Clonidine hydrochloride, an imidazoline-derivative hypotensive agent, is a selective α2-adrenergic agonist.153
Oral clonidine hydrochloride or transdermal clonidine is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.1200 However, because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).502, 1200 Centrally acting agents such as clonidine may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs.501, 502, 503, 504, 1200 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) Some experts state that centrally acting agents such as clonidine generally are reserved as a last-line treatment option because of the drugs' ability to cause substantial adverse CNS effects, especially in geriatric patients.1200
Clonidine may be more effective when used with a diuretic. Clonidine hydrochloride has been used in conjunction with thiazide diuretics, chlorthalidone, or furosemide, producing a greater reduction in blood pressure than is obtained with either drug alone. Use of a diuretic may aid in overcoming tolerance to clonidine and permit reduction of clonidine dosage.
Clonidine may be useful in some patients who are unable to tolerate other adrenergic blocking agents because of severe postural hypotension. Clonidine hydrochloride has been used with other hypotensive agents such as hydralazine, reserpine, or methyldopa, permitting a reduction in the dosage of each drug and, in some patients, minimizing adverse effects while maintaining blood pressure control. As when clonidine is used alone, satisfactory results are obtained in both supine and standing patients during combined drug therapy; marked fluctuations in blood pressure because of postural changes usually do not occur during combined therapy. As with other hypotensive agents, treatment with clonidine is not curative; upon withdrawal of the drug, blood pressure returns to pretreatment levels or greater. (See Cautions: Withdrawal Effects.)
Transdermal clonidine has been effective 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 and also has been substituted for oral clonidine hydrochloride in some patients with mild to moderate hypertension whose therapy included the oral form of the drug.106, 110, 115
For additional information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Oral loading-dose regimens of clonidine hydrochloride have been effective in rapidly reducing blood pressure in patients with severe hypertension in whom reduction of blood pressure was considered urgent, but not requiring emergency treatment†. Hypertensive urgencies are those situations in which there is a severe elevation in blood pressure without progressive target organ damage.1200 Hypertensive urgencies can be managed by intensification or reinstitution (e.g., following noncompliance) of the current antihypertensive regimen and treatment of anxiety if needed.1200 Experts state that there is no need for rapid reduction of blood pressure in such patients in the emergency department and hospitalization also is unnecessary.1200
Some experts suggest that oral clonidine may be used for the initial treatment of acute severe hypertension in children and adolescents† who are able to tolerate oral therapy and who have not developed life-threatening symptoms.1150
Clonidine hydrochloride administered by epidural infusion is used as adjunctive therapy in combination with opiates in the management of severe cancer pain that is not relieved by opiate analgesics alone.151, 155 Epidural administration of analgesics should be considered only when maximum tolerated doses of opiate and adjunct analgesics administered by other routes (e.g., oral, transdermal, subcutaneous, IV) fail to relieve pain.145, 155 (See Cautions: Precautions and Contraindications.) Consistent with the drug's mechanism of action, epidural clonidine is more likely to be effective in patients with neuropathic pain rather than somatic or visceral pain.151, 155
In a double-blind, placebo-controlled, randomized study, cancer patients with severe intractable pain below the cervical dermatomes not controlled by oral, epidural, or IV opiate analgesics received epidural morphine with either clonidine hydrochloride 30 mcg/hour by continuous epidural infusion or placebo for 14 days.151, 155 Pain relief, measured by a decrease in use of epidural morphine or a decrease in visual analog pain score, was reported in 45 or 21% of patients receiving epidural clonidine or placebo, respectively.151, 155 In this study, substantial analgesic effects of clonidine appeared to be restricted to patients with neuropathic pain, characterized as localized, burning, shooting, or electric-like pain in a dermatomal or peripheral nerve distribution.151, 155
Clonidine is not indicated in patients with pheochromocytoma; however, unlike reserpine and guanethidine, it does not cause acute cardiovascular collapse in patients with this condition. Because of clonidine's ability to suppress plasma norepinephrine concentration in healthy individuals via stimulation of central α-adrenergic receptors, the drug has been used as an aid in the diagnosis of pheochromocytoma in hypertensive patients with suggestive symptoms and borderline catecholamine values†; in patients with pheochromocytoma, plasma norepinephrine concentration is generally unchanged following administration of a single oral dose of clonidine, while patients with sympathetic hyperactivity exhibit a decrease in plasma norepinephrine concentration.
Although clonidine has been used in the prophylaxis of migraine headaches†, the efficacy of the drug for this condition is questionable.158 Results of most studies using α-adrenergic agents (e.g., clonidine) for prevention of migraine headaches indicate that these drugs have limited or no efficacy in most patients,178 and therefore, some experts state that such use is not recommended.158 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.
Because clonidine reduces the responsiveness of blood vessels to vasodilators or vasoconstrictors, the drug has been used for the treatment of severe dysmenorrhea†.
Vasomotor Symptoms Associated with Menopause
Clonidine has been used orally and transdermally for the management of vasomotor symptoms† (e.g., hot flashes) associated with menopause.159, 160 Although limited data indicate that the drug may improve the severity and frequency of vasomotor symptoms in some patients, albeit modestly, the required dosages (exceeding the equivalent of 0.1 mg daily administered orally) may result in increased and, sometimes, intolerable adverse effects.159 Therefore, some clinicians recommend the use of clonidine for management of vasomotor symptoms mainly in postmenopausal women in whom estrogen replacement therapy is contraindicated or in those with preexisting hypertension.159, 160
Clonidine hydrochloride has been used safely and effectively for symptomatic relief in the management of opiate withdrawal in opiate-dependent individuals†, in both inpatient and outpatient settings.54, 55, 56, 1300, 1301, 1302, 1303, 1304, 1305, 1306, 1307, 1308
In patients with opiate dependence (i.e., opiate use disorder), opiate withdrawal management (also referred to as detoxification) generally involves short-term use of tapering dosages of buprenorphine (an opiate partial agonist) or methadone (a full opiate agonist) to reduce withdrawal symptoms.1300, 1301, 1302, 1306, 1308, 1312 However, prescribing restrictions may limit use of these drugs,1308, 1312 and α2-adrenergic agonists (e.g., clonidine, lofexidine) also have been used for symptomatic relief of noradrenergic-mediated opiate withdrawal symptoms (e.g., lacrimation, sweating, shivering, rhinorrhea) in both inpatient and outpatient settings and may allow for withdrawal over a shorter period of time.1304, 1305, 1306 The α2-adrenergic agonists appear to be less effective than buprenorphine or methadone in the management of opiate withdrawal,1300, 1301, 1302, 1303, 1308 and some experts suggest that α2-adrenergic agonists may be most useful in withdrawal management as adjuncts to opiate agonists or partial agonists,1302, 1308 to facilitate transition to opiate antagonist (naltrexone) treatment for relapse prevention,55, 1302, 1303, 1306, 1307, 1310 or in settings where therapy with opiate agonists or partial agonists is contraindicated, unacceptable, or unavailable.55, 1300, 1302, 1303, 1308, 1310, 1312 While α2-adrenergic agonists relieve noradrenergic-mediated symptoms of opiate withdrawal, concomitant supportive therapy for other withdrawal symptoms (e.g., abdominal cramping, diarrhea, nausea and vomiting, muscle spasms, anxiety or restlessness, insomnia) may improve patient comfort, particularly in patients treated principally with an α2-adrenergic agonist.1300, 1301, 1303, 1304, 1306, 1308
Although direct comparisons between lofexidine and clonidine are limited, results of several small comparative studies suggest that lofexidine and clonidine have similar efficacy in managing opiate withdrawal symptoms but lofexidine may be associated with less hypotension.1304, 1305, 1306, 1307, 1309, 1311 However, the greater cost of lofexidine compared with off-label clonidine use also must be considered.1311, 1312
Because of the potential for hypotension and bradycardia, some experts state that α2-adrenergic agonists are not drugs of choice for opiate withdrawal management in geriatric patients or patients with coronary insufficiency, ischemic heart disease, bradycardia, or cerebrovascular disease.1306
Withdrawal management alone does not provide adequate treatment for opiate use disorder; withdrawal management should be employed in patients with opiate use disorder only in conjunction with a comprehensive treatment program.1302, 1303, 1310 Opiate withdrawal without subsequent maintenance treatment is associated with high rates of relapse in patients with opiate use disorder.1300, 1303, 1308, 1310 For most patients with opioid use disorder, maintenance treatment with buprenorphine or methadone or treatment with naltrexone for relapse prevention is superior to opiate withdrawal management.1300, 1303, 1310
In patients receiving long-term opiate analgesia, withdrawal symptoms generally are managed by slow tapering of the opiate analgesic dosage.1310
Clonidine also has been used in conjunction with benzodiazepines for the management of alcohol withdrawal†.148, 149, 150 Clonidine appears to be effective in reducing symptoms of the hyperadrenergic state associated with alcohol withdrawal, including elevated blood pressure, increased heart rate, tremor, sweating, and anxiety.148, 154 However, clonidine has not been shown to prevent delirium or seizures, and the drug should be used only as an adjunct to benzodiazepines ( not as monotherapy) for the treatment of alcohol withdrawal (see Uses: Alcohol Withdrawal, in the Benzodiazepines General Statement).149, 150, 154 Some clinicians state that the use of clonidine may be particularly helpful in patients with certain coexisting conditions (e.g., opiate withdrawal).149
Clonidine is 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 Because effective nicotine dependence therapies are available, every patient should be offered effective treatment, and those who are unwilling to attempt cessation should be provided at least brief interventions designed to increase their motivation to stop tobacco use.167 The US Public Health Service (USPHS) guideline for the treatment of tobacco use and dependence currently recommends clonidine as a second-line drug for use under the supervision of a clinician.167 Second-line pharmacotherapy (e.g., clonidine, nortriptyline) is of a more limited role than first-line pharmacotherapy (i.e., bupropion [as extended-release tablets], nicotine polacrilex gum or lozenge, transdermal nicotine, nicotine nasal spray, nicotine oral inhaler, varenicline) in part because of more concerns about potential adverse effects.167 The use of second-line pharmacotherapy should be considered after first-line therapies have been used without success or are contraindicated.167 For additional information on smoking cessation, see Guidelines under Uses: Smoking Cessation, in Nicotine 12:92, and also consult the most current USPHS Clinical Practice Guideline on Treating Tobacco Use and Dependence available at [Web].
Because of its GI effects (see Pharmacology: Other Effects), clonidine hydrochloride has been used with some success in a limited number of patients for the management of diarrhea† of various etiologies (e.g., narcotic bowel syndrome, idiopathic diarrhea associated with diabetes).
