug. Rare cases of sinus bradycardia and atrioventricular block, with and without concomitant cardiac glycoside therapy, have been reported. Congestive heart failure, Raynaud's phenomenon, flushes, facial pallor, syncope, chest pain, increases in blood pressure, palpitations, and ECG abnormalities (e.g., arrhythmias, sick sinus syndrome disturbances, sinus node arrest, conduction disturbances such as AV block) also have been reported.

Hypotension occurred in about 45% of patients receiving clonidine by epidural infusion as adjunctive therapy with epidural morphine for the treatment of cancer pain. In a 14-day clinical trial, hypotension usually was reported within the first 4 days of epidural clonidine therapy; however, hypotension also occurred throughout the duration of the study. Hypotension, which can be severe, usually responds to treatment with IV fluids and, if necessary, parenteral ephedrine. Hypotension appears to occur more frequently in women, in patients with a lower body weight, and in patients with higher serum clonidine concentrations.

Decreased heart rate has been reported frequently in patients receiving epidural clonidine, while AV block greater than first degree in severity has been reported rarely. Atropine may be used to treat symptomatic bradycardia when necessary. Increases in heart rate associated with hypovolemia may be masked by clonidine therapy.

Metabolic and Endocrine Effects

Weight gain has been reported in about 1% of patients receiving oral clonidine. Some patients gain weight during the first few days of oral clonidine therapy because of sodium and fluid retention. Sodium retention usually lasts only 3 or 4 days and may be avoided or relieved by administration of a diuretic. Gynecomastia has occurred in about 0.1% of patients receiving oral clonidine during clinical trials, and in up to 0.5% of patients during postmarketing experience with transdermal clonidine. Transient elevation of blood glucose concentration after single large doses of clonidine hydrochloride has been reported; however, no effects on glucose metabolism have been reported during long-term use of the drug, and diabetic patients have remained in control while taking clonidine hydrochloride. Rarely, transient elevation of serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations have been associated with use of the drug.

Dermatologic Effects

Rash has occurred in about 1% of patients; pruritus in about 0.7% of patients; angioedema and urticaria in about 0.5% of patients; and alopecia in about 0.2% of patients receiving oral clonidine.

Dermatologic effects were the most frequently occurring adverse effects in clinical trials of transdermal clonidine. In clinical studies, localized skin reactions (i.e., erythema, pruritus) occurred in up to 50% of patients receiving transdermal clonidine therapy. Localized skin reactions occur more commonly in patients who use an adhesive cover over the transdermal system for the entire 7-day application period. Localized skin reactions usually are readily reversible following removal of the transdermal system and have usually not required discontinuance of transdermal therapy. Allergic contact sensitization to clonidine has occurred in about 20% of patients with transdermal therapy, most frequently in white females and least frequently in black males; the dermatitis may require discontinuance of transdermal therapy. Although systemic anaphylactic reactions have not been reported to date, subsequent administration of oral clonidine (or continued administration of transdermal clonidine) to patients who experience allergic reactions with transdermal therapy may result in a recurrence of the reaction or development of a generalized rash, urticaria, or angioedema. (See Cautions: Precautions and Contraindications.) Localized vesiculation, hyperpigmentation (at the application site), edema, excoriation, burning, throbbing, blanching, generalized macular rash, urticaria, contact dermatitis, alopecia, and localized hypopigmentation or hyperpigmentation also have occurred in patients receiving transdermal clonidine.

Genitourinary Effects

Decreased sexual activity, impotence, and loss of libido have occurred in about 3% of patients receiving oral clonidine. Nocturia has occurred in about 1% of patients, difficulty in micturition in about 0.2% of patients, and urinary retention in about 0.1% of patients receiving oral clonidine. Impotence/sexual dysfunction has been reported in about 2% of patients receiving transdermal clonidine, and loss of libido or decreased sexual activity and difficulty in micturition have been reported in up to 0.5% of patients receiving transdermal clonidine.

