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Clonidine

Pronunciation

Class: Central alpha-Agonists
VA Class: CV490
CAS Number: 4205-90-7
Brands: Catapres, Catapres-TTS, Clorpres, Duraclon

Warning(s)

  • Dilution Warning
  • Concentrate for epidural injection must be diluted prior to administration.151

  • Obstetric, Postpartum, and Perioperative Pain
  • Not recommended for obstetric, postpartum, or perioperative pain management.151

  • Risk of hemodynamic instability, especially hypotension and bradycardia, from epidural use may be unacceptable in these patients.151

  • Rarely, potential benefits may outweigh possible risks in obstetric, postpartum, or perioperative patients.151

Introduction

Imidazoline-derivative hypotensive agent; selective α2-adrenergic agonist.153

Uses for Clonidine

Hypertension

Used alone or in combination with other classes of antihypertensive agents in the management of hypertension.181 185

Thiazide diuretics are considered the preferred initial monotherapy for uncomplicated hypertension by JNC 7.181 184 185

May be more effective when used with a diuretic.b

Has been used in conjunction with thiazide diuretics, chlorthalidone, or furosemide, producing a greater reduction in BP than is obtained with either drug alone.b

Use of a diuretic may aid in overcoming tolerance to clonidine and permit reduction of clonidine dosage.b

May be useful in some patients unable to tolerate other adrenergic blocking agents because of severe postural hypotension;b geriatric patients may not tolerate the adverse cognitive effects of central α2-adrenergic agonists such as clonidine.135

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 BP control.b

Transdermal clonidine has been effective in many patients for the management of mild to moderate hypertension when used alone106 107 108 109 117 118 or in combination with an oral thiazide diuretic.106 110 115 118

Transdermal clonidine has been successfully substituted for oral clonidine hydrochloride in mild to moderate hypertension.106 110 115

Role of transdermal versus oral therapy remains to be more fully evaluated;105 106 107 108 109 110 115 116 117 118 transdermal therapy may prove to be convenient (e.g., in those in whom compliance with a daily dosing regimen may be a problem),110 116 135 136 but adverse dermatologic reactions occur frequently.105 108 109 115 116 117

The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage.167 183 184 The higher the baseline BP, the more likely the development of MI, heart failure, stroke, and renal disease.167 183 184

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Effective antihypertensive therapy reduces the risk of stroke by about 34–40%, MI by about 20–25%, and heart failure by more than 50%.167 173 184 190

Antihypertensive drug therapy is recommended for all patients with SBP/DBP ≥140/90 mm Hg who fail to respond to lifestyle/behavioral modifications.167

Initial antihypertensive therapy with drugs generally is recommended for anyone with diabetes mellitus, chronic renal impairment, or heart failure having SBP ≥130 mm Hg or DBP ≥80 mm Hg.181 182 184 189 191

Hypertensive Crises

Oral clonidine, including loading-dose regimens, has been effective in rapidly reducing BP in patients with severe hypertension when reduction of BP was considered urgent (i.e., hypertensive urgency), but not requiring emergency treatment.b

Hypertensive urgencies are those situations in which it is desirable to reduce BP within a few hours.135 185

Avoid excessive falls in BP since they may precipitate renal, cerebral, or coronary ischemia.125 135

Recommended by some experts to be administered orally for rapidly reducing BP in pediatric patients 1–17 years of age when reduction of BP is considered a hypertensive urgency or in some hypertensive emergencies.187

Has been used IV in the management of acute hypertensive crisis and in hypertensive episodes during labor, as well as IM or sub-Q in the management of late-onset toxemia of pregnancy, with satisfactory results; however, other antihypertensives are preferred.185

Pain

Used epidurally as adjunctive therapy in combination with opiates in the management of severe cancer pain that is not relieved by opiate analgesics alone.151 155

Epidural analgesia should be considered only when maximum tolerated doses of opiate and adjunct analgesics administered by other routes (e.g., oral, transdermal, sub-Q, IV) fail to relieve pain.145 155

Epidural clonidine is more likely to be effective in patients with neuropathic pain rather than somatic or visceral pain.151 155

Opiate Dependence

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.b

Exact role and its efficacy compared with other methods of detoxification (e.g., methadone) remain to be clearly determined.b

Appears to be most useful as a transitional treatment between opiate dependence and administration of the opiate antagonist naltrexone.b

May be especially useful when detoxification using methadone is inappropriate, unsuccessful, or unavailable.b

Alcohol Dependence

Has been used in conjunction with benzodiazepines for the management of alcohol withdrawal.148 149 150

May be effective in reducing symptoms of the hyperadrenergic state associated with alcohol withdrawal, including elevated BP, increased heart rate, tremor, sweating, and anxiety.148 154

Has not been shown to prevent delirium or seizures, and should be used only as an adjunct to benzodiazepines (not as monotherapy) for the management of alcohol withdrawal.149 150 154

