KAPVAY (Brand for CLONIDINE HCL ER)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer the last dose of the day immediately prior to bedtime. If doses are not equal, the largest portion of the daily dose should be taken just before bedtime.
Oral Solid Formulations
Immediate-release tablets (e.g., Catapres)
-May be taken with or without food.
-Upon discontinuation, slowly taper dose over 2 to 4 days to avoid withdrawal symptoms and rebound hypertension.

Extended-release tablets (e.g., Kapvay)
-May be taken with or without food.
-Swallow whole; do not crush, cut, or chew.
-Upon discontinuation, slowly taper dose by decrements of no more than 0.1 mg every 3 to 7 days to avoid withdrawal symptoms and rebound hypertension.


Oral Liquid Formulations
NOTE: Enteral administration of clonidine solution for injection is not approved by the FDA.
-The 100 mcg/mL clonidine solution for epidural administration, diluted to a concentration of 5 mcg/mL, has been administered orally to neonatal patients for the treatment of neonatal abstinence syndrome.

Extemporaneous Compounding-Oral
Extemporaneous 0.02 mg/mL Clonidine Oral Solution Preparation
-Triturate six (6) 0.1-mg clonidine hydrochloride tablets (total: 0.6 mg) in a glass mortar.
-Levigate with 1 to 2 mL Simple Syrup NF and combine with sufficient additional syrup to yield 30 mL.
-Storage: The resulting solution is stable in an amber plastic bottle for 35 days under refrigeration (2 to 8 degrees C).

Extemporaneous 0.01 mg/mL Clonidine Oral Suspension Preparation
-Crush and grind twenty-five (25) 0.1-mg clonidine hydrochloride tablets (total: 2.5 mg clonidine) to a fine powder using a mortar and pestle.
-Add Ora-Blend in geometric amounts until approximately half of the total volume (125 ml) is added.
-Transfer the suspension to a graduated cylinder, rinse the mortar and pestle with additional Ora-Blend, and continue to add Ora-Blend to a final volume of 250 ml.
-Shake until well suspended before transferring to appropriate storage container.
-Storage: The resulting suspension is stable for 91 days when stored in clear plastic syringes at either 4 or 25 degrees C.

Extemporaneous 0.1mg/mL Clonidine Oral Suspension Preparation
-Crush and grind thirty (30) 0.2-mg clonidine hydrochloride tablets (total: 6 mg clonidine) to a fine powder in a glass mortar.
-Add enough Purified Water, USP to form a paste (roughly 2 mL).
-Add 15 mL Simple Syrup, NF to the paste and triturate well.
-Transfer mortar contents to a 60 mL amber glass bottle.
-Continue to add Simple Syrup, NF in increments to a total of 60 mL; shake after each increment until well suspended.
-Storage: The resulting suspension is stable for 28 days when stored in 60 mL amber glass bottles at 4 degrees C and protected from light.



Injectable Administration
Other Injectable Administration
Epidural Injection
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Epidural clonidine is preservative-free.
-Dilute the 500 mcg/mL strength to a final concentration of 100 mcg/mL with 0.9% Sodium Chloride Injection prior to administration.
-Health care professionals should be familiar with epidural infusion devices when administering epidural infusions.



Topical Administration
Transdermal Patch Formulations
-Do not cut or trim patch; however, if it is necessary to use a smaller dosage than what is commercially available, placing impermeable material (e.g., adhesive bandage) on the skin under the patch may be effective. The surface area that is blocked should be proportional to the desired reduction in dose. Place an adhesive bandage over the top of the entire transdermal system to secure it in place.
-Clonidine is absorbed better from the patch if applied on the upper arm or torso.
-Apply to any hairless site at the same time each week. Avoid applying to areas with cuts or calluses. Wash area with soap and water. Dry thoroughly. Apply patch using firm pressure over patch to ensure contact with skin, especially around edges. If patch becomes loose during the 7-day wearing period, apply the adhesive overlay over the patch. If patch is overly loose or falls off, apply another patch. Rotate sites each week.
-Instruct patient on proper application of patch. Patches should not be affected by showering, bathing, or swimming.
-Patches must be removed prior to cardioversion or defibrillation to prevent burns to the patient. Also, removal of the Catapres-TTS patch before undergoing magnetic resonance imaging (MRI) is recommended because the patch contains aluminum.