Hepatic Effects

Mild, transient abnormalities in liver function test results have occurred in about 1% of patients during oral clonidine therapy. Hepatitis has been reported rarely; one case of hepatitis without icterus and hyperbilirubinemia occurred in a patient receiving clonidine hydrochloride, chlorthalidone, and papaverine, but a relationship to clonidine has not been established.

Other Adverse Effects

Muscle or joint pain has occurred in about 0.6% of patients and leg cramps in about 0.3% of patients receiving oral clonidine. Dryness of the nasal mucosa; blurred vision; dryness and burning of the eyes; weakly positive Coombs' test results; fever, pallor, thrombocytopenia, and increased sensitivity to alcohol also have been reported in patients receiving oral clonidine.

Fever, malaise, pallor, muscle or joint pain, and leg cramps have been reported in up to 0.5% of patients during postmarketing experience with transdermal clonidine.

In several studies in albino rats receiving oral clonidine hydrochloride for 6 months or longer, the drug produced a dose-dependent increase in the frequency and severity of spontaneous retinal degeneration. Distribution studies in dogs and monkeys showed that clonidine is concentrated in the choroid of the eye. Ophthalmologic examinations performed prior to and periodically during oral clonidine hydrochloride therapy in humans (for 24 months or longer in some) revealed no evidence of drug-induced ophthalmologic abnormalities, except dry eyes, nor was there evidence of altered retinal function as determined by specialized tests such as electroretinography and macular dazzle. Blurred vision and burning and/or dryness of the eyes have been reported in up to 0.5% of patients during postmarketing experience with transdermal clonidine.

Implantable epidural catheters are associated with a risk of infection, including meningitis and/or epidural abscess. The incidence of catheter-related infections is about 5-20%, and depends on several factors, including the clinical status of the patient, type of catheter used, catheter placement technique, quality of catheter care, and duration of catheter placement. The possibility of catheter-related infection should be considered in patients receiving epidural clonidine who develop a fever.

Withdrawal Effects

Abrupt withdrawal of clonidine therapy may result in a rapid increase of systolic and diastolic blood pressures with associated symptoms such as nervousness, agitation, confusion, restlessness, anxiety, insomnia, headache, sweating, palpitation, increased heart rate, tremor, hiccups, stomach pains, nausea, muscle pains, and increased salivation. The exact mechanism(s) of the withdrawal syndrome following discontinuance of α-adrenergic agonists has not been determined but may involve increased concentrations of circulating catecholamines, increased sensitivity of adrenergic receptors, enhanced renin-angiotensin system activity, decreased vagal function, failure of autoregulation of cerebral blood flow, and/or failure of central α₂-adrenergic receptor mechanisms that regulate sympathetic outflow from the CNS and modulate baroreflex function.

Withdrawal syndrome has been reported in about 1% of patients receiving oral clonidine. The clonidine withdrawal syndrome is more pronounced after abrupt cessation of long-term therapy than after short-term (1-2 months) therapy and has usually been associated with previous administration of high oral dosages (greater than 1.2 mg daily) and/or with continuation of concomitant β-adrenergic blocking therapy. In addition, the risk of adverse effects following abrupt discontinuance of clonidine therapy may be increased in patients with a history of hypertension and/or other underlying cardiovascular conditions.(See Cautions: Precautions and Contraindications.) When the drug is discontinued abruptly, symptoms such as restlessness and headache may begin to appear 2-3 hours after a dose is missed and blood pressure may increase substantially within 8-24 hours. In a few patients, blood pressure exceeded pretreatment levels. Rare cases of hypertensive encephalopathy, cerebrovascular accidents, and death occurring after abrupt cessation of clonidine therapy have been reported. It has been postulated that the risk of precipitating the withdrawal syndrome should be reduced substantially with use of transdermal clonidine because of the pharmacodynamics associated with this dosage form; however, withdrawal symptoms have been reported occasionally (in up to 0.5% of patients) following discontinuance of transdermal therapy or when absorption of the drug was impaired because of dermatologic changes (e.g., contact dermatitis) under the transdermal system. In one patient, withdrawal symptoms (severe rebound hypertension, tachycardia, headache, diaphoresis) appeared approximately 36-72 hours after discontinuance of transdermal therapy but responded to sublingual nifedipine and oral clonidine therapy. In a few geriatric patients, blood pressure has increased to levels exceeding baseline approximately 3-7 days after transdermal therapy was discontinued, although other signs of a hyperadrenergic state were not evident.