Smoking Cessation

Used for the management of nicotine (tobacco) dependence.167

Nicotine dependence is a chronic relapsing disorder that requires ongoing assessment and often repeated intervention.167

US Public Health Service (USPHS) currently recommends clonidine as a second-line drug for use under the supervision of a clinician.167

Second-line pharmacotherapy (e.g., clonidine, nortriptyline, combined therapy with 2 forms of nicotine replacement) is of a more limited role than first-line pharmacotherapy (i.e., bupropion [as extended-release tablets], nicotine polacrilex gum, transdermal nicotine, nicotine nasal spray, nicotine nasal inhaler) in part because of more concerns about potential adverse effects with second-line drugs than with first-line drugs.167

Use of second-line pharmacotherapy should be considered after first-line pharmacotherapy was attempted or considered and should be individualized based on patient considerations.167

Attention Deficit Hyperactivity Disorder

Has been used for the treatment of attention deficit hyperactivity disorder (ADHD).161 162 163 164

Produces a moderate reduction in symptoms of ADHD;163 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).161 162 168 169 170 171 172 173 174 175 176

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 (motor tics in patients with Tourette’s syndrome), especially sleep disturbances.161 164 178

Use in pediatric patients for the treatment of ADHD usually is not recommended without such comorbid psychiatric disorders due to current lack of evidence establishing safety and efficacy.161

Pheochromocytoma

Not indicated in the treatment of pheochromocytoma; however, unlike reserpine and guanethidine, it does not cause acute cardiovascular collapse in patients with this condition.b

Has been used as an aid in the diagnosis of pheochromocytoma in hypertensive patients with suggestive symptoms and borderline catecholamine values; plasma norepinephrine concentration generally is unchanged following administration of a single oral dose of clonidine in pheochromocytoma, while decrease in plasma norepinephrine concentration occurs with sympathetic hyperactivity.b

Migraine Headaches

Has been used in the prophylaxis of migraine headaches, but efficacy for this condition is questionable.158

Dysmenorrhea

Has been used for the treatment of severe dysmenorrhea.

Vasomotor Symptoms Associated with Menopause

Has been used orally and transdermally for the management of vasomotor symptoms (e.g., hot flashes) associated with menopause.159 160

May improve the severity and frequency of vasomotor symptoms, albeit modestly; however, required dosages (exceeding the equivalent of 0.1 mg daily administered orally) may result in increased and, sometimes, intolerable adverse effects.159

Use for management of vasomotor symptoms mainly in postmenopausal women in whom estrogen replacement therapy is contraindicated or in those with preexisting hypertension.159 160

Glaucoma

Has been used topically to reduce IOP in the treatment of open-angle (chronic simple) and secondary glaucoma and hemorrhagic glaucoma associated with hypertension.b

Diarrhea

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 wtih diabetes).b

Clonidine Dosage and Administration

Administration

Administer orally, by epidural infusion, or percutaneously by topical application of a transdermal system.b

Has been administered by sub-Q, IM, or slow IV injection.b

For solution and drug compatibility information, see Compatibility under Stability.

Oral Administration

Administer the last dose of the day immediately before retiring to ensure overnight BP control.b

Transdermal Administration

Expose the adhesive surface of the system by peeling and discarding the clear plastic protective strip prior to administration.101

Apply the transdermal system 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.101

Apply an adhesive cover directly over the system to ensure good adhesion if the system becomes loose during the period of use.101

Development of isolated mild localized skin irritation before completion of the intended period of use warrants removal and replacement with a new system at a different application site.101

Apply each transdermal system at a different site to minimize and/or prevent potential skin irritation101 (e.g., systems may be applied progressively across the arms and chest in one direction or the other).104

Epidural Administration

Specialized techniques are required for continuous epidural administration.115

Limit epidural administration to qualified individuals familiar with the techniques and patient management problems associated with this route of administration.151

Screen to ensure adequate response to epidural therapy prior to the implantation of a permanent controlled infusion device.145

Only use chronically when adequate pain relief cannot be achieved with less invasive therapies.145

Discard partially used vials of the drug.151

Dilution

The concentrate for injection containing 500 mcg/mL must be diluted prior to administration.151

Dilute in sodium chloride 0.9% injection to a final concentration of 100 mcg/mL.151

Use a controlled-infusion device for continuous epidural infusion.151

Substantial decreases in BP may be associated with infusion into the upper thoracic spinal segments.151

Administration above the C4 dermatome is contraindicated because of inadequate safety data supporting such use.151

Carefully monitor the infusion pump function and inspect the catheter tubing for obstruction or dislodgement to reduce the risk of inadvertent abrupt withdrawal of the epidural infusion.151

Dosage

Tablets: Available as clonidine hydrochloride. Dosage expressed in terms of clonidine hydrochloride.

Transdermal: Available as clonidine. Dosage expressed in terms of clonidine.

Epidural: Available as clonidine hydrochloride. Dosage expressed in terms of clonidine hydrochloride.