Clonidine hydrochloride is administered orally or by epidural infusion, and clonidine is administered percutaneously by topical application of a transdermal system. To ensure overnight blood pressure control with oral administration, the last dose of the day should be administered immediately before retiring. If oral clonidine therapy is to be discontinued, dosage of the drug should be slowly reduced over a period of 2-4 days to avoid the possibility of precipitating a withdrawal syndrome. (See Cautions: Withdrawal Effects.)
Patients receiving transdermal clonidine therapy should be carefully instructed in the use of the transdermal system.101 To obtain optimum results, patients should also be given a copy of the patient instructions provided by the manufacturer.101 To expose the adhesive surface of the system, the clear plastic protective strip should be peeled and discarded prior to administration.101 The transdermal system is applied topically to a dry, hairless area of intact skin on the upper arm or chest by firmly pressing the system with the adhesive side touching the skin.101 If the system becomes loose during the period of use, an adhesive cover should be applied directly over the system to ensure good adhesion.101 If the patient develops isolated, mild localized skin irritation before completion of the intended period of use, the system may be removed and replaced with a new system at a different application site.101 To minimize and/or prevent potential skin irritation, each transdermal system should be applied at a different site (e.g., systems may be applied progressively across the arms and chest in one direction or the other).101
Specialized techniques are required for continuous epidural administration of clonidine hydrochloride; the drug should be administered via this route only by qualified individuals familiar with the techniques of administration and patient management problems associated with this route of clonidine administration.151 Prior to the implantation of a permanent controlled infusion device, screening should be conducted to ensure adequate response to epidural therapy.145 Chronic epidural analgesia should only be used when adequate pain relief cannot be achieved with less invasive therapies.145
The injection for epidural use concentrate containing 500 mcg/mL must be diluted prior to use in sodium chloride 0.9% injection to provide a final concentration of 100 mcg/mL.151
For continuous epidural infusion of clonidine hydrochloride, a controlled-infusion device is used to administer the drug.151 Infusion of clonidine into the upper thoracic spinal segments may be associated with substantial decreases in blood pressure.151 (See Cautions: Cardiovascular Effects.) The manufacturer states that administration of epidural clonidine above the C4 dermatome is contraindicated because of inadequate safety data supporting such use.151 Careful monitoring of infusion pump function and inspection of catheter tubing for obstruction or dislodgement is recommended to reduce the risk of inadvertent abrupt withdrawal of epidural clonidine infusion.151 Clonidine hydrochloride injection for epidural infusion contains no preservatives, and partially used vials of the drug should be discarded.151 Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.151
Standardized concentrations for epidural clonidine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 251Multidisciplinary expert panels were convened to determine recommended standard concentrations. 251Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 251 For additional information on S4S (including updates that may be available), see [Web].251
Patient Population | Concentration Standards |
|---|---|
Adults | 100 mcg/mL |
Pediatric patients (<50 kg) | 0.3 mcg/mL |
0.5 mcg/mL |
Drug Combinations | Anesthetic Concentration | Narcotic Concentration | Alpha Agonist Concentration |
|---|---|---|---|
Bupivacaine with clonidine | Bupivacaine 0.125% | Clonidine 1 mcg/mL | |
Bupivacaine with fentanyl and clonidine | 1. Bupivacaine 0.0625% | 1. Fentanyl 2 mcg/mL | 1. Clonidine 1 mcg/mL |
2. Bupivacaine 0.0625% | 2. Fentanyl 5 mcg/mL | 2. Clonidine 1 mcg/mL | |
3. Bupivacaine 0.125% | 3. Fentanyl 2 mcg/mL | 3. Clonidine 1 mcg/mL | |
4. Bupivacaine 0.125% | 4. Fentanyl 5 mcg/mL | 4. Clonidine 1 mcg/mL | |
Ropivacaine with clonidine | 1. Ropivacaine 0.1% | 1. Clonidine 1 mcg/mL | |
2. Ropivacaine 0.1% | 2. Clonidine 2 mcg/mL | ||
3. Ropivacaine 0.2% | 3. Clonidine 1 mcg/mL | ||
4. Ropivacaine 0.2% | 4. Clonidine 2 mcg/mL | ||
Ropivacaine with fentanyl and clonidine | 1. Ropivacaine 0.1% | 1. Fentanyl 2 mcg/mL | 1. Clonidine 0.3 mcg/mL |
2. Ropivacaine 0.1% | 2. Fentanyl 2 mcg/mL | 2. Clonidine 0.5 mcg/mL | |
3. Ropivacaine 0.2% | 3. Fentanyl 2 mcg/mL | 3. Clonidine 0.3 mcg/mL | |
4. Ropivacaine 0.2% | 4. Fentanyl 2 mcg/mL | 4. Clonidine 0.5 mcg/mL |
Drug Combinations | Anesthetic Concentration | Narcotic Concentration | Alpha Agonist Concentration |
|---|---|---|---|
Bupivacaine with clonidine | 1. Bupivacaine 0.0625% | 1. Clonidine 0.3 mcg/mL | |
2. Bupivacaine 0.125% | 2. Clonidine 0.5 mcg/mL | ||
3. Bupivacaine 0.125% | 3. Clonidine 1 mcg/mL | ||
Bupivacaine with fentanyl and clonidine | 1. Bupivacaine 0.0625% | 1. Fentanyl 2 mcg/mL | 1. Clonidine 0.3 mcg/mL |
2. Bupivacaine 0.0625% | 2. Fentanyl 2 mcg/mL | 2. Clonidine 0.5 mcg/mL | |
3. Bupivacaine 0.125% | 3. Fentanyl 2 mcg/mL | 3. Clonidine 0.3 mcg/mL | |
4. Bupivacaine 0.125% | 4. Fentanyl 2 mcg/mL | 4. Clonidine 0.5 mcg/mL | |
Ropivacaine with clonidine | 1. Ropivacaine 0.1% | 1. Clonidine 0.5 mcg/mL | |
2. Ropivacaine 0.1% | 2. Clonidine 1 mcg/mL | ||
3. Ropivacaine 0.2% | 3. Clonidine 1 mcg/mL | ||
Ropivacaine with fentanyl and clonidine | 1. Ropivacaine 0.1% | 1. Fentanyl 2 mcg/mL | 1. Clonidine 0.3 mcg/mL |
2. Ropivacaine 0.1% | 2. Fentanyl 2 mcg/mL | 2. Clonidine 0.5 mcg/mL | |
3. Ropivacaine 0.2% | 3. Fentanyl 2 mcg/mL | 3. Clonidine 0.3 mcg/mL | |
4. Ropivacaine 0.2% | 4. Fentanyl 2 mcg/mL | 4. Clonidine 0.5 mcg/mL |
Extemporaneously Compounded Oral Liquid
An extemporaneously compounded oral liquid formulation of clonidine has been prepared.57
Standardized concentrations for an extemporaneously prepared oral liquid preparation of clonidine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label .252 For additional information on S4S (including updates that may be available), see [Web].
Concentration Standards |
|---|
20 mcg/mLa |
aISMP has recommended clonidine concentrations be displayed as mcg/mL and not mg/mL given the most common doses used. This may need to be addressed for ordering the drug and what is placed on pharmacy labels on products dispensed
To avoid the possibility of precipitating the withdrawal syndrome, clonidine therapy should not be discontinued abruptly.601, 1200 (See Cautions: Withdrawal Effects.)
Dosage of clonidine and clonidine hydrochloride must be adjusted according to the patient's blood pressure response and tolerance. Adverse effects such as drowsiness and dry mouth may be minimized by increasing dosage gradually and/or by taking the larger portion of the daily dose at bedtime.
Tolerance to the hypotensive effect of clonidine or clonidine hydrochloride may develop in some patients necessitating increased dosage or concomitant administration of a diuretic to enhance the hypotensive response to the drug.
For the management of hypertension, the usual initial oral dosage of clonidine hydrochloride (as conventional tablets) in adults is 0.1 mg twice daily.600 Geriatric patients may benefit from a lower initial dosage of 0.05 mg twice daily.186 Dosage may be increased by 0.1 mg at weekly intervals600 until the desired response is achieved. In clinical studies, the most commonly used dosages have ranged from 0.2-0.6 mg daily, administered in divided doses.600 Some experts state that the usual dosage range for adults is 0.1-0.8 mg daily, administered in 2 divided doses.1200 The maximum effective dosage in adults is 2.4 mg daily.600
For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Smaller than usual dosages of clonidine hydrochloride may be adequate in patients who are also receiving diuretics or other hypotensive drugs.
When transdermal clonidine therapy is used for the management of hypertension in adults, transdermal therapy is initiated with one system delivering 0.1 mg/24 hours applied once every 7 days.601 Because of interpatient variability in transdermal absorption, it is recommended that this initial dosage be used in all patients, including those who had been receiving oral clonidine hydrochloride therapy, and that dosage subsequently be titrated according to individual requirements;105, 601 the relationship between the effective dosage of oral clonidine hydrochloride and that of transdermal clonidine is not predictable.105
If the desired reduction in blood pressure is not achieved after 1 or 2 weeks with the initial dosage, dosage may be increased by using 2 systems delivering 0.1 mg/24 hours or a larger dosage system.601 Subsequent dosage adjustments may be made at weekly intervals.107, 109, 110 Some experts state that the usual dosage range for transdermal clonidine is 0.1-0.3 mg/24 hours applied once every 7 days.1200 Transdermal dosages exceeding 0.6 mg/24 hours (2 systems each delivering 0.3 mg/24 hours) are usually not associated with additional efficacy.601 In patients who develop localized skin irritation during the intended period of use (7 days), it may be necessary to move the transdermal system to a different site or replace it with another system at shorter intervals (e.g., every 3-5 days).106, 109 Replacement of the transdermal system following a duration of less than 7 days may be required rarely to maintain blood pressure control.601
When transdermal therapy is initiated in patients who have been receiving low dosages of oral clonidine hydrochloride, some clinicians recommend continuing the usual oral dosage the first day the initial transdermal system is applied.105 When transdermal clonidine therapy is administered to patients already receiving other hypotensive agents, dosage of the other hypotensive agents should be gradually reduced when transdermal therapy is initiated since the hypotensive effect of transdermal clonidine may not begin until 2-3 days after application of the initial system; the other hypotensive agents may have to be continued, particularly in patients with more severe hypertension.601
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200, 1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with clonidine, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505, 506, 507, 508, 515, 1201, 1207, 1209, 1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200, 1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200, 1220
For rapid reduction of blood pressure in patients with hypertensive urgencies†, clonidine hydrochloride has been administered orally (as conventional tablets) in an initial dose of 0.1-0.2 mg, followed by hourly doses of 0.05-0.2 mg until a total dose of 0.5-0.7 mg has been given or diastolic blood pressure has been controlled.119, 128 Oral loading doses of antihypertensive agents may have cumulative effects and may cause hypotension after a patient has been discharged from a hospital or clinic setting.1200 Excessive falls in blood pressure should be avoided since they may precipitate renal, cerebral, or coronary ischemia.1200 Maintenance dosage of clonidine hydrochloride should be adjusted according to the patient's response and tolerance.119
For rapid reduction of blood pressure in children and adolescents with acute severe hypertension who can tolerate oral therapy and have not developed life-threatening symptoms†, some experts recommend an initial oral clonidine hydrochloride dose of 2-5 mcg/kg per dose (up to 10 mcg/kg per dose), which may be administered every 6-8 hours.1150
When used for the relief of severe, intractable cancer pain that is unresponsive to epidural or spinal opiate analgesia or other more conventional methods of analgesia, the recommended initial epidural dosage of clonidine hydrochloride in adults is 30 mcg/hour, administered by continuous epidural infusion.151 The dosage may be adjusted based on clinical response and tolerance; however, clinical experience with infusion rates exceeding 40 mcg/hour is limited.151 Patients should be closely monitored, particularly during the first few days of epidural clonidine therapy.151
The recommended initial dosage of epidural clonidine hydrochloride in pediatric patients is 0.5 mcg/kg of body weight per hour.151 The dosage of epidural clonidine in pediatric patients should be cautiously adjusted based on clinical response.151
As an aid in the diagnosis of pheochromocytoma†, clonidine hydrochloride has been administered orally as a single 0.3-mg dose (as conventional tablets). To conduct the test, patients should rest in the supine position for 30 minutes, after which time, 2 blood samples for baseline determination of catecholamine concentrations are drawn at 5-minute intervals. The 0.3-mg dose is then administered and blood samples for catecholamine determinations are drawn at hourly intervals for 3 hours. In patients with pheochromocytoma, plasma norepinephrine concentrations generally remain unchanged following administration of clonidine, whereas plasma norepinephrine concentrations generally decrease in patients without pheochromocytoma.