The safety profile of extended-release clonidine for attention-deficit hyperactivity disorder (ADHD) was evaluated in 391 children and adolescents (6-17 years of age) in trials lasting 8-40 weeks. The most commonly reported reactions included somnolence, sedation, other sleep disturbances, and dry mouth. In general, the adverse events related to clonidine are mild and tend to diminish with continued therapy.

Transient blood glucose elevations have been reported , although clonidine has been administered safely to diabetic patients. In addition, clonidine has been used in the treatment of loose stools in adult diabetic patients.

Drowsiness/somnolence, sedation, and fatigue were commonly reported adverse reactions during extended-release clonidine clinical trials for attention-deficit hyperactivity disorder (ADHD); such events were associated with therapy discontinuation in approximately 5% of study patients. In patients who completed 5 weeks of therapy for ADHD, 31-38% of patients receiving monotherapy and 19% of those receiving adjunctive therapy with a stimulant reported somnolence compared to 4% and 7%, respectively, of those receiving placebo. During the monotherapy trial taper period, 2-3% of patients reported somnolence. Fatigue (13-16%), insomnia (4-6%), and nightmare (4-9%) were also commonly reported. Other sleep-related events reported include night terror (<= 3%), poor quality sleep (<= 3%), and abnormal sleep-related events (1-3%). Adverse reactions noted with other dosage forms of clonidine in adult patients include drowsiness (12-25%), fatigue (4-6%), lethargy (3%), asthenia/weakness (5-10%), malaise (1%), sedation (3%), insomnia (0.5-2%), sleep disorder, vivid dreams/nightmares, and restlessness. Hypoventilation (2.5%) has been reported with epidural clonidine (and adjunctive morphine) use.

Headache (2-20%) was commonly associated with extended-release clonidine use during pediatric clinical trials for attention-deficit hyperactivity disorder (ADHD). In addition, tremor was reported in 1-4% of patients. One patient receiving clonidine with adjunctive stimulant therapy discontinued clonidine therapy because of severe bradyphrenia with severe fatigue. Central nervous system reactions noted with other dosage forms of clonidine in adult patients include headache (1-5%), paresthesias, hyperesthesia (5%), and localized numbness. Rarely, cerebrovascular accident/stroke has occurred.

Psychiatric effects including irritability (2-9%), emotional disorder (2-4%), aggression (1-3%), tearfulness (1-3%), and emotional lability (2% when used as an adjunct to stimulant therapy) have been reported during extended-release clonidine trials for pediatric attention-deficit hyperactivity disorder (ADHD). Hallucinations have been reported with post-marketing use of extended-release clonidine, and both visual and auditory hallucinations have been reported in adult patients receiving other dosage forms of clonidine. Other psychiatric effects noted with other dosage forms of clonidine in adult patients include agitation (3%), anxiety, delirium, delusional perception, depression (1%), nervousness (1-3%), and behavioral changes. Specifically, anxiety (38%), confusion (13-38%), diaphoresis (5%), and hallucination (5%) have been reported during epidural clonidine trials in which epidural morphine was also administered.