Discontinuation of oral therapy requires slow dosage reduction over a period of 2–4 days to avoid the possible precipitation of the withdrawal syndrome.b (See Withdrawal Effects under Cautions.)

Pediatric Patients

Hypertension
Oral

Children ≥12 years of age: 0.1 mg twice daily.114 187 Increase dosage by 0.1 mg daily at weekly intervals until the desired response is achieved.114

Maintenance: 0.2–0.6 mg daily in divided doses.114 Manufacturers report 2.4 mg daily to be the maximum effective dosage.114 187

Transdermal

Children ≥12 years of age: Initially, apply one system delivering 0.1 mg/24 hours once every 7 days.101 188

Increase initial dosage by using 2 systems delivering 0.1 mg/24 hours or a larger dosage system if the desired reduction in BP is not achieved after 1–2 weeks;188 subsequent dosage adjustments may be made at weekly intervals.188

Dosages exceeding 0.6 mg/24 hours (2 systems each delivering 0.3 mg/24 hours) usually are not associated with additional efficacy.188

Gradually reduce dosage of other hypotensive agents 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.188

Pain
Epidural

Initially, 0.5 mcg/kg of body weight per hour.151

Adjust cautiously based on clinical response.151

Hypertensive Crises
Hypertensive Emergencies
Oral

Children 1–17 years of age: Initially for some hypertensive emergencies: 0.05–0.1 mg, may repeat up to maximum of 0.8 mg.187

Hypertensive Urgencies
Oral

Children 1–17 years of age: Initially, 0.05–0.1 mg, may repeat up to maximum of 0.8 mg.187

Attention Deficit Hyperactivity Disorder
Oral

Initially, 0.05 mg daily given as a single dose at bedtime.162

Increase cautiously over a period of 2–4 weeks as needed, in order to minimize development of adverse effects (e.g., sedation).162

Maintenance: 0.05–0.4 mg daily (depending on tolerance and patient’s weight).162 Usually, give the maximum tolerated dosage for 2–8 weeks in order to assess treatment response, although the onset of action of clonidine may be more variable than that associated with stimulants or antidepressants.162

According to the AHA, ECG monitoring is not required in pediatric patients receiving clonidine for ADHD;162 however, some experts recommend weekly office visits during clonidine titration period to monitor both erect and supine BP and heart rate.162

Adults

Hypertension

Adjust dosage according to the patient’s BP response and tolerance.b

Minimize adverse effects such as drowsiness and dry mouth by increasing dosage gradually and/or taking the larger portion of the daily dose at bedtime.b

Tolerance to the antihypertensive effect may develop, necessitating increased dosage or concomitant use of a diuretic to enhance the hypotensive response to the drug.b

BP Monitoring and Treatment Goals

Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.135 181

Avoid large or abrupt reductions in BP.135

Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients [stage 2 hypertension, comorbid conditions]) if BP control is inadequate at a given dosage; it may take months to control hypertension adequately while avoiding adverse effects of therapy.135 181

SBP is the principal clinical end point, especially in middle-aged and geriatric patients.156 157 181 Once the goal SBP is attained, the goal DBP usually is achieved.181

The goal is to achieve and maintain a lifelong SBP <140 mm Hg and a DBP <90 mm Hg if tolerated.135 181 183

The goal in hypertensive patients with diabetes mellitus or renal impairment is to achieve and maintain a SBP <130 mm Hg and a DBP <80 mm Hg.135 165 181 182 183

Monotherapy
Oral

Initially, 0.1 mg twice daily.114 Geriatric patients may benefit from a lower initial dosage of 0.05 mg twice daily.b

Most clinicians have reported satisfactory results with administration of the drug in 2 or 3 divided doses daily.125 135

Increase dosage by 0.1 mg daily at weekly intervals until the desired response is achieved.114 Manufacturers report 2.4 mg daily to be the maximum effective dosage.114

Usual dosage, per JNC 7 guidelines: 0.05–0.4 mg twice daily.181

Transdermal

Initiate with one system delivering 0.1 mg/24 hours applied once every 7 days.101 181

Initiate therapy with this initial dosage in all patients, including those who had been receiving oral therapy, due to interpatient variability; titrate initial dosage subsequently according to individual requirements;101 105

Increase initial dosage by using 2 systems delivering 0.1 mg/24 hours or a larger dosage system if the desired reduction in BP is not achieved after 1–2 weeks;101 subsequent dosage adjustments may be made at weekly intervals.107 109 110

Usual dosage, per JNC 7 guidelines: 0.1–0.3 mg/24 hours applied once every 7 days.181

Dosages exceeding 0.6 mg/24 hours (2 systems each delivering 0.3 mg/24 hours) usually are not associated with additional efficacy.101

Consider continuing the usual oral dosage the first day the initial transdermal system is applied when transdermal therapy is initiated in patients who have been receiving low dosages of oral clonidine.105

Gradually reduce dosage of other hypotensive agents 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.101

Combination Therapy
Oral

Preparations containing clonidine hydrochloride in fixed combination with chlorthalidone should not be used initially.b

Adjust dosage initially by administering each drug separately.b

Fixed combination may be used if it is determined that the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation; administer each drug separately whenever dosage adjustment is necessary.b

Smaller than usual dosages of clonidine hydrochloride may be adequate in patients who are also receiving diuretics or other hypotensive drugs.b

Hypertensive Crises
IV

IV injection in sodium chloride 0.9% injection: 0.15–0.3 mg administered over a period of 5 minutes.