The oral dosage of clonidine hydrochloride (as conventional tablets) used in the prophylaxis of migraine† is 0.025 mg 2-4 times a day or up to 0.15 mg daily in divided doses.
For the treatment of dysmenorrhea†, 0.025 mg of clonidine hydrochloride has been administered orally twice daily (as conventional tablets) for 14 days before and during menses.
Vasomotor Symptoms Associated with Menopause
Oral clonidine hydrochloride dosages of 0.025-0.2 mg twice daily (as conventional tablets) have been employed in the management of vasomotor symptoms (e.g., hot flashes) associated with menopause†.
While comparative efficacy of various transdermal clonidine dosages have not been established, patients in clinical studies have received one transdermal system delivering 0.1 mg/24 hours applied once every 7 days.160
For symptomatic relief of opiate withdrawal in opiate-dependent individuals†, various dosage regimens of oral clonidine hydrochloride (as conventional tablets) have been used.54, 55, 56, 1301, 1302, 1303, 1306, 1307, 1308 Some experts state that the usual clonidine hydrochloride dosage for opiate withdrawal management is 0.1-0.3 mg every 6-8 hours, with dosage guided by withdrawal symptoms and adverse effects.1302, 1303, 1306, 1307, 1308 Other experts recommend administration of an initial 0.1-mg test dose of clonidine hydrochloride; a 0.2-mg test dose may be considered for patients with severe manifestations of opiate withdrawal or for those weighing more than 200 pounds (91 kg).1301 If blood pressure remains adequate (generally systolic and diastolic blood pressures of least 90 and 60 mm Hg, respectively) following the test dose, a clonidine hydrochloride dosage of 0.1-0.2 mg may be administered every 4-6 hours as needed; scheduled dosing may be considered in patients with severe withdrawal.1301 Under this dosing method, the total dose administered during the initial 24 hours of treatment is tabulated to establish the patient's daily dosage requirement and is administered in 3 or 4 divided doses.1301
Doses of clonidine hydrochloride should be reduced, delayed, or omitted in individuals demonstrating greater sensitivity to the drug's adverse effects (e.g., hypotension, orthostasis, bradycardia).1301, 1305, 1306, 1307, 1308 Individuals treated in the outpatient setting should be capable of performing self-monitoring for these adverse effects,1308 and some experts suggest that lower dosages may be appropriate in this setting.1306, 1307 As opiate withdrawal symptoms wane, clonidine hydrochloride dosage may be reduced gradually (e.g., by 0.1 mg per dose every 1-2 days).1308 Other tapering schedules also have been used to discontinue therapy (e.g., dosage has been reduced by decrements of 50% per day for 3 days and then discontinued,54 or reduced by 0.1-0.2 mg daily55 ). Clinicians should consult published protocols for more specific information.
While dosages of clonidine hydrochloride in the management of alcohol withdrawal† have not been established, oral dosages of 0.5 mg 2 or 3 times daily (as conventional tablets) have been shown to reduce tremor, heart rate, and blood pressure in patients with alcohol withdrawal.154
Optimum dosage of oral clonidine hydrochloride (as conventional tablets) or transdermal clonidine for smoking cessation† (nicotine [tobacco] dependence) has not been established, and various regimens have been employed.167
For use in the cessation of smoking†, the initial adult oral dosage of clonidine hydrochloride is typically 0.1 mg twice daily (as conventional tablets).167 Therapy with the drug is initiated on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior).167 Dosage may be increased each week by 0.1 mg daily, if needed.167 In clinical studies, oral dosages varied from 0.15-0.75 mg daily without a clear relationship to achievement of cessation of smoking.167 The duration of oral therapy with clonidine hydrochloride also varied in these studies, ranging from 3-10 weeks.167
When transdermal clonidine is used for the cessation of smoking†, therapy is initiated typically in adults with one system delivering 0.1 mg/24 hours applied once every 7 days.167 Therapy with the drug is initiated on the day set as the date of cessation of smoking or shortly before this date (e.g., up to 3 days prior).167 Dosage may be increased at weekly intervals by 0.1 mg/24 hours, if needed.167 In clinical studies, the transdermal dosage varied from 0.1-0.2 mg/24 hours without a clear relationship to achievement of cessation of smoking.167 The duration of transdermal clonidine therapy also varied in these studies, ranging from 3-10 weeks.167
Smaller than usual dosages of clonidine or clonidine hydrochloride may be adequate in patients with renal impairment. Dosage should be adjusted according to the degree of renal impairment. Some clinicians suggest that adjustment of clonidine hydrochloride dosage is not necessary in patients with creatinine clearances of 10 mL/minute or greater, but those with lower clearances can receive 50-75% of the usual dosage.122 Supplemental doses after hemodialysis are not necessary.101, 114, 122, 151
Adverse effects occurring most frequently during oral clonidine hydrochloride therapy are dry mouth, dizziness, drowsiness and sedation, and constipation; these adverse effects appear to be dose related. Headache, fatigue, and weakness also have been reported. Generally, these adverse effects are mild and tend to diminish with continued therapy or may be relieved by a reduction in dosage. Adverse effects occurring with transdermal clonidine generally appear to be similar to those occurring with oral therapy;101, 105, 106, 107, 108, 109, 110, 115, 116, 117 however, systemic adverse 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 adverse systemic effects occurring during transdermal therapy have been mild and have tended to diminish with continued treatment.101, 105, 106, 107, 109, 115, 116 The most frequently occurring adverse effects during transdermal therapy have been dry mouth, drowsiness, and local adverse dermatologic effects.101, 108, 109, 115, 116, 117 Adverse effects reported most frequently in patients with cancer receiving clonidine by epidural infusion in combination with epidural morphine in a controlled clinical trial included hypotension,151, 155 postural hypotension,151, 155 and dry mouth,151, 155 which occurred in 45, 32, and 16% of patients, respectively.155
Drowsiness has been reported in about 33, 13, or 12% of patients receiving oral, epidural, or transdermal clonidine, respectively.101, 114, 151 In addition to drowsiness, sedation, dizziness, headache, fatigue, and weakness, other adverse nervous system effects of clonidine include lethargy, vivid dreams, nightmares, insomnia, behavioral changes, nervousness, restlessness, anxiety, agitation, irritability, mental depression, visual and auditory hallucinations, delirium, localized numbness, and cerebrovascular accidents.