An excessive rise in blood pressure after oral or transdermal clonidine withdrawal can be reversed and symptoms relieved by resumption of oral clonidine or by combined administration of α- and β-adrenergic blocking agents (e.g., phentolamine or prazosin with atenolol, labetalol, or propranolol). Rebound hypertension may present a particular problem if oral clonidine therapy must be interrupted for surgery. It has been reported that when the drug was discontinued 8 hours or more prior to surgery, hypertension resulted during and after surgery; however, when clonidine was administered 4-6 hours preoperatively, only minor hypertension developed and hypotension requiring treatment did not occur.

The manufacturer of oral clonidine states that because children frequently experience vomiting associated with GI illnesses, they may be particularly susceptible to hypertensive episodes resulting from sudden inability to ingest the drug.

In a controlled clinical trial in cancer patients receiving epidural clonidine as an adjunct to epidural morphine for the treatment of pain, about 10% of patients receiving 720 mcg of clonidine hydrochloride daily experienced rebound hypertension following abrupt discontinuance of the drug; one patient subsequently suffered a cerebrovascular accident. Rebound hypertension following discontinuance of epidural clonidine can be reversed by administration of clonidine or IV phentolamine. In patients who are receiving concomitant therapy with a β-adrenergic blocking agent, the β-blocker should be discontinued several days prior to discontinuance (by gradual tapering) of epidural clonidine.

Precautions and Contraindications

When clonidine hydrochloride is used as a fixed-combination preparation that includes chlorthalidone, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with clonidine.

Because of the risk of rebound hypertension, patients receiving clonidine preparations should be warned of the danger of missing doses or stopping the drug without consulting their clinician. (See Cautions: Withdrawal Effects.) When discontinuing clonidine therapy, a rapid rise in blood pressure may be minimized or prevented by tapered withdrawal of the drug over 2-4 days. Tapered withdrawal of transdermal clonidine or initiation of a tapered regimen of oral clonidine also is recommended by some clinicians when the transdermal dosage form is discontinued, particularly in geriatric patients. If clonidine therapy is to be discontinued in patients receiving clonidine and a β-adrenergic blocking agent concomitantly, the β-adrenergic blocker should be discontinued several days before clonidine therapy is discontinued. It is recommended that clonidine therapy not be interrupted for surgery; transdermal therapy can be continued throughout the perioperative period and oral therapy should be continued to within 4 hours before surgery. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if necessary. If clonidine therapy must be interrupted for surgery, parenteral hypotensive therapy should be administered as necessary, and clonidine therapy should be resumed as soon as possible. If transdermal therapy is initiated during the perioperative period, it must be kept in mind that therapeutic plasma clonidine concentrations are not achieved until 2-3 days after initial application of the transdermal system.

Clonidine transdermal systems should be removed from the site(s) of application prior to attempting defibrillation or cardioversion since altered electrical conductivity and enhanced potential for electrical arcing may occur.

Patients receiving transdermal clonidine therapy should be advised that if the transdermal system begins to loosen from the skin after application, an adhesive cover should be applied directly over the system to ensure good adhesion over the period of application. Patients receiving transdermal therapy who develop moderate or severe localized erythema and/or localized vesicle formation at the application site or who develop a generalized rash should consult their physician promptly about the need to remove the transdermal system. If patients develop isolated, mild localized skin irritation before completion of the intended period of use (7 days), the system may be removed and replaced with a new system at a different application site. In patients who develop localized contact sensitization to clonidine with transdermal therapy, subsequent administration of oral clonidine hydrochloride (or continued administration of transdermal clonidine) may be associated with development of a generalized rash. In patients receiving transdermal therapy who develop an allergic reaction, subsequent administration of oral clonidine hydrochloride also may elicit an allergic reaction (e.g., generalized rash, urticaria, angioedema). Patients receiving transdermal clonidine therapy should be instructed to keep both used and unused transdermal systems out of the reach of children. In addition, these patients should be cautioned that even after use, the transdermal system contains active medication that may be harmful if accidentally applied or ingested by infants or children.(See Acute Toxicity: Manifestations.) Patients should be instructed to handle the used transdermal system carefully (e.g., fold the system in half with the sticky sides together) and to dispose of the system out of the reach of children.