Hypertensive Emergencies119 128
IV

Initial goal: Reduce mean arterial BP by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2–6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.135

If this BP is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24–48 hours.185

Reduce SBP to <100 mm Hg if tolerated in patients with aortic dissection.185

Hypertensive Urgencies
Oral

Initial dose: 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 DBP is controlled.119 128

Avoid excessive falls in BP since they may precipitate renal, cerebral, or coronary ischemia.125 135

Observe patient for several hours after last dose and ensure follow-up within 1 to a few days.185

Maintenance dose: Adjust according to the patient’s response and tolerance.119

Pain
Severe Intractable Cancer Pain Unresponsive to Epidural or Spinal Opiates, or Conventional Analgesia
Epidural

Initial dosage: 30 mcg/hour, administered by continuous epidural infusion.151

Adjust dose based on clinical response and tolerance; however, clinical experience with infusion rates exceeding 40 mcg/hour is limited.151

Monitor closely, particularly during the first few days of epidural clonidine therapy.151

Opiate Dependence

Various dosage regimens have been used.b

Carefully individualize dosage according to patient response and tolerance, and closely monitor and supervise.b

May be difficult or impossible to establish a dosage regimen that adequately suppresses withdrawal without producing intolerable adverse effects because of varying sensitivity to clonidine’s sedative, hypotensive, and withdrawal-suppressing effects.

Oral

Initial Test Dose: 0.005 or 0.006 mg/kg; if signs and symptoms of withdrawal are suppressed, then give an oral dosage of 0.017 mg/kg daily, in 3 or 4 divided doses, generally for about 10 days.b

Initial Oral Dosage, Alternatively: 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.b

Dosage usually ranges from 0.3–1.2 mg daily.b

Discontinuing Therapy: Dosage has been reduced by increments of 50% per day for 3 days and then discontinued, or reduced by 0.1–0.2 mg daily.b

Alcohol Dependence

Optimal dosages have not been established.b

Oral

0.5 mg twice or 3 times daily has reduced tremor, heart rate, and BP in alcohol withdrawal.154

Smoking Cessation

Optimal dosages have not been established and various regimens have been employed.167

Oral

Initial dosage: Typically, 0.1 mg twice daily;167 initiate therapy on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior).167

May increase dosage each week by 0.1 mg daily, if needed.167

Transdermal

Initial dosage: Typically, one system delivering 0.1 mg/24 hours applied once every 7 days;167 intiate therapy on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior).167

May increase dose at weekly intervals by 0.1 mg/24 hours, if needed.167

Pheochromocytoma, Diagnostic Use
Oral

Administer a single 0.3-mg dose.b

Interpretation

Patient rests 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.b Administer the 0.3-mg dose; blood samples for catecholamine determinations are drawn at hourly intervals for 3 hours.b

Patients with Pheochromocytoma: Plasma norepinephrine concentrations generally remain unchanged following administration of clonidine.b

Patients without Pheochromocytoma: plasma norepinephrine concentrations generally decrease.b

Migraine Headache Prophylaxis
Oral

Usually, 0.025 mg 2–4 times daily or up to 0.15 mg daily in divided doses.b

Dysmenorrhea
Oral

Usually, 0.025 mg twice daily for 14 days before and during menses.b

Vasomotor Symptoms Associated with Menopause
Oral

Usually, 0.025–0.2 mg twice daily.b

Transdermal

Apply one transdermal system delivering 0.1 mg/24 hours once every 7 days.160

Glaucoma
Topical

0.125, 0.25, or 0.5% ophthalmic solutions have been used; alternatively, 0.1% ophthalmic ointment; 0.25% solution appears to provide maximum effectiveness with minimum adverse effects.b

Special Populations

Renal Impairment

Smaller than usual doses may be adequate in patients with renal impairment. Adjust dosage according to the degree of renal impairment.b

Clcr ≥10 mL/minute: Dosage adjustment does not appear necessary.122

Clcr <10 mL/minute: Give 50–75% of the usual dosage.122

Supplemental doses after hemodialysis are not necessary.101 114 122 151

Geriatric Patients

May benefit from lower initial dosages of 0.05 mg twice daily for the management of hypertension.186

Cautions for Clonidine

Contraindications

  • 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.151

  • Epidural administration above the C4 dermatome is contraindicated because of inadequate safety data supporting such use.151

  • Known hypersensitivity to the drug or any ingredient or component in the formulation.101 114 151

  • Epidural administration also is not recommended in most patients with severe cardiovascular disease or in patients who are hemodynamically unstable.151