Depression, which occurs often in patients with cancer, may be exacerbated by the use of epidural clonidine.151 Therefore, the manufacturer recommends that patients be monitored for signs and symptoms of depression (especially those with a history of affective disorders).151 Sedation and ventilatory abnormalities, usually mild, have been reported in patients receiving bolus epidural doses of clonidine that were substantially higher than the infusion rate recommended for the treatment of cancer pain.151 Tolerance to these effects may occur with chronic administration of the drug.151
Dry mouth has been reported in about 40, 25, or 13% of patients receiving oral, transdermal, or epidural clonidine, respectively.101, 114, 151 Nausea and vomiting have occurred in about 5% of patients and anorexia and malaise in about 1% of patients receiving oral clonidine.101, 114 In addition, parotid pain, parotitis, pseudo-obstruction, abdominal pain, and constipation have occurred rarely in patients receiving oral clonidine.101, 114 Nausea and vomiting were reported in about 13 and 11%, respectively, of patients receiving clonidine by epidural infusion in combination with epidural morphine for the treatment of intractable cancer pain in a controlled clinical trial.151 Dry throat, constipation, nausea, dysgeusia, anorexia, and vomiting have been reported in patients receiving transdermal clonidine.101
Orthostatic symptoms have occurred in about 3% of patients receiving oral clonidine; palpitation and tachycardia, and bradycardia have occurred in about 0.5% of patients receiving the oral drug.101, 114 Rare cases of sinus bradycardia and atrioventricular block, with and without concomitant cardiac glycoside therapy, have been reported.101, 114 Congestive heart failure, Raynaud's phenomenon, flushes, facial pallor, syncope, chest pain, increases in blood pressure, palpitations, and ECG abnormalities (e.g., arrhythmias, sick sinus syndrome disturbances, sinus node arrest, conduction disturbances such as AV block) also have been reported.101, 114
Hypotension occurred in about 45% of patients receiving clonidine by epidural infusion as adjunctive therapy with epidural morphine for the treatment of cancer pain.151 In a 14-day clinical trial, hypotension usually was reported within the first 4 days of epidural clonidine therapy; however, hypotension also occurred throughout the duration of the study.151 Hypotension, which can be severe, usually responds to treatment with IV fluids and, if necessary, parenteral ephedrine.151 Hypotension appears to occur more frequently in women, in patients with a lower body weight, and in patients with higher serum clonidine concentrations.151
Decreased heart rate has been reported frequently in patients receiving epidural clonidine, while AV block greater than first degree in severity has been reported rarely.151 Atropine may be used to treat symptomatic bradycardia when necessary.151 Increases in heart rate associated with hypovolemia may be masked by clonidine therapy.151
Metabolic and Endocrine Effects
Weight gain has been reported in about 1% of patients receiving oral clonidine.101, 114 Some patients gain weight during the first few days of oral clonidine therapy because of sodium and fluid retention. Sodium retention usually lasts only 3 or 4 days and may be avoided or relieved by administration of a diuretic. Gynecomastia has occurred in about 0.1% of patients receiving oral clonidine during clinical trials,101, 114 and in up to 0.5% of patients during postmarketing experience with transdermal clonidine.101 Transient elevation of blood glucose concentration after single large doses of clonidine hydrochloride has been reported; however, no effects on glucose metabolism have been reported during long-term use of the drug, and diabetic patients have remained in control while taking clonidine hydrochloride. Rarely, transient elevation of serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations have been associated with use of the drug.101, 114
Rash has occurred in about 1% of patients; pruritus in about 0.7% of patients; angioedema and urticaria in about 0.5% of patients; and alopecia in about 0.2% of patients receiving oral clonidine.101, 114
Dermatologic effects were the most frequently occurring adverse effects in clinical trials of transdermal clonidine.101 In clinical studies, localized skin reactions (i.e., erythema, pruritus) occurred in up to 50% of patients receiving transdermal clonidine therapy.101 Localized skin reactions occur more commonly in patients who use an adhesive cover over the transdermal system for the entire 7-day application period.101 Localized skin reactions usually are readily reversible following removal of the transdermal system and have usually not required discontinuance of transdermal therapy.106, 107, 108, 109, 116 Allergic contact sensitization to clonidine has occurred in about 20% of patients with transdermal therapy, most frequently in white females and least frequently in black males; the dermatitis may require discontinuance of transdermal therapy.101 Although systemic anaphylactic reactions have not been reported to date,105 subsequent administration of oral clonidine (or continued administration of transdermal clonidine) to patients who experience allergic reactions with transdermal therapy may result in a recurrence of the reaction or development of a generalized rash, urticaria, or angioedema.101 (See Cautions: Precautions and Contraindications.) Localized vesiculation, hyperpigmentation (at the application site), edema, excoriation, burning, throbbing, blanching, generalized macular rash, urticaria, contact dermatitis, alopecia, and localized hypopigmentation or hyperpigmentation also have occurred in patients receiving transdermal clonidine.101
Decreased sexual activity, impotence, and loss of libido have occurred in about 3% of patients receiving oral clonidine.101, 114 Nocturia has occurred in about 1% of patients, difficulty in micturition in about 0.2% of patients, and urinary retention in about 0.1% of patients receiving oral clonidine.101, 114 Impotence/sexual dysfunction has been reported in about 2% of patients receiving transdermal clonidine, and loss of libido or decreased sexual activity and difficulty in micturition have been reported in up to 0.5% of patients receiving transdermal clonidine.101
Mild, transient abnormalities in liver function test results have occurred in about 1% of patients during oral clonidine therapy.101, 114 Hepatitis has been reported rarely;101, 114 one case of hepatitis without icterus and hyperbilirubinemia occurred in a patient receiving clonidine hydrochloride, chlorthalidone, and papaverine, but a relationship to clonidine has not been established.
Muscle or joint pain has occurred in about 0.6% of patients and leg cramps in about 0.3% of patients receiving oral clonidine.101, 114 Dryness of the nasal mucosa; blurred vision; dryness and burning of the eyes; weakly positive Coombs' test results; fever, pallor, thrombocytopenia, and increased sensitivity to alcohol also have been reported in patients receiving oral clonidine.101, 114
Fever, malaise, pallor, muscle or joint pain, and leg cramps have been reported in up to 0.5% of patients during postmarketing experience with transdermal clonidine.101
In several studies in albino rats receiving oral clonidine hydrochloride for 6 months or longer, the drug produced a dose-dependent increase in the frequency and severity of spontaneous retinal degeneration.101 Distribution studies in dogs and monkeys showed that clonidine is concentrated in the choroid of the eye.101 Ophthalmologic examinations performed prior to and periodically during oral clonidine hydrochloride therapy in humans (for 24 months or longer in some) revealed no evidence of drug-induced ophthalmologic abnormalities, except dry eyes, nor was there evidence of altered retinal function as determined by specialized tests such as electroretinography and macular dazzle.101 Blurred vision and burning and/or dryness of the eyes have been reported in up to 0.5% of patients during postmarketing experience with transdermal clonidine.101
Implantable epidural catheters are associated with a risk of infection, including meningitis and/or epidural abscess.151 The incidence of catheter-related infections is about 5-20%, and depends on several factors, including the clinical status of the patient, type of catheter used, catheter placement technique, quality of catheter care, and duration of catheter placement.151 The possibility of catheter-related infection should be considered in patients receiving epidural clonidine who develop a fever.151
Abrupt withdrawal of clonidine therapy may result in a rapid increase of systolic and diastolic blood pressures with associated symptoms such as nervousness, agitation, confusion,101 restlessness, anxiety, insomnia, headache, sweating, palpitation, increased heart rate, tremor, hiccups, stomach pains, nausea, muscle pains, and increased salivation. The exact mechanism(s) of the withdrawal syndrome following discontinuance of α-adrenergic agonists has not been determined but may involve increased concentrations of circulating catecholamines, increased sensitivity of adrenergic receptors, enhanced renin-angiotensin system activity, decreased vagal function, failure of autoregulation of cerebral blood flow, and/or failure of central α2-adrenergic receptor mechanisms that regulate sympathetic outflow from the CNS and modulate baroreflex function.
Withdrawal syndrome has been reported in about 1% of patients receiving oral clonidine.101, 114 The clonidine withdrawal syndrome is more pronounced after abrupt cessation of long-term therapy than after short-term (1-2 months) therapy and has usually been associated with previous administration of high oral dosages (greater than 1.2 mg daily) and/or with continuation of concomitant β-adrenergic blocking therapy. In addition, the risk of adverse effects following abrupt discontinuance of clonidine therapy may be increased in patients with a history of hypertension and/or other underlying cardiovascular conditions.151 (See Cautions: Precautions and Contraindications.) When the drug is discontinued abruptly, symptoms such as restlessness and headache may begin to appear 2-3 hours after a dose is missed and blood pressure may increase substantially within 8-24 hours. In a few patients, blood pressure exceeded pretreatment levels. Rare cases of hypertensive encephalopathy, cerebrovascular accidents, and death occurring after abrupt cessation of clonidine therapy have been reported.101, 114, 151 It has been postulated that the risk of precipitating the withdrawal syndrome should be reduced substantially with use of transdermal clonidine because of the pharmacodynamics associated with this dosage form;118, 120, 123 however, withdrawal symptoms have been reported occasionally (in up to 0.5% of patients)101 following discontinuance of transdermal therapy or when absorption of the drug was impaired because of dermatologic changes (e.g., contact dermatitis) under the transdermal system.105, 120, 123, 124 In one patient, withdrawal symptoms (severe rebound hypertension, tachycardia, headache, diaphoresis) appeared approximately 36-72 hours after discontinuance of transdermal therapy but responded to sublingual nifedipine and oral clonidine therapy.123 In a few geriatric patients, blood pressure has increased to levels exceeding baseline approximately 3-7 days after transdermal therapy was discontinued, although other signs of a hyperadrenergic state were not evident.120
An excessive rise in blood pressure after oral or transdermal clonidine withdrawal can be reversed and symptoms relieved by resumption of oral clonidine or by combined administration of α- and β-adrenergic blocking agents (e.g., phentolamine or prazosin with atenolol, labetalol, or propranolol). Rebound hypertension may present a particular problem if oral clonidine therapy must be interrupted for surgery. It has been reported that when the drug was discontinued 8 hours or more prior to surgery, hypertension resulted during and after surgery; however, when clonidine was administered 4-6 hours preoperatively, only minor hypertension developed and hypotension requiring treatment did not occur.
The manufacturer of oral clonidine states that because children frequently experience vomiting associated with GI illnesses, they may be particularly susceptible to hypertensive episodes resulting from sudden inability to ingest the drug.114
In a controlled clinical trial in cancer patients receiving epidural clonidine as an adjunct to epidural morphine for the treatment of pain, about 10% of patients receiving 720 mcg of clonidine hydrochloride daily experienced rebound hypertension following abrupt discontinuance of the drug; one patient subsequently suffered a cerebrovascular accident.151 Rebound hypertension following discontinuance of epidural clonidine can be reversed by administration of clonidine or IV phentolamine.151 In patients who are receiving concomitant therapy with a β-adrenergic blocking agent, the β-blocker should be discontinued several days prior to discontinuance of epidural clonidine (by gradual tapering).151
Precautions and Contraindications
Because of the risk of rebound hypertension, patients receiving clonidine preparations should be warned of the danger of missing doses or stopping the drug without consulting their clinician. (See Cautions: Withdrawal Effects.) When discontinuing clonidine therapy, a rapid rise in blood pressure may be minimized or prevented by tapered withdrawal of the drug over 2-4 days.101, 114, 151 Tapered withdrawal of transdermal clonidine120, 123 or initiation of a tapered regimen of oral clonidine123 also is recommended by some clinicians when the transdermal dosage form is discontinued,120, 123 particularly in geriatric patients.120 If clonidine therapy is to be discontinued in patients receiving clonidine and a β-adrenergic blocking agent concomitantly, the β-blocker should be discontinued several days before clonidine therapy is discontinued.101, 114, 151 It is recommended that clonidine therapy not be interrupted for surgery; transdermal therapy can be continued throughout the perioperative period and oral therapy should be continued to within 4 hours before surgery. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if necessary.101, 114 If clonidine therapy must be interrupted for surgery, parenteral hypotensive therapy should be administered as necessary, and clonidine therapy should be resumed as soon as possible. If transdermal therapy is initiated during the perioperative period, it must be kept in mind that therapeutic plasma clonidine concentrations are not achieved until 2-3 days after initial application of the transdermal system.