Treatment with clonidine can cause dose-related decreases in blood pressure and heart rate. Bradycardia (<= 4%), dizziness (3-7%), and sinus tachycardia (<= 3%) were reported in patients receiving extended-release (ER) clonidine during pediatric clinical trials for attention-deficit hyperactivity disorder (ADHD). In patients who completed 5 weeks of treatment, the maximum placebo-subtracted mean change in heart rate was -4 and -7.7 beats per minute (bpm) in patients receiving doses of 0.2 and 0.4 mg/day, respectively. Maximum placebo-subtracted mean change in blood pressure was -4 mmHg (systolic) and -4 mmHg (diastolic) in patients receiving clonidine 0.2 mg/day and -8.8 mmHg (systolic) and -7.3 mmHg (diastolic) in those receiving 0.4 mg/day. During the taper period, maximum placebo-subtracted mean change in blood pressure was +3.4 mmHg (systolic) and +3.3 mmHg (diastolic) on doses of 0.2 mg/day and -5.6 mmHg (systolic) and -5.4 mmHg (diastolic) on 0.4 mg/day. Maximum placebo-subtracted mean change in heart rate was -0.6 and -3 bpm in those receiving 0.2 and 0.4 mg/day, respectively. Although reports of sudden death and hypotension in children receiving oral clonidine in combination with other therapies for ADHD have been published, causality has not been established and not all ADHD clinical trials evaluating clonidine have reported adverse cardiac reactions. Other adverse cardiovascular reactions to clonidine therapy in adult patients include bradycardia (0.5%), heart failure, electrocardiogram (ECG) abnormalities (e.g., sinus node arrest, junctional bradycardia, high degree AV block, arrhythmias [arrhythmia exacerbation], sick sinus syndrome), orthostatic hypotension, palpitations (0.5%), tachycardia (0.5%), increased blood pressure, Raynaud's phenomenon with peripheral vasoconstriction, syncope, and chest pain (unspecified). Adverse events most frequently reported with continuous epidural administration include hypotension including orthostatic hypotension (32-47%) and bradycardia. Hypotension associated with epidural clonidine is usually responsive to fluids and is observed more commonly in women and in lower weight patients, but no dose-response relationship has been established. Dizziness (13%), chest pain (5%), and tachycardia (2.5%) have also been reported with epidural clonidine use. QT prolongation has been reported with post-marketing use of clonidine ER for ADHD.

Hypersensitivity reactions, including generalized rash, urticaria, and angioedema have occurred with systemic use of clonidine. Rash (unspecified) was reported in 2% of pediatric patients receiving extended-release clonidine adjunctive to stimulant therapy during clinical trials. Transient, localized, dermatological effects have occurred following the administration of clonidine transdermal patches in adult patients (n = 101) and include erythema (26%), pruritus (26%), contact dermatitis (5%), vesicular rash (7%), skin hyperpigmentation (5%), edema (3%), excoriation (3%), burning (3%), papules (1%), throbbing (1%), blanching (1%), and generalized macular rash (1%). Contact dermatitis resulted in the discontinuation of the transdermal clonidine patch in 19% of adult patients in trials (n = 673) and was greatest between weeks 6 and 26. In patients who develop contact dermatitis, continuation of the transdermal patch or substitution of oral clonidine may result in a generalized skin rash. Substitution of oral clonidine in patients who develop an allergic reaction (generalized rash, urticaria, or angioedema) to the transdermal patch may also generate a reaction. In another study (n = 3539), maculopapular rash, urticaria, and angioedema of the face/tongue were reported in < 1% of patients. Alopecia (0.2%), angioneurotic edema (0.5%), hives, pruritus (0.7%), rash (unspecified) (1%), pallor, and urticaria (0.5%) have been reported in patients receiving other forms clonidine. Skin ulcer (5%) has been noted with the epidural use of clonidine.

Urinary incontinence (enuresis) was reported in <= 4% of pediatric patients during clinical trials for extended-release clonidine. Other urogenital adverse reactions reported with clonidine therapy in adult patients include urinary retention (0.1%), difficulty in micturition (0.2%), and nocturia (1%).

Metabolic adverse reactions associated with clonidine in adult patients include gynecomastia (1%), transient elevation of blood glucose (rare), elevation of serum creatine phosphokinase (rare), and weight gain (0.1%). Weight gain is commonly associated with fluid retention, especially during the initiation of clonidine treatment.

Upper abdominal pain (<= 15%), nausea (4-5%), constipation (1-6%), xerostomia (<= 5%), anorexia (3-4% with monotherapy, 6% with adjunctive stimulant use), and viral gastroenteritis (<= 5%) have been associated with extended-release clonidine use during pediatric clinical trials. In adult patients, xerostomia (13-40%) and constipation (1-10%) are among the most frequently reported adverse events. Additionally, nausea (1-13%), vomiting (5-10.5%), anorexia (1%), dry throat (2%), dysgeusia (1%), mildly elevated hepatic enzymes (1%), and salivary gland pain have been reported in adult patients. Rarely, hepatitis, parotitis, ileus, and pseudo-GI obstruction (including colonic pseudo-obstruction) have occurred.

Nasal congestion (2-4%) and throat irritation/pain (3%) were both reported during pediatric clinical trials when extended-release clonidine was used as an adjunct to stimulant therapy. The administration of epidural clonidine has been associated with dyspnea (6%). Rarely, nasal dryness has been associated with clonidine therapy.