Warnings/Precautions

Warnings

Withdrawal Effects

Risk of rebound hypertension if doses are missed or drug is stopped abruptly.b

Abrupt withdrawal may result in a rapid increase of systolic and diastolic BPs, 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.b

Withdrawal syndrome (reported in about 1% of patients receiving oral clonidine) 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 (>1.2 mg daily) and/or with continuation of concomitant β-adrenergic blocking therapy.101 115 b

Risk of adverse effects following abrupt discontinuance may be increased in patients with a history of hypertension and/or other underlying cardiovascular conditions.151

When discontinued abruptly, symptoms such as restlessness and headache may begin to appear 2–3 hours after a dose is missed and BP may increase substantially within 8–24 hours.b

Discontinuing Therapy

Taper withdrawal over 2–4 days when discontinuing oral or epidural clonidine therapy to prevent or minimize a rapid rise in BP.101 151

Tapered withdrawal of transdermal clonidine120 123 or initiation of a tapered oral regimen 123 is recommended when the transdermal dosage form is discontinued,120 123 particularly in geriatric patients.120

Discontinue the β-adrenergic blocker several days before clonidine therapy is discontinued if patient is receiving clonidine and a β-adrenergic blocking agent concomitantly.101 114 151

Discontinuing Therapy in Surgery

Generally, do not interrupt for surgery. Transdermal therapy can be continued throughout the perioperative period and oral therapy should be continued to within 4 hours before surgery.b

BP should be carefully monitored during surgery and additional measures to control BP should be available if necessary.101 114

If surgery requires discontinuation, administer parenteral antihypertensive therapy as necessary, and resume clonidine therapy as soon as possible.b

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.

Defibrillation and Cardioversion

Remove transdermal systems from the site(s) of application prior to attempting defibrillation or cardioversion since altered electrical conductivity and enhanced potential for electrical arcing may occur.101 121

Transdermal Dosage Form Handling

Even after use, the transdermal system contains active medication that may be harmful if accidentally applied or ingested by infants or children.127

Handle the used transdermal system carefully (e.g., fold the system in half with the sticky sides together) and dispose of the system out of the reach of children.101 126 127

Epidural Therapy

Only indicated for severe cancer pain that has failed to respond to an adequate trial with opiate analgesics.151

Limit continuous epidural administration to qualified individuals familiar with the techniques of administration and patient management problems associated with this route of administration.145 151

Inform patients to notify a clinician immediately in case of inadvertent interruption of epidural clonidine.151

Pain Therapy

Not recommended for the epidural management of obstetric, postpartum, or perioperative pain.151

Epidural Infusion Pump

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.151

Use with caution in patients with severe coronary insufficiency, recent MI, cerebrovascular disease, chronic renal failure, Raynaud’s disease, or thromboangiitis obliterans.b

Depressive Episodes

Carefully supervise patients with a history of mental depression as they may be subject to further depressive episodes.b

CNS Effects

Performance of activities requiring mental alertness and physical coordination may be impaired.b Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.101 151

BP Decrease in Nonhypertensive Patients

Consider BP lowering effects in patients receiving the drug for conditions other than hypertension (e.g., smoking cessation, pain management, ADHD), and monitor BP as appropriate.151 162 167

Rebound hypertension and other withdrawal effects should be considered when the drug is discontinued in such patients; abrupt discontinuance should be avoided.167

Ocular Effects

Perform periodic eye examinations in patients receiving the drug.b

Sensitivity Reactions

Rash

Development of a localized contact sensitization to clonidine with transdermal therapy may be associated with development of a generalized rash with subsequent administration of oral clonidine hydrochloride.101

Patients receiving transdermal therapy who develop an allergic reaction to clonidine that extends beyond the local application site (e.g., generalized rash, urticaria, angioedema) are at risk of developing a similar reaction with oral therapy.101

General Precautions

Transdermal Rash and Adhesion

Moderate to severe erythema and/or localized vesicle formation can occur at the site of transdermal application.101 Generalized rash also can occur.101 (See Advice to Patients.)

Specific Populations

Pregnancy

Category C.101 114 151

Smoking cessation programs consisting of behavioral and educational rather than pharmacologic interventions should be tried in pregnant women before drug therapy is considered.167

Smoking cessation therapy with clonidine, which is a second-line agent, should be used during pregnancy only if the increased likelihood of smoking cessation, with its potential benefits, justifies the potential risk to the fetus and patient of clonidine and possible continued smoking, and first-line pharmacotherapy (e.g., bupropion, nicotine replacement) has failed.167

Lactation

Distributed into milk.101 114 167 Use the oral or transdermal preparation with caution in nursing women.101 114 167

Discontinue nursing or the epidural formulation, taking into account the importance of the drug to the woman.151

Pediatric Use

Safety and efficacy of oral clonidine hydrochloride and clonidine transdermal system for the management of hypertension in children <12 years of age have not been established.b 101 Safe use of oral clonidine hydrochloride for the management of ADHD in children has not been established, but clinical studies are currently under way to determine safety and efficacy.b