Clonidine transdermal systems should be removed from the site(s) of application prior to attempting defibrillation or cardioversion since altered electrical conductivity and enhanced potential for electrical arcing may occur.101, 121
Patients receiving transdermal clonidine therapy should be advised that if the transdermal system begins to loosen from the skin after application, an adhesive cover should be applied directly over the system to ensure good adhesion over the period of application.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 their physician promptly about the need to remove the transdermal system.101 If patients develop isolated, mild localized skin irritation before completion of the intended period of use (7 days), the system may be removed and replaced with a new system at a different application site.101 In patients who develop localized contact sensitization to clonidine with transdermal therapy, subsequent administration of oral clonidine hydrochloride (or continued administration of transdermal clonidine) may be associated with development of a generalized rash.101 In patients receiving transdermal therapy who develop an allergic reaction, subsequent administration of oral clonidine hydrochloride also may elicit an allergic reaction (e.g., generalized rash, urticaria, angioedema).101, 114 Patients receiving transdermal clonidine therapy should be instructed to keep both used and unused transdermal systems out of the reach of children.101 In addition, these patients should be cautioned that even after use, the transdermal system contains active medication that may be harmful if accidentally applied or ingested by infants or children.101, 127 (See Acute Toxicity: Manifestations.) Patients should be instructed to handle the used transdermal system carefully (e.g., fold the system in half with the sticky sides together) and to dispose of the system out of the reach of children.101, 126, 127
In rare instances, loss of blood pressure control has been reported in patients using transdermal clonidine therapy according to the instructions for use.101
Epidural clonidine should be used only in patients with severe cancer pain that has failed to respond to an adequate trial with opiate analgesics.151 The drug is not recommended for the management of obstetric, postpartum, or perioperative pain.151 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 Patients should be instructed to notify their clinician immediately in case of inadvertent interruption of epidural clonidine administration.151 Specialized techniques are required for continuous epidural administration of clonidine hydrochloride; the drug should be administered via this route only by qualified individuals familiar with the techniques of administration and patient management problems associated with this route of clonidine administration.145, 151 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 Administration of epidural clonidine also is not recommended in most patients with severe cardiovascular disease or in patients who are hemodynamically unstable.151 The manufacturer states that administration of epidural clonidine above the C4 dermatome is contraindicated because of inadequate safety data supporting such use.151
Clonidine should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, conduction disturbances,101, 114 cerebrovascular disease, chronic renal failure, Raynaud's disease, or thromboangiitis obliterans. Patients with a history of mental depression require careful supervision while receiving clonidine as they may be subject to further depressive episodes. Patients who engage in potentially hazardous activities such as operating machinery or driving should be warned of the possible sedative effect of the drug.101, 114 In addition, patients should be informed that clonidine may be additive with, or may potentiate the action of, other CNS depressants such as opiate agonists or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol.101, 114
The possibility that clonidine may lower blood pressure in patients receiving the drug for conditions other than hypertension (e.g., opiate withdrawal, smoking cessation, pain management) should be considered, and blood pressure should be monitored as appropriate.151, 162, 167, 1301, 1303 In addition, the possibility of rebound hypertension and other withdrawal effects should be considered when the drug is discontinued in such patients; abrupt discontinuance should be avoided.167, 1301
Patients who wear contact lenses should be cautioned that clonidine may cause dryness of the eyes.600
A dose-dependent increase in the incidence and severity of spontaneously occurring retinal degeneration was observed in albino rats receiving the drug for 6 months or longer, especially those receiving strong exposure to light. In 353 of 908 patients undergoing eye examinations over periods of at least 24 months in clinical trials, no drug-related ophthalmologic findings were recorded except for some dryness of the eyes, and retinal function as measured by specialized tests (e.g., electroretinography, macular dazzle) was unchanged.600
Clonidine is contraindicated in patients with known hypersensitivity to the drug or to any ingredient or component in the formulation.101, 114, 151
Safety and efficacy of oral clonidine hydrochloride and clonidine transdermal system for the management of hypertension in children have not been established.600, 601 Some experts have recommended oral dosages of clonidine for pediatric patients with hypertension or severe hypertension based on clinical experience.187 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
The safety and efficacy of clonidine hydrochloride epidural infusion have been established in pediatric patients who are old enough to tolerate placement and management of an epidural catheter, based on evidence from adequate, well-controlled studies in adults and experience with the use of clonidine in pediatric patients for other indications.151 Epidural clonidine should be used only in pediatric patients with severe, intractable cancer pain that is unresponsive to epidural or spinal opiates and to other conventional analgesic therapy.151
Children may be more likely to experience CNS depression associated with clonidine overdosage than adults.101, 114 In children, signs of toxicity have occurred with clonidine doses as low as 0.1 mg.101, 114 Rare cases of clonidine toxicity (many involving children) associated with accidental or deliberate mouthing or ingestion of clonidine transdermal systems have been reported.101
The manufacturer of oral clonidine states that because children frequently experience vomiting associated with GI illnesses, they may be particularly susceptible to hypertensive episodes resulting from sudden inability to ingest the drug.114
Mutagenicity and Carcinogenicity
There was no evidence of clonidine-induced mutagenesis in vitro in the Ames microbial mutagen test.101, 114 Clonidine was not clastogenic in the mouse micronucleus test.101, 114 Studies to determine the carcinogenic potential of clonidine were performed in rats receiving oral dosages up to 46 times the maximum recommended human dosage on a mg/kg basis for 132 weeks and in mice receiving up to 70 times the maximum recommended human dosage on a mg/kg basis for up to 78 weeks. 101, 114 These dosages were approximately 9 and 6 times the maximum recommended human daily dosage on a mg/m2 basis in rats and mice, respectively.101, 114
Pregnancy, Fertility, and Lactation
Reproduction studies in rabbits using oral clonidine hydrochloride dosages up to about 3 times the maximum recommended human dosage have not revealed evidence of teratogenicity or embryotoxicity.101, 114 However, in female rats receiving the drug continuously for 2 months prior to mating, an increased incidence of fetal resorptions occurred with oral dosages as low as one-third the maximum recommended human dosage (1/15th the maximum recommended human dosage on a mg/m2 basis); resorptions were not increased when these or higher dosages (up to 3 times the maximum recommended human dosage) were administered during days 6-15 of gestation.101, 114 An increased incidence of fetal resorptions was observed when much higher dosages (40 times the maximum recommended human dosage on a mg/kg basis and 4-8 times the maximum recommended human dosage on a mg/m2 basis) were administered to mice and rats during days 1-14 of gestation; the lowest dosage used in the study was 0.5 mg/kg.101, 114 There are no adequate and controlled studies to date using clonidine in pregnant women, and the drug should be used during pregnancy only when clearly needed.101, 114, 151
Reproduction studies in rats using oral clonidine hydrochloride dosages up to 0.15 mg/kg daily (about 3 times the maximum recommended human dosage) have not revealed evidence of impaired fertility; however, fertility in female rats was impaired at oral dosages ranging from 0.5-2 mg/kg daily (about 10-40 times the maximum recommended human oral dosage on a mg/kg basis [2-8 times the maximum recommended human dosage on a mg/m2 basis]).101, 114
Since clonidine is distributed into milk, the drug should be used with caution in nursing women.101, 114 The manufacturer of parenteral clonidine states that because of the potential for serious adverse reactions to clonidine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.151
Clonidine may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol. Concomitant administration of opiate analgesics with clonidine also may potentiate the hypotensive effects of clonidine.151
Tricyclic antidepressants (i.e., imipramine, desipramine) have reportedly inhibited the hypotensive effect of clonidine. The increase in blood pressure usually occurs during the second week of tricyclic antidepressant therapy, but occasionally may occur during the first several days of concomitant therapy. The possibility of this interaction should be considered in patients receiving clonidine and tricyclic antidepressants concomitantly; blood pressure should be closely monitored during the first several weeks of concurrent therapy, and dosage of clonidine should be increased to adequately control hypertension if necessary. Alternatively, other hypotensive agents that do not interact with tricyclic antidepressants may be substituted, but clonidine therapy should not be discontinued abruptly. If tricyclic antidepressant therapy is discontinued in patients receiving clonidine, the hypotensive effect of clonidine may increase; blood pressure should be monitored and dosage of clonidine reduced if necessary. In rats, concurrent administration of clonidine and amitriptyline has produced corneal lesions within 5 days.101, 114 The effects of tricyclic antidepressants on the analgesic effect of epidural clonidine hydrochloride are not known.151
Clonidine withdrawal may result in an excess of circulating catecholamines; therefore, caution should be exercised in concomitant use of drugs which affect the metabolism or tissue uptake of these amines (monoamine oxidase inhibitors or tricyclic antidepressants, respectively).
Acute delirium has been reported in at least one patient receiving fluphenazine concomitantly with oral clonidine.151 The symptoms resolved following discontinuance of clonidine and recurred upon rechallenge with the drug.151
When clonidine is administered with other hypotensive agents, including diuretics, the hypotensive effect of clonidine may be increased. This effect is usually used to therapeutic advantage in antihypertensive therapy; however, careful adjustment of dosage is necessary when these drugs are used concomitantly.
Because clonidine may produce bradycardia and atrioventricular (AV) block, the possibility of additive effects should be considered if it is given concomitantly with other drugs that affect sinus node function or AV nodal conduction (e.g., guanethidine), β-adrenergic blocking agents (e.g., propranolol), calcium-channel blocking agents, or cardiac glycosides.