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

Epidural clonidine should be used only in patients with severe cancer pain that has failed to respond to an adequate trial with opiate analgesics. The drug is not recommended for the management of obstetric, postpartum, or perioperative pain. Careful monitoring of infusion pump function and inspection of catheter tubing for obstruction or dislodgement is recommended to reduce the risk of accidental abrupt withdrawal of epidural clonidine. Patients should be instructed to notify their clinician immediately in case of inadvertent interruption of epidural clonidine administration. Specialized techniques are required for continuous epidural administration of clonidine hydrochloride; the drug should be administered via this route only by qualified individuals familiar with the techniques of administration and patient management problems associated with this route of clonidine administration. Epidural drug administration is contraindicated in patients receiving anticoagulant therapy, in those with a bleeding diathesis, and in the presence of an injection site infection. Administration of epidural clonidine also is not recommended in most patients with severe cardiovascular disease or in patients who are hemodynamically unstable. The manufacturer states that administration of epidural clonidine above the C4 dermatome is contraindicated because of inadequate safety data supporting such use.

Clonidine should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, conduction disturbances, cerebrovascular disease, chronic renal failure, Raynaud's disease, or thromboangiitis obliterans. Patients with a history of mental depression require careful supervision while receiving clonidine as they may be subject to further depressive episodes. Patients who engage in potentially hazardous activities such as operating machinery or driving should be warned of the possible sedative effect of the drug. In addition, patients should be informed that clonidine may be additive with, or may potentiate the action of, other CNS depressants such as opiate agonists or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol.

The possibility that clonidine may lower blood pressure in patients receiving the drug for conditions other than hypertension (e.g., smoking cessation, pain management, attention deficit hyperactivity disorder) should be considered, and blood pressure should be monitored as appropriate. In addition, the possibility of rebound hypertension and other withdrawal effects should be considered when the drug is discontinued in such patients; abrupt discontinuance should be avoided.

A dose-dependent increase in the incidence and severity of spontaneously occurring retinal degeneration was observed in albino rats receiving the drug for 6 months or longer, especially those receiving strong exposure to light. Although serious adverse ophthalmologic effects have not been reported in patients receiving clonidine, periodic eye examinations should be performed in patients receiving the drug.

Clonidine is contraindicated in patients with known hypersensitivity to the drug or to any ingredient or component in the formulation.

Pediatric Precautions

Safe use of oral clonidine hydrochloride for the management of attention deficit hyperactivity disorder in children has not been established, but clinical studies are currently under way to determine pediatric safety and efficacy. Safety and efficacy of oral clonidine hydrochloride and clonidine transdermal system for the management of hypertension in children younger than 12 years of age have not been established. Some experts have recommended oral dosages of clonidine for pediatric patients 1-17 years of age with severe hypertension based on currently limited clinical experience. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, . The safety and efficacy of clonidine hydrochloride epidural infusion have been established in pediatric patients who are old enough to tolerate placement and management of an epidural catheter, based on evidence from adequate, well-controlled studies in adults and experience with the use of clonidine in pediatric patients for other indications. Epidural clonidine should be used only in pediatric patients with severe, intractable cancer pain that is unresponsive to epidural or spinal opiates and to other conventional analgesic therapy.

Children may be more likely to experience CNS depression associated with clonidine overdosage than adults. In children, signs of toxicity have occurred with clonidine doses as low as 0.1 mg. Rare cases of clonidine toxicity (many involving children) associated with accidental or deliberate mouthing or ingestion of clonidine transdermal systems have been reported.