Safety and efficacy of epidural clonidine 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.151

Use epidural clonidine only in pediatric patients with severe, intractable cancer pain that is unresponsive to epidural or spinal opiates and to other conventional analgesic therapy.151

Clonidine overdosage may be more likely to cause CNS depression in children, and signs of toxicity have occurred with doses as low as 0.1 mg.101 114 Rarely, toxicity in children has been associated with accidental or deliberate mouthing or ingestion of transdermal systems.101

Children commonly have GI illnesses leading to frequent vomiting and may be more susceptible to hypertensive episodes resulting from inability to ingest oral clonidone.114

Common Adverse Effects

Oral therapy

Adverse effects occurring most frequently and which appear to be dose-related are dry mouth, dizziness, drowsiness and sedation, and constipation.b Headache, fatigue, and weakness also reported.b

Generally, these adverse effects tend to be mild, and diminish with continued therapy or may be relieved by a reduction in dosage.

Transdermal therapy

Adverse effects generally appear to be similar to those occurring with oral therapy;101 105 106 107 108 109 110 115 116 117 however, adverse systemic effects with transdermal clonidine appear to be less severe and possibly may occur less frequently than with oral therapy.101 105 106 107 109 110 115 116 117

Most frequently occurring adverse effects have been dry mouth, drowsiness, and local adverse dermatologic effects.101 108 109 115 116 117

Interactions for Clonidine

Specific Drugs

Drug

Interaction

Comments

Anesthetics, local (epidural)

Epidural clonidine may prolong the duration of the pharmacologic effects, including both sensory and motor blockade of epidural local anesthetics151

Use concomitantly with caution

Antidepressants, MAO inhibitors

See MAO inhibitors

Antidepressants, tricyclic (imipramine, desipramine)

May inhibit the hypotensive effect of clonidine. The increase in BP usually occurs during the second week of tricyclic antidepressant therapy, but occasionally may occur during the first several days of concomitant therapyb

Clonidine withdrawal may result in an excess of circulating catecholamines; therefore, caution should be exercised in concomitant use of drugs that affect the tissue uptake of these aminesb

BP should be closely monitored during the first several weeks of concomitant therapy, and clonidine dosage should be increased to adequately control hypertension if necessary.b Consider substitution with other hypotensive agents that do not interact with tricyclic antidepressants; clonidine therapy should not be discontinued abruptly.b If tricyclic antidepressant therapy is discontinued in patients receiving clonidine, the hypotensive effect of clonidine may increase; monitor BP and reduce dosage of clonidine if necessaryb

Antihypertensive agents

Additive/potentiated hypotensive effectb

Usually used to therapeutic advantage in antihypertensive therapy; however, carefully adjust dosage

β-adrenergic blocking agents (propranolol)

Possible additive bradycardia, AV block when clonidine is used with drugs that affect sinus nodal function or AV nodal conduction101 114

β-Adrenergic blocking agents may exacerbate rebound hypertension that may occur following discontinuance of clonidine therapy

Use concomitantly with caution101 114

β-Adrenergic blocking agents should be discontinued several days before gradual withdrawal of clonidine139

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 discontinued139 140

Calcium-channel blocking agents

Possible additive bradycardia, AV block when clonidine is used with drugs that affect sinus nodal function or AV nodal conduction101 114

Use concomitantly with caution101 114

Cardiac glycosides

Possible additive bradycardia, AV block when clonidine is used with drugs that affect sinus nodal function or AV nodal conduction101 114

Use concomitantly with caution101 114

CNS depressants (e.g., opiates or other analgesics, barbiturates or other sedatives, anesthetics, alcohol)

May potentiate CNS depressionb

Use concomitantly with caution

MAO inhibitors

Clonidine withdrawal may result in an excess of circulating catecholaminesb

Use concomitantly with caution

Opiates

May potentiate CNS depression and hypotensive effects

Use concomitantly with caution

Clonidine Pharmacokinetics

Absorption

Bioavailability

Oral: Well absorbed from the GI tract.b

Topical, ophthalmic: May be absorbed when applied to the eye.b

Topical, transdermal system: Well absorbed percutaneously following transdermal system application to the arm or chest.102 103 104 115 117 118

Epidural, single bolus dose in healthy individuals and patients with cancer: Rapidly absorbed into systemic circulation.141

Onset

Oral: BP begins to decrease within 30–60 minutes; maximum decrease occurs in approximately 2–4 hours.114 146

Topical, transdermal system: Therapeutic plasma concentrations are attained within 2–3 days.101 102 103 104 118

Epidural, single dose: Near maximal analgesia occurs within 30–60 minutes;141 analgesic effects appear to correlate with drug concentrations in the CSF.141 142

IV:Hypotensive effect within minutes and peak effect within 30–60 minutes.b

Duration

Oral: Hypotensive effect lasts up to 8 hours.b

Topical, 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, BP returns gradually to pretreatment levels.101 102 103 117 118