Because β-blockers may exacerbate rebound hypertension that may occur following discontinuance of clonidine therapy, such drugs should be discontinued several days before gradual withdrawal of clonidine when clonidine therapy is to be discontinued.139 If clonidine therapy is to be replaced by a β-blocker, administration of the β-blocker should be delayed for several days after clonidine therapy has been discontinued.139, 140
Epidural clonidine may prolong the duration of the pharmacologic effects, including both sensory and motor blockade, of epidural local anesthetics.151
The oral LD50 of clonidine hydrochloride is 206 and 465 mg/kg in mice and rats, respectively.101, 114, 151
Signs and symptoms of overdosage of clonidine include hypotension (which may be profound), transient hypertension, weakness, vomiting, irritability, diminished or absent reflexes, lethargy, somnolence, drowsiness, deep sedation, irritability, skin pallor, hypothermia, decreased or irregular heart rate, dryness of the mouth, constricted pupils with poor reaction to light, respiratory depression, and hypoventilation. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures.101, 114, 151 Signs and symptoms of clonidine overdosage usually occur within 30-120 minutes after ingestion.101, 114 Children may be more likely to experience CNS depression associated with clonidine overdosage.101, 114 In children, signs of toxicity have occurred with oral clonidine doses as low as 0.1 mg.101, 114, 151 Rare cases of clonidine toxicity (many involving children) associated with accidental or deliberate mouthing or ingestion of clonidine transdermal systems have been reported.101 In one individual who reportedly ingested 100 mg of clonidine hydrochloride, plasma clonidine concentrations were 60, 90, 370, 120, and 120 ng/mL 1, 1.5, 2, 5.5, and 6.5 hours after ingestion.101, 114, 151 Signs and symptoms of overdosage in this patient included transient hypertension followed by hypotension, bradycardia, apnea, hallucinations, partial coma, and ventricular premature contractions; the patient recovered following intensive symptomatic and supportive treatment.101, 114, 151 In a 2-year old infant who apparently ingested clonidine from a used and discarded transdermal system, a serum clonidine concentration determined 24 hours after ingestion was approximately 8 ng/mL (therapeutic range: 0.5-4.5 ng/mL).126 In this infant, lethargy developed over several hours and was accompanied by bradycardia, hypotension, miosis, and gasping respirations; the patient was monitored in an intensive care unit and recovered over a period of 16 hours without specific treatment.126
There is no known specific antidote for clonidine overdosage.101, 114, 151 If signs and symptoms of clonidine overdosage occur in patients receiving transdermal therapy, all transdermal systems should be removed.101 Following removal of the transdermal system(s), plasma concentrations of clonidine will persist for about 8 hours and then decline slowly over several days.101 Ipecac-induced emesis and gastric lavage would not be expected to remove significant amounts of clonidine following transdermal exposure.101 If the transdermal system has been ingested, whole bowel irrigation may be considered, and the administration of activated charcoal and/or cathartic agents may be beneficial.101
In acute overdosage with oral clonidine, gastric lavage may be indicated following recent and/or large ingestions; administration of an activated charcoal slurry and/or cathartic agents may be beneficial.114 Because clonidine overdosage may result in the rapid development of CNS depression, induction of emesis using ipecac syrup is not recommended.114 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Supportive and symptomatic treatment should be initiated and an adequate airway established and maintained since respiratory depression or apnea may ensue. Supportive care may include atropine sulfate for symptomatic bradycardia, IV fluids and/or vasopressor agents for hypotension, and vasodilators for hypertension.101, 114, 151 Patients with hypotension also may be placed in Trendelenburg's position; IV infusion of dopamine may be useful for severe, persistent hypotension. The manufacturers state that administration of tolazoline has yielded inconsistent results and is not recommended as first-line therapy for clonidine overdosage.101, 114, 151 Hypertension has been managed with IV furosemide or diazoxide (parenteral formulation no longer commercially available in the US) or α-adrenergic blocking agents (e.g., phentolamine).151 Additional information on the efficacy of α-adrenergic blockers in the treatment of clonidine overdosage is necessary. Naloxone may be a useful adjunct for the management of respiratory depression, hypotension, and/or coma associated with clonidine overdosa because paradoxical hypertension occasionally has been reported with the use of naloxone, blood pressure should be monitored.101 114, 151 Seizures can be managed with IV administration of a benzodiazepine (e.g., diazepam). Although forced diuresis has been suggested to enhance the elimination of clonidine, there is no current evidence to support this procedure for clonidine overdosa in addition, forced diuresis may potentiate clonidine-induced hypotension. Hemodialysis is of limited value in the treatment of clonidine overdosage, since a maximum of 5% of circulating drug is removed.101, 114, 151
Clonidine 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. The central effects of the drug result in reduced peripheral sympathetic nervous system activity, reduced peripheral and renovascular resistance, reduction of systolic and diastolic blood pressure, and bradycardia.151 Peripheral venous pressure remains unchanged. It has been postulated that the hypotensive response to clonidine may result from reduced angiotensin II generation because of inhibition of renin release or from reduced stimulation of medullary vasomotor centers responsive to circulating angiotensin II; however, the exact relationship between the action of the drug in reducing renin activity and excretion of aldosterone and catecholamines and the hypotensive effect of the drug has not been fully elucidated.
Clonidine reduces blood pressure to essentially the same extent in both supine and standing patients; therefore, orthostatic effects are mild and infrequently encountered. However, the underlying hemodynamic effects differ with position of the patient. Administration of a single dose of clonidine hydrochloride to supine patients results in a reduction in cardiac output and decreased stroke volume. Total peripheral resistance remains unchanged. In patients in the standing position or at a 45° tilt, a smaller decrease in cardiac output occurs and total peripheral resistance is decreased, but stroke volume is maintained. Prolonged therapy results in circulatory adjustments, so that the hypotensive effect of the drug largely results from reduced peripheral resistance. Rapid IV, but not oral or IM, administration of clonidine produces direct stimulation of peripheral α2-adrenergic receptors, resulting in transient vasoconstriction and a rise in systolic and diastolic blood pressure.
Urinary excretion of catecholamines is decreased during clonidine hydrochloride therapy; however, unlike reserpine, clonidine does not deplete catecholamines from the heart or other tissues. Abrupt withdrawal of clonidine following prolonged oral administration may cause increased urinary excretion of catecholamines and rebound of systolic and diastolic blood pressure.
Blood volume, as determined using iodinated I 131 serum albumin, is not substantially affected by clonidine. Circulation time is prolonged during use of the drug.
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 Stimulation of spinal α2-adrenergic receptors by clonidine inhibits sympathetically mediated ascending pain pathways that are activated by nociceptive stimuli and prevents transmission of pain signals to the brain.142, 143, 151 Activation of α2-adrenergic receptors by α2-adrenergic agonists also stimulates acetylcholine release and inhibits the release of substance P, an inflammatory neuropeptide.141, 142, 143 Clonidine-mediated analgesia is dose-dependent and is limited to regions of the body that are innervated by spinal segments containing analgesic concentrations of the drug.151 Analgesia resulting from clonidine therapy is not antagonized by opiate antagonists.151
Acute or chronic administration of clonidine hydrochloride produces no substantial change in renal blood flow, renal plasma flow, or glomerular filtration rate. In standing patients, renal vascular resistance is substantially reduced. The moderate reduction in renal blood flow and glomerular filtration rate produced by head-up tilting are unchanged by administration of the drug. The increased renal vascular resistance which normally occurs after tilting does not occur in patients receiving clonidine.
Sodium and chloride excretion are markedly reduced after initial administration of clonidine hydrochloride; however, potassium excretion is not substantially changed. Sodium retention probably results from enhanced tubular reabsorption being stimulated by decreased renal perfusion pressure and generally persists for only 3-4 days after which natriuresis occurs. Renal vein plasma renin activity and aldosterone excretion rate are consistently reduced as a result of centrally mediated sympathetic inhibition.
Acute administration of clonidine 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 sedative effect of clonidine is thought to result from central α2-agonist activity. The decrease in salivation induced by clonidine appears to result from both central and peripheral mechanisms, probably involving the drug's α2-agonist activity. The peripheral mechanism of decreased salivation may involve inhibition of cholinergic transmission via stimulation of α2-adrenergic receptors.
Clonidine has been shown to decrease GI motility and control diarrhea in animals, probably secondary to the drug's α2-agonist activity. Clonidine has also been shown to increase intestinal absorption of sodium and chloride, with a secondary passive increase in water absorption.
IV or ocular administration of clonidine hydrochloride (ophthalmic preparation no longer commercially available in the US) in patients with glaucoma decreases intraocular pressure, reportedly by decreasing production of aqueous humor. It has been reported that when only one eye is treated topically with clonidine, ocular pressure in the untreated eye is also reduced.
Clonidine has been shown to reduce the signs and symptoms of opiate withdrawal in individuals physically dependent on opiates. Clonidine 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.
Clonidine hydrochloride is well absorbed from the GI tract. The drug may also be absorbed when applied topically to the eye (ophthalmic preparation no longer commercially available in the US). Clonidine is well absorbed percutaneously following topical application of a transdermal system to the arm or chest.102, 103, 104, 115, 117, 118 Plasma clonidine concentrations of 2 ng/mL have been detected 1 hour after administration of a single 0.39-mg oral dose of radiolabeled drug. Peak plasma concentrations following oral administration occur in approximately 3-5 hours.
Following initial application of a transdermal system of clonidine, the initial release of the drug saturates skin sites beneath the system;101 therapeutic plasma concentrations are attained within 2-3 days.101, 102, 103, 104, 118 To provide the concentration gradient necessary for controlled release and percutaneous absorption of drug, clonidine transdermal systems contain an excess amount of drug.101, 102 Following removal of the systems in one study in healthy adults, analysis of residual concentration of drug in transdermal systems that initially contained 2.5 mg of clonidine per 3.5 cm2 surface area indicated that release of clonidine averaged 48 and 65% after 7 and 11 days of wear, respectively, following topical application to the upper outer arm and averaged 70% after 11 days of wear following topical application to the chest.104 When given in dosages that produce comparable blood pressure reduction, steady-state plasma clonidine concentrations attained with the transdermal systems are generally similar to trough concentrations attained with twice-daily oral dosing regimens of the drug.102, 103, 105, 106, 110, 115, 118 Mean steady-state plasma clonidine concentrations of 0.39, 0.84, or 1.12 ng/mL have been reported following topical application of the 3.5-, 7-, or 10.5-cm2 transdermal system (see Preparations), respectively, to the upper outer arm of healthy adults.104 Percutaneous absorption of the drug from the upper arm or chest is similar,104 but less drug is absorbed from the thigh.105 Replacement of the transdermal system at a different site at weekly intervals continuously maintains therapeutic plasma clonidine concentrations.101, 104 Following discontinuance of transdermal therapy, therapeutic plasma drug concentrations persist for about 8 hours and then decline slowly over several days; over this time period, blood pressure returns gradually to pretreatment levels.101, 102, 103, 117, 118 If a transdermal system of clonidine is not removed after 7 days as recommended, absorption of the drug from the system may continue; if an additional system is then applied, higher plasma drug concentrations may result and, if an additional system is not applied, plasma drug concentrations may not decrease substantially for at least 2-4 more days while the system is still being worn.104
Reduction in blood pressure is maximal at plasma clonidine concentrations less than 2 ng/mL.111, 112 Blood pressure begins to decrease within 30-60 minutes after an oral dose of clonidine hydrochloride; the maximum decrease occurs in approximately 2-4 hours.114 The hypotensive effect lasts up to 8 hours. Following administration of clonidine by slow IV injection† in patients with acute hypertensive crisis, a hypotensive effect occurred within minutes, peaked in 30-60 minutes, and lasted more than 4 hours.
