Has been used in conjunction with thiazide diuretics, chlorthalidone, or furosemide, producing a greater reduction in BP than is obtained with either drug alone.
Use of a diuretic may aid in overcoming tolerance to clonidine and permit reduction of clonidine dosage.
May be useful in some patients unable to tolerate other adrenergic blocking agents because of severe postural hypotension; geriatric patients may not tolerate the adverse cognitive effects of central α2-adrenergic agonists such as clonidine.
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.
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.
Transdermal clonidine has been successfully substituted for oral clonidine hydrochloride in mild to moderate hypertension.
Role of transdermal versus oral therapy remains to be more fully evaluated; transdermal therapy may prove to be convenient (e.g., in those in whom compliance with a daily dosing regimen may be a problem), but adverse dermatologic reactions occur frequently.
The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage. The higher the baseline BP, the more likely the development of MI, heart failure, stroke, and renal disease.
Effective antihypertensive therapy reduces the risk of stroke by about 34–40%, MI by about 20–25%, and heart failure by more than 50%.
Antihypertensive drug therapy is recommended for all patients with SBP/DBP ≥140/90 mm Hg who fail to respond to lifestyle/behavioral modifications.
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.
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.
Hypertensive urgencies† are those situations in which it is desirable to reduce BP within a few hours.
Avoid excessive falls in BP since they may precipitate renal, cerebral, or coronary ischemia.
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.†
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.
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.
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.
Epidural clonidine is more likely to be effective in patients with neuropathic pain rather than somatic or visceral pain.
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.
Exact role and its efficacy compared with other methods of detoxification (e.g., methadone) remain to be clearly determined.
Appears to be most useful as a transitional treatment between opiate dependence† and administration of the opiate antagonist naltrexone.
May be especially useful when detoxification using methadone is inappropriate, unsuccessful, or unavailable.
Alcohol Dependence
Has been used in conjunction with benzodiazepines for the management of alcohol withdrawal†.
May be effective in reducing symptoms of the hyperadrenergic state associated with alcohol withdrawal†, including elevated BP, increased heart rate, tremor, sweating, and anxiety.
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†.
Nicotine dependence† is a chronic relapsing disorder that requires ongoing assessment and often repeated intervention.
US Public Health Service (USPHS) currently recommends clonidine as a second-line drug† for use under the supervision of a clinician.
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.
Use of second-line pharmacotherapy should be considered after first-line pharmacotherapy was attempted or considered and should be individualized based on patient considerations.
Attention Deficit Hyperactivity Disorder
Has been used for the treatment of attention deficit hyperactivity disorder† (ADHD).
Produces 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).
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.
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.
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.
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.
Migraine Headaches
Has been used in the prophylaxis of migraine headaches†, but efficacy for this condition is questionable.
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.
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.
Use for management of vasomotor symptoms† mainly in postmenopausal women in whom estrogen replacement therapy is contraindicated or in those with preexisting hypertension.
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†.
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).
Dosage and Administration
Administration
Administer orally, by epidural infusion, or percutaneously by topical application of a transdermal system.
Oral Administration
Administer the last dose of the day immediately before retiring to ensure overnight BP control.
Transdermal Administration
Expose the adhesive surface of the system by peeling and discarding the clear plastic protective strip prior to administration.
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.
Apply an adhesive cover directly over the system to ensure good adhesion if the system becomes loose during the period of use.
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.
Apply each transdermal system at a different site to minimize and/or prevent potential skin irritation (e.g., systems may be applied progressively across the arms and chest in one direction or the other).
Epidural Administration
Specialized techniques are required for continuous epidural administration.
Limit epidural administration to qualified individuals familiar with the techniques and patient management problems associated with this route of administration.
Screen to ensure adequate response to epidural therapy prior to the implantation of a permanent controlled infusion device.
Only use chronically when adequate pain relief cannot be achieved with less invasive therapies.
Discard partially used vials of the drug.
Dilution
The concentrate for injection containing 500 mcg/mL must be diluted prior to administration.
Dilute in sodium chloride 0.9% injection to a final concentration of 100 mcg/mL.
Use a controlled-infusion device for continuous epidural infusion.
Substantial decreases in BP may be associated with infusion into the upper thoracic spinal segments.
Administration above the C4 dermatome is contraindicated because of inadequate safety data supporting such use.
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.
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. (See Withdrawal Effects under Cautions.)
Pediatric Patients
Hypertension
Oral
Children ≥12 years of age: 0.1 mg twice daily. Increase dosage by 0.1 mg daily at weekly intervals until the desired response is achieved.
