Clonidine

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

• 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 alone^{106 107 108 109 117 118} 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}

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

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 Emergencies†^{119 128}

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

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

Cl_cr <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 clonidine^{120 123} 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 amines