IV:Hypotensive effect persists for >4 hours.b

Plasma Concentrations

Reduction in BP is maximal at plasma clonidine concentrations <2 ng/mL.111 112

Epidural: Accumulation does not appear to occur following continuous epidural infusion of the drug in adult cancer patients.152

Distribution

Extent

After oral administration: Highest concentrations in the kidneys, liver, spleen, and GI tract.b High concentrations also in the lacrimal and parotid glands.b

Distributed into CSF when administered systematically.b

Crosses the placenta.129 151

Distributes into breast milk.130 151

Plasma Protein Binding

Approximately 20–40% bound to plasma proteins, mainly albumin.151

Elimination

Metabolism

Metabolized in the liver.b

Elimination Route

Oral: 40–60% is excreted in urine as unchanged drug.101 114 116 Approximately 20% excreted in feces.b

Half-life

Normal renal function: 6–20 hours.101 114

May be dose dependent, increasing with increasing dose.113

Special Populations

Renal impairment: 18–41 hours.111 114 146 151

Hemodialysis patients: Only 5% of a dose was removed into the dialysate.151

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).114

Parenteral

Injection

25°C (may be exposed to15–30°C);151 any unused should be discarded.151

Transdermal

<30°C.101

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Solution Compatibility

Injections containing a preservative should not be used to dilute the epidural injection.151

Do not dilute with bacteriostatic sodium chloride injection.151

CompatibleHID

0.9% sodium chloride injection

Drug CompatibilityHID
Admixture Compatibility

Compatible

Baclofen

Bupivacaine HCl with fentanyl citrate

Hydromorphone HCI

Meperidine HCl

Ropivacaine HCl

Ziconotide acetate

Y-Site CompatibilityHID

Compatible

Aminophylline

Dobutamine HCl

Dopamine HCl

Epinephrine HCl

Fentanyl citrate

Labetalol HCl

Lorazepam

Magnesium sulfate

Nitroglycerin

Norepinephrine bitartrate

Potassium chloride

Theophylline

Verapamil HCl

Variable

Midazolam HCl

Actions

  • Cardiovascular effects: Appears to stimulate α2-adrenergic receptors in the CNS (mainly in the medulla oblongata), causing inhibition, but not blockade, of sympathetic vasomotor centers.b

  • Cardiovascular reflexes remain intact, and normal homeostatic mechanisms and hemodynamic responses to exercise are maintained.b

  • Central effects result in reduced peripheral sympathetic nervous system activity, reduced peripheral and renovascular resistance, reduction of SBP and DBP, and bradycardia.146 151

  • Peripheral venous pressure remains unchanged.b

  • Reduces BP to essentially the same extent in both supine and standing patients; therefore, orthostatic effects are mild and infrequently encountered.b

  • Rapid IV, but not oral or IM, administration produces direct stimulation of peripheral α2-adrenergic receptors, resulting in transient vasoconstriction and a rise in SBP and DBP.b

  • CNS effects: Epidurally administered α2-agonists, including clonidine, produce analgesia by mimicking the activation of descending pain-suppressing pathways arising from supraspinal control centers (i.e., cortex, thalamus, and brainstem) and terminating in the dorsal horn of the spinal cord.142 143

  • Clonidine-mediated analgesia is dose-dependent and is limited to regions of the body innervated by spinal segments containing analgesic concentrations of the drug.151

  • The sedative effect of clonidine is thought to result from central α2-agonist activity.b

  • Appears to reduce the severity of opiate withdrawal symptoms by stimulating central presynaptic α2-adrenergic receptors; the stimulation results in attenuation in noradrenergic activity in the CNS, which may be responsible for the behavioral symptoms of opiate withdrawal.b

  • Renal and metabolic effects: Acute or chronic administration produces no substantial change in renal blood flow, renal plasma flow, or GFR.b

  • Sodium and chloride excretion are markedly reduced after initial administration; however, potassium excretion is not substantially changed.b

  • Renal vein plasma renin activity and aldosterone excretion rate are consistently reduced as a result of centrally mediated sympathetic inhibition.

  • Other effects: Acute administration stimulates release of growth hormone in children and adults, but the drug does not produce sustained elevation of growth hormone during chronic administration.101

  • The decrease in salivation induced by clonidine appears to result from both central and peripheral mechanisms, probably involving the drug’s α2-agonist activity.b

  • IV or topical administration of clonidine hydrochloride in patients with glaucoma decreases IOP, reportedly by decreasing production of aqueous humor.b

Advice to Patients

  • Importance of warning patients of the danger of missing doses or stopping the drug without consulting a clinician due to the risk of rebound hypertension.b (See Withdrawal Effects under Cautions.)