Following epidural administration of a single bolus dose of clonidine in healthy individuals and patients with cancer, clonidine is rapidly absorbed into the systemic circulation.141 A mean peak plasma clonidine concentration of 4.4 ng/mL (range: 3-5.8 ng/mL) was reported on average 19 minutes following epidural administration of 700 mcg of clonidine hydrochloride given over 5 minutes in healthy individuals.151 Mean peak plasma concentrations of clonidine were reported to be higher in women than in men.151 Following continuous epidural infusion of clonidine hydrochloride (30 mcg/hour for 14 days in addition to administration of morphine sulfate for patient-controlled analgesia [PCA]) in cancer patients, mean steady-state plasma concentrations were approximately 2.2 and 2.4-2.5 ng/mL on days 7 and 14 of dosing, respectively.151 Accumulation of clonidine does not appear to occur following continuous epidural infusion of the drug in adult cancer patients.152
Following epidural administration of a single dose of clonidine hydrochloride, near maximal analgesia occurs within 30-60 minutes.141 Onset and duration of the analgesic effect of a single epidural dose of clonidine do not correlate with plasma drug concentrations; rather, analgesic effects appear to correlate with drug concentration in the CSF.141, 142 Although the CSF is not the presumed site of action of clonidine-mediated analgesia, the drug appears to diffuse rapidly from the CSF to the dorsal horn.142 A lumbar CSF concentration of 130 ng/mL reportedly was associated with a 95% maximal analgesic effect in healthy individuals.141
Animal studies indicate that clonidine is widely distributed into body tissues; tissue concentrations of the drug are higher than plasma concentrations. The mean volume of distribution of clonidine is reported to be 2.1 L/kg.151 After oral administration, highest concentrations of the drug are found in the kidneys, liver, spleen, and GI tract. High concentrations of the drug also appear in the lacrimal and parotid glands. Clonidine is concentrated in the choroid of the eye and is also distributed into the heart, lungs, testes, adrenal glands, fat, and muscle. The lowest concentration occurs in the brain. Clonidine is distributed into CSF. Following epidural infusion, clonidine is rapidly and extensively distributed into CSF and readily partitions into the plasma via epidural veins.141, 151 In vitro, clonidine is approximately 20-40% bound to plasma proteins, mainly albumin.151 Clonidine crosses the placenta129, 151 and is distributed into milk.130, 151 In one lactating woman who received approximately 0.04 mg of oral clonidine hydrochloride twice daily and 25 mg of oral dihydralazine 3 times daily, clonidine concentrations were 0.33 ng/mL in a plasma sample obtained 1 hour after a dose and 0.6 ng/mL in a milk sample obtained 2.5 hours after a dose; the drug was not detected in the plasma of the infant 1 hour after nursing.130
The plasma half-life of clonidine is 6-20 hours in patients with normal renal function. The half-life in patients with impaired renal function has been reported to range from 18-41 hours.111, 114, 151 The elimination half-life of the drug may be dose dependent, increasing with increasing dose.113
Clonidine hydrochloride is metabolized in the liver. In humans, 4 metabolites have been detected but only one, the inactive p -hydroxyclonidine, has been identified.
In humans, 40-60% of an orally administered dose of clonidine hydrochloride (as conventional tablets) is excreted in urine as unchanged drug within 24 hours.101, 114, 116 Following IV administration of radiolabeled clonidine, 72% of the administered dose is excreted in urine within 96 hours; about 40-50% is excreted as unchanged drug.151 In humans, less than 10% of a dose usually is excreted as p -hydroxyclonidine.151 Approximately 20% of the dose is excreted in feces, probably via enterohepatic circulation. Approximately 85% of a single dose is excreted within 72 hours, and excretion is complete after 5 days. Following IV administration of clonidine, renal clearance of the drug averages 133 mL/minute.151 In patients undergoing hemodialysis, only 5% of a dose was removed into the dialysate.151 Following continuous epidural infusion of clonidine hydrochloride (30 mcg/hour for 14 days in addition to morphine sulfate administered for patient-controlled analgesia [PCA]) in cancer patients, mean total body clearance of the drug was approximately 279 and 272 mL/minute on days 7 and 14 of dosing, respectively.151, 152
Clonidine hydrochloride, an imidazoline-derivative hypotensive agent, is a selective α2-adrenergic agonist.153 Clonidine is commercially available as the base and as the hydrochloride salt. Clonidine hydrochloride occurs as a white, crystalline powder that has a bitter taste and is freely soluble in water and soluble in alcohol. Clonidine hydrochloride also is commercially available as a clear, colorless, preservative-free aqueous sterile injection.151 Sodium hydroxide and/or hydrochloric acid may be added during manufacture of the injection to adjust the pH to 5-7.151
The commercially available transdermal system of clonidine consists of an outer layer of pigmented polyester film; a drug reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide; a microporous polypropylene membrane that controls the rate of diffusion of the drug; and a final adhesive layer that provides an initial release of drug and contains those ingredients found in the reservoir.101 The adhesive layer is covered by a protective slit release liner which is removed prior to application.101
The commercially available transdermal system of clonidine should be stored at a temperature less than 30°C.101 Clonidine hydrochloride tablets should be stored in tight, light-resistant containers at a controlled room temperature of 25°C, but may be exposed to temperatures ranging from 15-30°C.114 Commercially available clonidine hydrochloride tablets have an expiration date of 42 months following the date of manufacture. Commercially available clonidine hydrochloride injection should be stored at controlled room temperature of 25°C, but may be exposed to temperatures ranging from 15-30°C.151 The injection contains no preservatives; any unused portion should be discarded.151
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
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 |
Clonidine Transdermal System | ||||
0.2 mg/24 hours (5 mg/7 cm2)* | Catapres-TTS® | Boehringer Ingelheim | ||
Clonidine Transdermal System | ||||
0.3 mg/24 hours (7.5 mg/10.5 cm2)* | Catapres-TTS® | Boehringer Ingelheim | ||
Clonidine Transdermal System |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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 | Injection, concentrate, for epidural use | 500 mcg/mL* | Clonidine Hydrochloride Injection | |
Duraclon® | Mylan | |||
Injection, for epidural use | 100 mcg/mL* | Clonidine Hydrochloride Injection | ||
Duraclon® | Mylan |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
54. Gold MS, Pottash AC, Sweeney DR et al. Opiate withdrawal using clonidine. A safe, effective, and rapid nonopiate treatment. JAMA . 1980; 243:343-6. [PubMed 7351747]
55. Washton AM, Resnick RB. Clonidine in opiate withdrawal: review and appraisal of clinical findings. Pharmacotherapy . 1981 Sep-Oct; 1:140-6. [PubMed 6765486]
56. Bourret JA. Refocus on clonidine in opiate withdrawal--effects support noradrenergic hypothesis. Hosp Formul . 1981; 16:431.
57. Sauberan JB, Phuong P, Ilog ND, Rossi SS. Stability and Osmolality of Extemporaneously Prepared Clonidine Oral Liquid for Neonates. Ann Pharmacother. 2016 Mar;50(3):243-4. doi: 10.1177/1060028015620625. Epub 2016 Jan 4. PMID: 26728366.
101. Boehringer Ingelheim Pharmaceuticals, Inc. Catapres-TTS® (clonidine) Transdermal Therapeutic System prescribing information. Ridgefield, CT; 2004 Aug.
102. Shaw JE. Pharmacokinetics of nitroglycerin and clonidine delivered by the transdermal route. Am Heart J . 1984; 108:217-23. [PubMed 6428208]
103. Arndts D, Arndts K. Pharmacokinetics and pharmacodynamics of transdermally administered clonidine. Eur J Clin Pharmacol . 1984; 26:79-85. [PubMed 6714294]
104. MacGregor TR, Matzek KM, Keirns JJ et al. Pharmacokinetics of transdermally delivered clonidine. Clin Pharmacol Ther . 1985; 38:278-84. [PubMed 4028622]
105. Anon. Transdermal clonidine for hypertension. Med Lett Drugs Ther . 1985; 27:95-6. [PubMed 4058369]
106. Weber MA, Drayer JIM. Clinical experience with rate-controlled delivery of antihypertensive therapy by a transdermal system. Am Heart J . 1984; 108:231-6. [PubMed 6375331]
107. Weber MA, Drayer JIM, Brewer DD et al. Transdermal continuous antihypertensive therapy. Lancet . 1984; 1:9-11. [PubMed 6140393]
108. Schaller MD, Nussberger J, Waeber B et al. Transdermal clonidine therapy in hypertensive patients: effects on office and ambulatory recorded blood pressure values. JAMA . 1985; 253:233-5. [PubMed 3965774]
109. Weber MA, Drayer JIM, McMahon FG et al. Transdermal administration of clonidine for treatment of high BP. Arch Intern Med . 1984; 144:1211-3. [PubMed 6375613]
110. Popli S, Stroka G, Ing TS et al. Transdermal clonidine for hypertensive patients. Clin Ther . 1983; 5:624-8. [PubMed 6627288]
111. Lowenthal DT. Pharmacokinetics of clonidine. J Cardiovasc Pharmacol . 1980; 2(Suppl 1):S29-37.
112. Davies DS, Wing LMH, Reid JL et al. Pharmacokinetics and concentration-effect relationships of intravenous and oral clonidine. Clin Pharmacol Ther . 1977; 21:593-601. [PubMed 870272]
113. Frisk-Holmberg M, Paalzow L, Edlund PO. Clonidine kinetics in man—evidence for dose dependency and changed pharmacokinetics during chronic therapy. Br J Clin Pharmacol . 1981; 12:653-8. [PubMed 7332729]
114. Boehringer Ingelheim Pharmaceuticals, Inc. Catapres® (clonidine hydrochloride) prescribing information. Ridgefield, CT; 1998 Apr.
115. Burris JF, Mroczek WJ. Transdermal administration of clonidine: a new approach to antihypertensive therapy. Pharmacotherapy . 1986; 6:30-4. [PubMed 3952004]
116. Weber MA. Transdermal antihypertensive therapy: clinical and metabolic considerations. Am Heart J . 1986; 112:906-12. [PubMed 2945415]
117. Popli S, Daugirdas JT, Neubauer JA et al. Transdermal clonidine in mild hypertension: a randomized, double-blind, placebo-controlled trial. Arch Intern Med . 1986; 146:2140-4. [PubMed 3535714]
118. Lowenthal DT, Saris S, Paran E et al. Efficacy of clonidine as transdermal therapeutic system: the international clinical trial experience. Am Heart J . 1986; 112:893-900. [PubMed 3532747]
119. Houston MC. Treatment of hypertensive emergencies and urgencies with oral clonidine loading and titration: a review. Arch Intern Med . 1986; 146:586-9. [PubMed 3513726]
120. Metz S, Klein C, Morton N. Rebound hypertension after discontinuation of transdermal clonidine therapy. Am J Med . 1987; 82:17-19. [PubMed 3026180]
121. Babka JC. Does nitroglycerin explode? N Engl J Med . 1983; 309:379. Letter.
122. Bennett WM, Aronoff GR, Golper TA et al. Drug prescribing in renal failure: dosing guidelines for adults. Philadelphia: American College of Physicians; 1987:34-5.
123. Schmidt GR, Schuna AA. Rebound hypertension after discontinuation of transdermal clonidine. Clin Pharm . 1988; 7:772-4. [PubMed 3233898]
124. White TM, Guidry JR. Rebound hypertension associated with transdermal clonidine and contact dermatitis. West J Med . 1986; 145:104. [PubMed 3751022]
126. Corneli HM, Banner WW, Vernon DD et al. Toddler eats clonidine patch and nearly quits smoking for life. JAMA . 1989; 261:42. [PubMed 2908984]
127. Boehringer Ingelheim Pharmaceuticals, Inc. Catapres-TTS® (clonidine) Transdermal Therapeutic System patient information. Ridgefield, CT; 1988 Oct.