Maintenance: 0.2–0.6 mg daily in divided doses. Manufacturers report 2.4 mg daily to be the maximum effective dosage.
Transdermal
Children ≥12 years of age: Initially, apply one system delivering 0.1 mg/24 hours once every 7 days.
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; subsequent dosage adjustments may be made at weekly intervals.
Dosages exceeding 0.6 mg/24 hours (2 systems each delivering 0.3 mg/24 hours) usually are not associated with additional efficacy.
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.
Pain
Epidural
Initially, 0.5 mcg/kg of body weight per hour.
Adjust cautiously based on clinical response.
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.†
Hypertensive Urgencies
Oral
Children 1–17 years of age: Initially, 0.05–0.1 mg, may repeat up to maximum of 0.8 mg.†
Attention Deficit Hyperactivity Disorder
Oral
Initially, 0.05 mg daily given as a single dose at bedtime.†
Increase cautiously over a period of 2–4 weeks as needed, in order to minimize development of adverse effects (e.g., sedation).†
Maintenance: 0.05–0.4 mg daily (depending on tolerance and patient’s weight). 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.†
According to the AHA, ECG monitoring is not required in pediatric patients receiving clonidine for ADHD; however, some experts recommend weekly office visits during clonidine titration period to monitor both erect and supine BP and heart rate.†
Adults
Hypertension
Adjust dosage according to the patient’s BP response and tolerance.
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.
Tolerance to the antihypertensive effect may develop, necessitating increased dosage or concomitant use of a diuretic to enhance the hypotensive response to the drug.
BP Monitoring and Treatment Goals
Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.
Avoid large or abrupt reductions in BP.
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.
SBP is the principal clinical end point, especially in middle-aged and geriatric patients. Once the goal SBP is attained, the goal DBP usually is achieved.
The goal is to achieve and maintain a lifelong SBP <140 mm Hg and a DBP <90 mm Hg if tolerated.
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.
Monotherapy
Oral
Initially, 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.
Increase dosage by 0.1 mg daily at weekly intervals until the desired response is achieved. Manufacturers report 2.4 mg daily to be the maximum effective dosage.
Usual dosage, per JNC 7 guidelines: 0.05–0.4 mg twice daily.
Transdermal
Initiate with one system delivering 0.1 mg/24 hours applied once every 7 days.
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;
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; subsequent dosage adjustments may be made at weekly intervals.
Usual dosage, per JNC 7 guidelines: 0.1–0.3 mg/24 hours applied once every 7 days.
Dosages exceeding 0.6 mg/24 hours (2 systems each delivering 0.3 mg/24 hours) usually are not associated with additional efficacy.
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.
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.
Combination Therapy
Oral
Preparations containing clonidine hydrochloride in fixed combination with chlorthalidone should not be used initially.
Adjust dosage initially by administering each drug separately.
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.
Smaller than usual dosages of clonidine hydrochloride may be adequate in patients who are also receiving diuretics or other hypotensive drugs.
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
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.†
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.†
Reduce SBP to <100 mm Hg if tolerated in patients with aortic dissection.†
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.†
Avoid excessive falls in BP since they may precipitate renal, cerebral, or coronary ischemia.†
Observe patient for several hours after last dose and ensure follow-up within 1 to a few days.†
Maintenance dose: Adjust according to the patient’s response and tolerance.†
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.
Adjust dose based on clinical response and tolerance; however, clinical experience with infusion rates exceeding 40 mcg/hour is limited.
Monitor closely, particularly during the first few days of epidural clonidine therapy.
Opiate Dependence
Various dosage regimens have been used.†
Carefully individualize dosage according to patient response and tolerance, and closely monitor and supervise.†
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.†
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.†
Dosage usually ranges from 0.3–1.2 mg daily.†
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.†
Alcohol Dependence
Optimal dosages have not been established.†
Oral
0.5 mg twice or 3 times daily has reduced tremor, heart rate, and BP in alcohol withdrawal.†
Smoking Cessation
Optimal dosages have not been established and various regimens have been employed.†
Oral
Initial dosage: Typically, 0.1 mg twice daily; 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).†
May increase dosage each week by 0.1 mg daily, if needed.†
Transdermal
Initial dosage: Typically, one system delivering 0.1 mg/24 hours applied once every 7 days; 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).†
May increase dose at weekly intervals by 0.1 mg/24 hours, if needed.†
Pheochromocytoma, Diagnostic Use
Oral
Administer a single 0.3-mg dose.†
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. Administer the 0.3-mg dose; blood samples for catecholamine determinations are drawn at hourly intervals for 3 hours.†
Patients with Pheochromocytoma: Plasma norepinephrine concentrations generally remain unchanged following administration of clonidine.†
Patients without Pheochromocytoma: plasma norepinephrine concentrations generally decrease.†
Migraine Headache Prophylaxis
Oral
Usually, 0.025 mg 2–4 times daily or up to 0.15 mg daily in divided doses.†
Dysmenorrhea
Oral
Usually, 0.025 mg twice daily for 14 days before and during menses.†
Vasomotor Symptoms Associated with Menopause
Oral
Usually, 0.025–0.2 mg twice daily.†
Transdermal
Apply one transdermal system delivering 0.1 mg/24 hours once every 7 days.†
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.†
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.