  • Instruct patients to keep both unused and used transdermal systems out of the reach of children.101

  • Advise that even after use, the transdermal system contains active medication that may be harmful if accidentally applied or ingested by infants or children.101 127

  • Importance of handling the used transdermal system carefully (e.g., fold the system in half with the sticky sides together) and disposing of the system out of the reach of children.101 126 127

  • Advise patients to notify a clinician immediately in case of inadvertent interruption of epidural clonidine.151

  • Importance of not discontinuing therapy abruptly to avoid the possibility of precipitating the withdrawal syndrome.b (See Discontinuing Therapy under Cautions.)

  • For transdermal therapy, carefully instruct patients in the use of the transdermal system.b (See Transdermal Administration under Dosage and Administraion.)

  • For transdermal therapy, give patients a copy of the patient instructions provided by the manufacturer.101

  • 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 clinician promptly about the need to remove the transdermal system.101

  • Patients receiving transdermal therapy who develop isolated, mild localized skin irritation before completion of the intended period of use (7days) should be advised they may remove the transdermal system and replace it with a new system at a different site.101

  • Patients receiving transdermal therapy should be advised that if the transdermal system begins to loosen from the skin after application, an adhesive overlay should be applied directly over the system to ensure good adhesion over the period of application.101

  • Importance of warning patients who engage in potentially hazardous activities such as operating machinery or driving because of the possible sedative effect of the drug.101 114

  • Importance of warning patients that the sedative effect of clonidine may be increased when it is used while also taking alcohol, barbiturates, or other sedating drugs.101 114

  • Advise hypertensive patients of importance of continuing lifestyle/behavioral modifications that include weight reduction (for those who are overweight or obese), dietary changes to include foods that are rich in potassium and calcium and moderately restricted in sodium (adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), increased physical activity, smoking cessation, and moderation of alcohol intake.167 172 184

    Advise that lifestyle/behavioral modifications reduce BP, enhance antihypertensive drug efficacy, and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.167 183 184

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption as well as any concomitant illnesses.101 114

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Clonidine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Transdermal System

0.1 mg/24 hours (2.5 mg/3.5 cm2)

Catapres-TTS

Boehringer Ingelheim

0.2 mg/24 hours (5 mg/7 cm2)

Catapres-TTS

Boehringer Ingelheim

0.3 mg/24 hours (7.5 mg/10.5 cm2)

Catapres-TTS

Boehringer Ingelheim

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Clonidine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.1 mg*

Catapres (scored)

Boehringer Ingelheim

Clonidine Hydrochloride Tablets

0.2 mg*

Catapres (scored)

Boehringer Ingelheim

Clonidine Hydrochloride Tablets

0.3 mg*

Catapres (scored)

Boehringer Ingelheim

Clonidine Hydrochloride Tablets

Parenteral

For Injection, concentrate, for epidural use

500 mcg/mL

Duraclon

Xanodyne

Injection, for epidural use

100 mcg/mL

Duraclon

Xanodyne

Clonidine Hydrochloride and Chlorthalidone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

0.1 mg Clonidine Hydrochloride and Chlorthalidone 15 mg

Clorpres (scored)

Mylan Bertek

0.2 mg Clonidine Hydrochloride and Chlorthalidone 15 mg

Clorpres (scored)

Mylan Bertek

0.3 mg Clonidine Hydrochloride and Chlorthalidone 15 mg

Clorpres (scored)

Mylan Bertek

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Catapres 0.1MG Tablets (BOEHRINGER INGELHEIM): 60/$99.99 or 180/$289.96

Catapres 0.2MG Tablets (BOEHRINGER INGELHEIM): 60/$154.98 or 180/$447.96

Catapres 0.3MG Tablets (BOEHRINGER INGELHEIM): 60/$165.98 or 180/$455.94

Catapres-TTS-1 0.1MG/24HR Patches (BOEHRINGER INGELHEIM): 4/$165.98 or 12/$470.96

Catapres-TTS-2 0.2MG/24HR Patches (BOEHRINGER INGELHEIM): 4/$271.98 or 12/$790.00

Catapres-TTS-3 0.3MG/24HR Patches (BOEHRINGER INGELHEIM): 4/$369.99 or 12/$1,059.98

CloNIDine HCl 0.1MG/24HR Patches (TEVA PHARMACEUTICALS USA): 4/$109.99 or 12/$310.95

CloNIDine HCl 0.1MG Tablets (ACTAVIS ELIZABETH): 100/$19.99 or 200/$22.97

CloNIDine HCl 0.2MG/24HR Patches (TEVA PHARMACEUTICALS USA): 4/$179.99 or 12/$499.97

CloNIDine HCl 0.2MG Tablets (MYLAN): 100/$21.99 or 300/$42.97

CloNIDine HCl 0.3MG/24HR Patches (TEVA PHARMACEUTICALS USA): 4/$245.97 or 12/$709.95

CloNIDine HCl 0.3MG Tablets (ACTAVIS ELIZABETH): 100/$21.99 or 200/$35.98

Clorpres 0.1-15MG Tablets (MYLAN): 60/$127.99 or 180/$358.57

Clorpres 0.2-15MG Tablets (MYLAN BERTEK): 60/$115.99 or 180/$315.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 27, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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