The manufacturer of oral clonidine states that because children frequently experience vomiting associated with GI illnesses, they may be particularly susceptible to hypertensive episodes resulting from sudden inability to ingest the drug.

Mutagenicity and Carcinogenicity

There was no evidence of clonidine-induced mutagenesis in vitro in the Ames microbial mutagen test. Clonidine was not clastogenic in the mouse micronucleus test. Studies to determine the carcinogenic potential of clonidine were performed in rats receiving oral dosages up to 46 times the maximum recommended human dosage on a mg/kg basis for 132 weeks and in mice receiving up to 70 times the maximum recommended human dosage on a mg/kg basis for up to 78 weeks. These dosages were approximately 9 and 6 times the maximum recommended human daily dosage on a mg/m basis in rats and mice, respectively.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rabbits using oral clonidine hydrochloride dosages up to about 3 times the maximum recommended human dosage have not revealed evidence of teratogenicity or embryotoxicity. However, in female rats receiving the drug continuously for 2 months prior to mating, an increased incidence of fetal resorptions occurred with oral dosages as low as one-third the maximum recommended human dosage (1/15th the maximum recommended human dosage on a mg/m basis); resorptions were not increased when these or higher dosages (up to 3 times the maximum recommended human dosage) were administered during days 6-15 of gestation. An increased incidence of fetal resorptions was observed when much higher dosages (40 times the maximum recommended human dosage on a mg/kg basis and 4-8 times the maximum recommended human dosage on a mg/m basis) were administered to mice and rats during days 1-14 of gestation; the lowest dosage used in the study was 0.5 mg/kg. There are no adequate and controlled studies to date using clonidine in pregnant women, and the drug should be used during pregnancy only when clearly needed.

Fertility

Reproduction studies in rats using oral clonidine hydrochloride dosages up to 0.15 mg/kg daily (about 3 times the maximum recommended human dosage) have not revealed evidence of impaired fertility; however, fertility in female rats was impaired at oral dosages ranging from 0.5-2 mg/kg daily (about 10-40 times the maximum recommended human oral dosage on a mg/kg basis [2-8 times the maximum recommended human dosage on a mg/m basis]).

Lactation

Since clonidine is distributed into milk, the drug should be used with caution in nursing women. The manufacturer of parenteral clonidine states that because of the potential for serious adverse reactions to clonidine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

CNS Depressants

Clonidine may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol. Concomitant administration of opiate analgesics with clonidine also may potentiate the hypotensive effects of clonidine.

Psychotherapeutic Agents

Tricyclic antidepressants (i.e., imipramine, desipramine) have reportedly inhibited the hypotensive effect of clonidine. The increase in blood pressure usually occurs during the second week of tricyclic antidepressant therapy, but occasionally may occur during the first several days of concomitant therapy. The possibility of this interaction should be considered in patients receiving clonidine and tricyclic antidepressants concomitantly; blood pressure should be closely monitored during the first several weeks of concurrent therapy, and dosage of clonidine should be increased to adequately control hypertension if necessary. Alternatively, other hypotensive agents that do not interact with tricyclic antidepressants may be substituted, but clonidine therapy should not be discontinued abruptly. If tricyclic antidepressant therapy is discontinued in patients receiving clonidine, the hypotensive effect of clonidine may increase; blood pressure should be monitored and dosage of clonidine reduced if necessary. In rats, concurrent administration of clonidine and amitriptyline has produced corneal lesions within 5 days. The effects of tricyclic antidepressants on the analgesic effect of epidural clonidine hydrochloride are not known.

Clonidine withdrawal may result in an excess of circulating catecholamines; therefore, caution should be exercised in concomitant use of drugs which affect the metabolism or tissue uptake of these amines (monoamine oxidase inhibitors or tricyclic antidepressants, respectively).

Acute delirium has been reported in at least one patient receiving fluphenazine concomitantly with oral clonidine. The symptoms resolved following discontinuance of clonidine and recurred upon rechallenge with the drug.