Clcr ≥10 mL/minute: Dosage adjustment does not appear necessary.
Clcr <10 mL/minute: Give 50–75% of the usual dosage.
Supplemental doses after hemodialysis are not necessary.
Geriatric Patients
May benefit from lower initial dosages of 0.05 mg twice daily for the management of hypertension.
Cautions
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.
Epidural administration above the C4 dermatome is contraindicated because of inadequate safety data supporting such use.
Known hypersensitivity to the drug or any ingredient or component in the formulation.
Epidural administration also is not recommended in most patients with severe cardiovascular disease or in patients who are hemodynamically unstable.
Warnings/Precautions
Warnings
Withdrawal Effects
Risk of rebound hypertension if doses are missed or drug is stopped abruptly.
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.
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.
Risk of adverse effects following abrupt discontinuance may be increased in patients with a history of hypertension and/or other underlying cardiovascular conditions.
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.
Discontinuing Therapy
Taper withdrawal over 2–4 days when discontinuing oral or epidural clonidine therapy to prevent or minimize a rapid rise in BP.
Tapered withdrawal of transdermal clonidine or initiation of a tapered oral regimen is recommended when the transdermal dosage form is discontinued, particularly in geriatric patients.
Discontinue the β-adrenergic blocker several days before clonidine therapy is discontinued if patient is receiving clonidine and a β-adrenergic blocking agent concomitantly.
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.
BP should be carefully monitored during surgery and additional measures to control BP should be available if necessary.
If surgery requires discontinuation, administer parenteral antihypertensive therapy as necessary, and resume clonidine therapy 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.
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.
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.
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.
Epidural Therapy
Only indicated for severe cancer pain that has failed to respond to an adequate trial with opiate analgesics.
Limit continuous epidural administration to qualified individuals familiar with the techniques of administration and patient management problems associated with this route of administration.
Inform patients to notify a clinician immediately in case of inadvertent interruption of epidural clonidine.
Pain Therapy
Not recommended for the epidural management of obstetric, postpartum, or perioperative pain.
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.
Carefully supervise patients with a history of mental depression as they may be subject to further depressive episodes.
CNS Effects
Performance of activities requiring mental alertness and physical coordination may be impaired. Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.
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.
Rebound hypertension and other withdrawal effects should be considered when the drug is discontinued in such patients; abrupt discontinuance should be avoided.
Ocular Effects
Perform periodic eye examinations in patients receiving the drug.
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.
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.
General Precautions
Transdermal Rash and Adhesion
Moderate to severe erythema and/or localized vesicle formation can occur at the site of transdermal application. Generalized rash also can occur. (See Advice to Patients.)
Specific Populations
Pregnancy
Category C.
Smoking cessation programs consisting of behavioral and educational rather than pharmacologic interventions should be tried in pregnant women before drug therapy is considered.
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.
Lactation
Distributed into milk. Use the oral or transdermal preparation with caution in nursing women.
Discontinue nursing or the epidural formulation, taking into account the importance of the drug to the woman.
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. 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.
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.
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.
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. Rarely, toxicity in children has been associated with accidental or deliberate mouthing or ingestion of transdermal systems.
Children commonly have GI illnesses leading to frequent vomiting and may be more susceptible to hypertensive episodes resulting from inability to ingest oral clonidone.
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. Headache, fatigue, and weakness also reported.
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; however, adverse systemic effects with transdermal clonidine appear to be less severe and possibly may occur less frequently than with oral therapy.
Most frequently occurring adverse effects have been dry mouth, drowsiness, and local adverse dermatologic effects.