128. Gifford RW Jr. Management of hypertensive crises. JAMA . 1991; 266:829-35. [PubMed 1865522]
129. Boutroy MJ. Fetal effects of maternally administered clonidine and angiotensin-converting enzyme inhibitors. Dev Pharmacol Ther . 1989; 13:199-204. [PubMed 2693003]
130. Bunjes R, Schaerfer C, Holzinger D. Clonidine and breast-feeding. Clin Pharm . 1993; 12:178-9. [PubMed 8491075]
131. National Heart, Lung, and Blood Institute. NHLBI panel reviews safety of calcium channel blockers. Rockville, MD; 1995 Aug 31. Press release.
132. National Heart, Lung, and Blood Institute. New analysis regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. Rockville, MD; 1995 Sep 1.
133. Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA . 1995; 274:620-5. [PubMed 7637142]
134. Yusuf S. Calcium antagonists in coronary artery disease and hypertension: time for reevaluation? Circulation . 1995; 92:1079-82. Editorial.
136. Kaplan NM. Choice of initial therapy for hypertension. JAMA . 1996; 275:1577-80. [PubMed 8622249]
137. Psaty BM, Smith NL, Siscovich DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA . 1997; 277:739-45. [PubMed 9042847]
138. Whelton PK, Appel LJ, Espeland MA et al. for the TONE Collaborative Research Group. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA . 1998; 279:839-46. [PubMed 9515998]
139. Clonidine/beta blockers. In: Tatro DS, Olin BR, Hebel SK, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1992 (July):200.
140. Merck & Co. Blocadren® (timolol maleate) tablets prescribing information (dated 1997 Nov). In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998(Suppl A):A204-5.
141. Eisenach JC, De Kock M, Klimscha W. α2-adrenergic agonists for regional anesthesia: a clinical review of clonidine (1984-1995). Anesthesiology . 1996; 85:655-74. [PubMed 8853097]
142. Eisenach J, Detweiler D, Hood D. Hemodynamic and analgesic actions of epidurally administered clonidine. Anesthesiology . 1993; 78:277-87. [PubMed 8439023]
143. Cross sA. Pathophysiology of pain. Mayo Clin Proc . 1994; 69:375-83. [PubMed 8170183]
144. Ferrante FM, Bedder M, Caplan RA et al. Practice guidelines for cancer pain management: a report by the American Society of Anesthesiologists Task Force on Pain Management, Cancer Pain Section. Anesthesiology . 1996; 84:1243-57. [PubMed 8624021]
145. Agency for Health Care Policy and Research. Management of cancer pain. Rockville, MD: Agency for Health Care Policy and Research, 1994. Clinical Practice Guideline No. 9. (AHCPR Publication No. 94-0592.)
148. Erstad BL, Cotugno CL. Management of alcohol withdrawal. Am J Health-Syst Pharm . 1995; 52:697-709. [PubMed 7627738]
149. Mayo-Smith MF. Pharmacological management of alcohol withdrawal: a meta-analysis and evidence-based practice guideline. JAMA . 1997; 278:144-51. [PubMed 9214531]
150. O'Connor PG, Schottenfeld RS. Patients with alcohol problems. N Engl J Med . 1998; 338:592-602. [PubMed 9475768]
151. Roxane Laboratories. Duraclon® (clonidine hydrochloride) injection prescribing information. Columbus, OH; 2000 May.
152. Boswell G, Bekersky I, Mekki Q et al. Plasma concentrations and disposition of clonidine following a constant 14-day epidural infusion in cancer patients. Clin Ther . 1997; 19:1024-30. [PubMed 9385489]
153. Maze M, Tranquilli W. Alpha-2 adrenoceptor agonists: defining the role in clinical anesthesia. Anesthesiology . 1991; 74:581-605. [PubMed 1672060]
154. Mirin SM, McIntyre JS, Charles SC et al. Practice guidelines for the treatment of patients with substance abuse disorders: alcohol, cocaine, opioids. Am J Psychiatry . 1995; 152(Suppl):5-59.
155. Eisenach JC, DuPen S, Dubois M et al. Epidural clonidine analgesia for intractable cancer pain. Pain . 1995; 61:391-9. [PubMed 7478682]
156. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]
157. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]
158. Ramadan NM, Silberstein SD, Freitag FG et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. From the American Osteopathic Association web site. [Web]
159. Lucero MA, McCloskey WW. Alternatives to estrogen for the treatment of hot flashes. Ann Pharmacother . 1997; 31:915-7. [PubMed 9220057]
160. Nagamani M, Kelver ME, Smith ER. Treatment of menopausal hot flashes with transdermal administration of clonidine. Am J Obstet Gynecol . 1987; 156:561-5. [PubMed 3826200]
161. Pliszka SR, Greenhill LL, Crismon ML et al. The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I. J Am Acad Child Adolesc Psychiatry . 2000; 39:908-19. [PubMed 10892234]
162. Pliszka SR, Greenhill LL, Crismon ML et al. The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part II: Tactics. Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry . 2000; 39:920-7. [PubMed 10892235]
163. Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry . 1999; 38:1551-9. [PubMed 10596256]
164. Anon. Clonidine for treatment of attention-deficit/hyperactivity disorder. Med Lett Drugs Ther . 1996; 38:109-10. [PubMed 8957471]
165. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis . 2000; 36:646-61. [PubMed 10977801]
166. Associated Press (American Diabetes Association). Diabetics urged: drop blood pressure. Chicago, IL; 2000 Aug 29. Press Release from web site. [Web]
167. Fiore MC, Jaén CR, Baker TB, et al. Treating tobacco use and dependence: 2008 update. Clinical Practice Guideline. Rockville, MD: US Department of Health and Human Services, Public Health Service. 2008 May.
168. National Institutes of Health Office of Medical Applications Research. NIH Consensus statement: diagnosis and treatment of attention deficit hyperactivity disorder. 1998; 16(Nov 16-18): in press. From NIH web site. [1998 Nov 19]. [Web]
169. Swanson JM, Sergeant JA, Taylor E et al. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Drugs . 1998; 351:429-33.
170. Goldman LS, Genel M, Bexman RJ et al for the Council on Scientific Affairs et al. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA . 1998; 279:1100-7. [PubMed 9546570]
171. American Academy of Child and Adolescent Psychiatry. Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry . 1997; 36(Suppl):85-121S. [PubMed 9000785]
172. Shaffer D. Attention deficit hyperactivity disorder in adults. Am J Psychiatry . 1994; 151:633-8. [PubMed 7909410]
173. Spencer T, Biederman J, Wilens TE et al. Adults with attention-deficit/hyperactivity disorder: a controversial diagnosis. J Clin Psychiatry . 1998; 59(Supp 7):59-63. [PubMed 9680054]
174. Smith BH, Pelham WE, Gnagy E et al. Equivalent effects of stimulant treatment for attention-deficit hyperactivity disorder during childhood and adolescence. J Am Acad Child Adolesc Psychiatry . 1998; 37:314-21. [PubMed 9519637]
175. Dulcan M. Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry . 1997; 36(Suppl 10):85-121S. [PubMed 9000785]
178. Ramadan NM, Silberstein SD, Freitag FG et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. St. Paul, MN; 2001. From the American Academy of Neurology web site. [Web]
179. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA . 2002; 288:3039-60. [PubMed 12479770]
180. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA . 2002; 288:2981-97. [PubMed 12479763]
184. The Guidelines Subcommittee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension . 1999; 17:392-403.
186. Boehringer Ingelheim. Catapres® (clonidine hydrochloride) tablets prescribing information. Ridgefield, CT; 2011 Oct.
187. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004; 114(Suppl 2):555-76.
251. ASHP. Standardize 4 Safety: patient controlled analgesia (PCA) and epidural standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]
252. ASHP. Standardize 4 Safety: compounded oral liquid standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]
501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]
502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]
503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]
504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]
505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]
506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]
507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]
508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]
515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]
523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.
526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]
530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]
536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012: 2: 337-414.
600. Boehringer Ingelheim. Catapres® (clonidine hydrochloride) tablets prescribing information. Ridgefield, CT; 2016 Aug.
601. Boehringer Ingelheim Pharmaceuticals, Inc. Catapres-TTS® (clonidine) Transdermal Therapeutic System prescribing information. Ridgefield, CT; 2016 Aug.
1150. Flynn JT, Kaelber DC, Baker-Smith CM et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics . 2017; 140 [PubMed 28827377]
1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol . 2017; [PubMed 29146535]
1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]
1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]
1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]
1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]
1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]
1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]
1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]
1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]
1223. LeFevre M. ACC/AHA hypertension guideline: what is new? what do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]
1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]
1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]
1300. The Management of Substance Use Disorders Work Group, US Department of Veterans Affairs and Department of Defense. VA/DoD clinical practice guideline for the management of substance use disorders. 2015 Dec.
1301. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Substance Abuse Treatment. Detoxification and substance abuse treatment. Treatment improvement protocol (TIP) series, No. 45. HHS Publication No. (SMA) 15-4131. Rockville, MD; 2006. [Web]
1302. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Substance Abuse Treatment. Medications for opioid use disorder, for healthcare and addiction professionals, policymakers, patients, and families. Treatment improvement protocol (TIP) series, No. 63. HHS Publication No. (SMA) 18-5063. Rockville, MD; 2018. [Web]
1303. American Society of Addiction Medicine (ASAM). ASAM national practice guideline for the use of medications in the treatment of addiction involving opioid use. Chevy Chase, MD: ASAM. 2015 Jun 1. From ASAM website. [Web]
1304. National Collaborating Centre for Mental Health (UK), National Institute for Health and Clinical Excellence. Drug misuse: opioid detoxification, national clinical practice guideline number 52. Leicester (UK): The British Psychological Society and The Royal College of Psychiatrists; 2008.
1305. Gowing L, Farrell M, Ali R et al. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev . 2016; :CD002024. [PubMed 27140827]
1306. World Health Organization. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva: World Health Organization; 2009.
1307. Kleber HD, Weiss RD, Anton RF et al. Treatment of patients with substance use disorders, second edition. American Psychiatric Association. Am J Psychiatry . 2007; 164(4 Suppl):5-123. [PubMed 17569411]
1308. . Management of opioid withdrawal symptoms. Med Lett Drugs Ther . 2018; 60:137-141. [PubMed 30133420]
1309. Gish EC, Miller JL, Honey BL et al. Lofexidine, an {alpha}2-receptor agonist for opioid detoxification. Ann Pharmacother . 2010; 44:343-51. [PubMed 20040696]
1310. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 209229Orig1s000: Multi-discipline review. From FDA website. [Web]
1311. . Lofexidine (Lucemyra) for opioid withdrawal. Med Lett Drugs Ther . 2018; 60:115-117. [PubMed 30036346]
1312. Doughty B, Morgenson D, Brooks T. Lofexidine: A Newly FDA-Approved, Nonopioid Treatment for Opioid Withdrawal. Ann Pharmacother . 2019; :1060028019828954. [PubMed 30724094]