Cardiovascular Drugs

When clonidine is administered with other hypotensive agents, including diuretics, the hypotensive effect of clonidine may be increased. This effect is usually used to therapeutic advantage in antihypertensive therapy; however, careful adjustment of dosage is necessary when these drugs are used concomitantly.

Because clonidine may produce bradycardia and atrioventricular (AV) block, the possibility of additive effects should be considered if it is given concomitantly with other drugs that affect sinus node function or AV nodal conduction (e.g., guanethidine), β-adrenergic blocking agents (e.g., propranolol), calcium-channel blocking agents, or cardiac glycosides.

Because β-adrenergic blocking agents may exacerbate rebound hypertension that may occur following discontinuance of clonidine therapy, β-adrenergic blocking agents should be discontinued several days before gradual withdrawal of clonidine when clonidine therapy is to be discontinued in patients receiving a β-adrenergic blocking agent and clonidine concurrently. If clonidine therapy is to be replaced by a β-adrenergic blocking agent, administration of the β-adrenergic blocking agent should be delayed for several days after clonidine therapy has been discontinued.

Other Drugs

Epidural clonidine may prolong the duration of the pharmacologic effects, including both sensory and motor blockade, of epidural local anesthetics.

Pharmacokinetics

Absorption

Clonidine hydrochloride is well absorbed from the GI tract. The drug may also be absorbed when applied topically to the eye. Clonidine is well absorbed percutaneously following topical application of a transdermal system to the arm or chest. Plasma clonidine concentrations of 2 ng/mL have been detected 1 hour after administration of a single 0.39-mg oral dose of radiolabeled drug. Peak plasma concentrations following oral administration occur in approximately 3-5 hours.

Following initial application of a transdermal system of clonidine, the initial release of the drug saturates skin sites beneath the system; therapeutic plasma concentrations are attained within 2-3 days. To provide the concentration gradient necessary for controlled release and percutaneous absorption of drug, clonidine transdermal systems contain an excess amount of drug. Following removal of the systems in one study in healthy adults, analysis of residual concentration of drug in transdermal systems that initially contained 2.5 mg of clonidine per 3.5 cm surface area indicated that release of clonidine averaged 48 and 65% after 7 and 11 days of wear, respectively, following topical application to the upper outer arm and averaged 70% after 11 days of wear following topical application to the chest. When given in dosages that produce comparable blood pressure reduction, steady-state plasma clonidine concentrations attained with the transdermal systems are generally similar to trough concentrations attained with twice-daily oral dosing regimens of the drug. Mean steady-state plasma clonidine concentrations of 0.39, 0.84, or 1.12 ng/mL have been reported following topical application of the 3.5-, 7-, or 10.5-cm transdermal system (see Preparations), respectively, to the upper outer arm of healthy adults. Percutaneous absorption of the drug from the upper arm or chest is similar, but less drug is absorbed from the thigh. Replacement of the transdermal system at a different site at weekly intervals continuously maintains therapeutic plasma clonidine concentrations. Following discontinuance of transdermal therapy, therapeutic plasma drug concentrations persist for about 8 hours and then decline slowly over several days; over this time period, blood pressure returns gradually to pretreatment levels. If a transdermal system of clonidine is not removed after 7 days as recommended, absorption of the drug from the system may continue; if an additional system is then applied, higher plasma drug concentrations may result and, if an additional system is not applied, plasma drug concentrations may not decrease substantially for at least 2-4 more days while the system is still being worn.

Reduction in blood pressure is maximal at plasma clonidine concentrations less than 2 ng/mL. Blood pressure begins to decrease within 30-60 minutes after an oral dose of clonidine hydrochloride; the maximum decrease occurs in approximately 2-4 hours. The hypotensive effect lasts up to 8 hours. Following administration of clonidine by slow IV injection in patients with acute hypertensive crisis, a hypotensive effect occurred within minutes, peaked in 30-60 minutes, and lasted more than 4 hours.