Interactions
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 anesthetics
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 therapy
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
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. Consider substitution with other hypotensive agents that do not interact with tricyclic antidepressants; clonidine therapy should not be discontinued abruptly. 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 necessary
Antihypertensive agents
Additive/potentiated hypotensive effect
Usually used to therapeutic advantage in antihypertensive therapy; however, carefully adjust dosage
Possible additive bradycardia, AV block when clonidine is used with drugs that affect sinus nodal function or AV nodal conduction
β-Adrenergic blocking agents may exacerbate rebound hypertension that may occur following discontinuance of clonidine therapy
Use concomitantly with caution
β-Adrenergic blocking agents should be discontinued several days before gradual withdrawal of clonidine
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
Clonidine withdrawal may result in an excess of circulating catecholamines
Use concomitantly with caution
Opiates
May potentiate CNS depression and hypotensive effects
Use concomitantly with caution
Pharmacokinetics
Absorption
Bioavailability
Oral: Well absorbed from the GI tract.
Topical, ophthalmic: May be absorbed when applied to the eye.
Topical, transdermal system: Well absorbed percutaneously following transdermal system application to the arm or chest.
Epidural, single bolus dose in healthy individuals and patients with cancer: Rapidly absorbed into systemic circulation.
Onset
Oral: BP begins to decrease within 30–60 minutes; maximum decrease occurs in approximately 2–4 hours.
Topical, transdermal system: Therapeutic plasma concentrations are attained within 2–3 days.
Epidural, single dose: Near maximal analgesia occurs within 30–60 minutes; analgesic effects appear to correlate with drug concentrations in the CSF.
IV†:Hypotensive effect within minutes and peak effect within 30–60 minutes.
Duration
Oral: Hypotensive effect lasts up to 8 hours.
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.
IV†:Hypotensive effect persists for >4 hours.
Plasma Concentrations
Reduction in BP is maximal at plasma clonidine concentrations <2 ng/mL.
Epidural: Accumulation does not appear to occur following continuous epidural infusion of the drug in adult cancer patients.
Distribution
Extent
After oral administration: Highest concentrations in the kidneys, liver, spleen, and GI tract. High concentrations also in the lacrimal and parotid glands.
Distributed into CSF when administered systematically.
Crosses the placenta.
Distributes into breast milk.
Plasma Protein Binding
Approximately 20–40% bound to plasma proteins, mainly albumin.
Elimination
Metabolism
Metabolized in the liver.
Elimination Route
Oral: 40–60% is excreted in urine as unchanged drug. Approximately 20% excreted in feces.
Half-life
Normal renal function: 6–20 hours.
May be dose dependent, increasing with increasing dose.
Special Populations
Renal impairment: 18–41 hours.
Hemodialysis patients: Only 5% of a dose was removed into the dialysate.
Stability
Storage
Oral
Tablets
Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).
Parenteral
Injection
25°C (may be exposed to15–30°C); any unused should be discarded.
Transdermal
<30°C.
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.
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.
Cardiovascular reflexes remain intact, and normal homeostatic mechanisms and hemodynamic responses to exercise are maintained.
Central effects result in reduced peripheral sympathetic nervous system activity, reduced peripheral and renovascular resistance, reduction of SBP and DBP, and bradycardia.
Peripheral venous pressure remains unchanged.
Reduces BP to essentially the same extent in both supine and standing patients; therefore, orthostatic effects are mild and infrequently encountered.
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.
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.
Clonidine-mediated analgesia is dose-dependent and is limited to regions of the body innervated by spinal segments containing analgesic concentrations of the drug.
The sedative effect of clonidine is thought to result from central α2-agonist activity.
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.
Renal and metabolic effects: Acute or chronic administration produces no substantial change in renal blood flow, renal plasma flow, or GFR.
Sodium and chloride excretion are markedly reduced after initial administration; however, potassium excretion is not substantially changed.
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.
The decrease in salivation induced by clonidine appears to result from both central and peripheral mechanisms, probably involving the drug’s α2-agonist activity.
IV or topical administration of clonidine hydrochloride in patients with glaucoma decreases IOP, reportedly by decreasing production of aqueous humor.
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. (See Withdrawal Effects under Cautions.)
Instruct patients to keep both unused and used transdermal systems out of the reach of children.
Advise that even after use, the transdermal system contains active medication that may be harmful if accidentally applied or ingested by infants or children.
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.
Advise patients to notify a clinician immediately in case of inadvertent interruption of epidural clonidine.
Importance of not discontinuing therapy abruptly to avoid the possibility of precipitating the withdrawal syndrome. (See Discontinuing Therapy under Cautions.)
For transdermal therapy, carefully instruct patients in the use of the transdermal system. (See Transdermal Administration under Dosage and Administraion.)
For transdermal therapy, give patients a copy of the patient instructions provided by the manufacturer.
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.
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.
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.
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.
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.
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.
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.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and alcohol consumption as well as any concomitant illnesses.
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.
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 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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