Following epidural administration of a single bolus dose of clonidine in healthy individuals and patients with cancer, clonidine is rapidly absorbed into the systemic circulation. A mean peak plasma clonidine concentration of 4.4 ng/mL (range: 3-5.8 ng/mL) was reported on average 19 minutes following epidural administration of 700 mcg of clonidine hydrochloride given over 5 minutes in healthy individuals. Mean peak plasma concentrations of clonidine were reported to be higher in women than in men. Following continuous epidural infusion of clonidine hydrochloride (30 mcg/hour for 14 days in addition to administration of morphine sulfate for patient-controlled analgesia [PCA]) in cancer patients, mean steady-state plasma concentrations were approximately 2.2 and 2.4-2.5 ng/mL on days 7 and 14 of dosing, respectively. Accumulation of clonidine does not appear to occur following continuous epidural infusion of the drug in adult cancer patients.

Following epidural administration of a single dose of clonidine hydrochloride, near maximal analgesia occurs within 30-60 minutes. Onset and duration of the analgesic effect of a single epidural dose of clonidine do not correlate with plasma drug concentrations; rather, analgesic effects appear to correlate with drug concentration in the CSF. Although the CSF is not the presumed site of action of clonidine-mediated analgesia, the drug appears to diffuse rapidly from the CSF to the dorsal horn. A lumbar CSF concentration of 130 ng/mL reportedly was associated with a 95% maximal analgesic effect in healthy individuals.

Distribution

Animal studies indicate that clonidine is widely distributed into body tissues; tissue concentrations of the drug are higher than plasma concentrations. The mean volume of distribution of clonidine is reported to be 2.1 L/kg. After oral administration, highest concentrations of the drug are found in the kidneys, liver, spleen, and GI tract. High concentrations of the drug also appear in the lacrimal and parotid glands. Clonidine is concentrated in the choroid of the eye and is also distributed into the heart, lungs, testes, adrenal glands, fat, and muscle. The lowest concentration occurs in the brain. Clonidine is distributed into CSF. Following epidural infusion, clonidine is rapidly and extensively distributed into CSF and readily partitions into the plasma via epidural veins. In vitro, clonidine is approximately 20-40% bound to plasma proteins, mainly albumin. Clonidine crosses the placenta and is distributed into milk. In one lactating woman who received approximately 0.04 mg of oral clonidine hydrochloride twice daily and 25 mg of oral dihydralazine 3 times daily, clonidine concentrations were 0.33 ng/mL in a plasma sample obtained 1 hour after a dose and 0.6 ng/mL in a milk sample obtained 2.5 hours after a dose; the drug was not detected in the plasma of the infant 1 hour after nursing.

Elimination

The plasma half-life of clonidine is 6-20 hours in patients with normal renal function. The half-life in patients with impaired renal function has been reported to range from 18-41 hours. The elimination half-life of the drug may be dose dependent, increasing with increasing dose.

Clonidine hydrochloride is metabolized in the liver. In humans, 4 metabolites have been detected but only one, the inactive p-hydroxyclonidine, has been identified.

In humans, 40-60% of an orally administered dose of clonidine hydrochloride is excreted in urine as unchanged drug within 24 hours. Following IV administration of radiolabeled clonidine, 72% of the administered dose is excreted in urine within 96 hours; about 40-50% is excreted as unchanged drug. In humans, less than 10% of a dose usually is excreted as p-hydroxyclonidine. Approximately 20% of the dose is excreted in feces, probably via enterohepatic circulation. Approximately 85% of a single dose is excreted within 72 hours, and excretion is complete after 5 days. Following IV administration of clonidine, renal clearance of the drug averages 133 mL/minute. In patients undergoing hemodialysis, only 5% of a dose was removed into the dialysate. Following continuous epidural infusion of clonidine hydrochloride (30 mcg/hour for 14 days in addition to morphine sulfate administered for patient-controlled analgesia [PCA]) in cancer patients, mean total body clearance of the drug was approximately 279 and 272 mL/minute on days 7 and 14 of dosing, respectively.