Rarely, thrombocytopenia has been associated with clonidine use.

Leg cramps (muscle cramps) and musculoskeletal pain or joint pain (arthralgia) have been reported in clonidine clinical trials in adult patients.

Ocular adverse reactions associated with clonidine therapy include accommodation disorder, blurred vision, ocular burning, decreased lacrimation, and xerophthalmia.

Catheter-related infection, including meningitis and epidural abscess, occurs in 5-20% of patients receiving epidural clonidine. Fever (6%), general infection (6%) and urinary tract infection (22%) were also noted with epidural clonidine. Fever has also been associated with oral and transdermal use. If fever occurs with epidural clonidine use, patients should be promptly evaluated for a catheter-related infection. Acute otitis media (<= 3%) was reported during extended-release clonidine trials for pediatric attention-deficit hyperactivity disorder (ADHD).

Severe rebound hypertension can occur during withdrawal from clonidine. This reaction is more likely to occur if clonidine is abruptly discontinued regardless of route of administration. Symptoms associated with withdrawal may include nervousness, agitation, headache, tremor, sinus tachycardia, nausea, flushing, lightheadedness, chest pain/tightness, and anxiety. This effect is probably due to a drug-induced increase in the level of circulating catecholamines that follows abrupt cessation of therapy. If it is necessary to discontinue immediate-release (IR) clonidine, slowly taper doses over 2-4 days to avoid withdrawal symptoms. If it is necessary to discontinue extended-release (ER) clonidine, reduce the dose by increments of <= 0.1 mg every 3-7 days. Do not interrupt chronic clonidine therapy for surgery; transdermal systems may be left in place during surgery.

Clonidine is contraindicated in patients with a hypersensitivity to clonidine. Generalized rash, urticaria, and angioedema have occurred with clonidine use.

Administration of epidural clonidine above the C4 dermatome is contraindicated because there are no adequate safety data to support such use.

Abrupt discontinuation of clonidine, regardless of route of administration, can precipitate a withdrawal syndrome consisting of rebound increases in both serum and urine catecholamines. Symptoms of nervousness, agitation, headache, tremor, and rebound hypertension have been associated with clonidine withdrawal. Rarely, hypertensive encephalopathy, cerebrovascular accidents, and death have been reported. Patients at higher risk of experiencing adverse consequences of withdrawal include those with a history of hypertension or other cardiovascular disorders, receiving higher doses of clonidine, or receiving concomitant beta-blocker therapy. Pediatric patients receiving oral clonidine who experience gastrointestinal illness associated with vomiting may also be at risk for withdrawal due to abrupt inability to take medication. Careful monitoring of infusion pump function and catheter tubing for obstruction or dislodgement is recommended in patients receiving epidural clonidine to prevent inadvertent abrupt discontinuation. If it is necessary to discontinue clonidine, slowly taper doses over 2-4 days to avoid withdrawal symptoms. Patients who have received clonidine therapy for greater than 4 weeks may require slower dosage tapers (i.e., dosage reduction every 3 days). If it is necessary to discontinue extended-release clonidine (Kapvay), reduce the dose by increments of <= 0.1 mg every 3-7 days. Although reports of sudden death and hypotension in children receiving oral clonidine in combination with other therapies for attention-deficit hyperactivity disorder (ADHD) have been published, causality has not been established and not all ADHD clinical trials evaluating clonidine have reported adverse cardiac effects. Monitoring of blood pressure and heart rate during weaning is recommended, even when clonidine is used for psychotropic indications.

The hypotensive effects of clonidine may decrease perfusion and worsen ischemia in patients with cerebrovascular disease, recent myocardial infarction, or severe heart failure. The sympatholytic action of clonidine may worsen sinus node dysfunction, including sick sinus syndrome, and AV block, especially in patients taking other sympatholytic agents. Use epidural clonidine cautiously in patients with severe cardiac disease or who are hemodynamically unstable due to the potential for severe hypotension. When clonidine is administered into the upper thoracic spinal segments, more profound decreases in blood pressure may be seen. Because clonidine decreases blood pressure and heart rate, the manufacturer of clonidine extended-release tablets (Kapvay) recommends cautious use of clonidine in patients with a history of hypotension, AV block, bradycardia, or cardiovascular disease. Although reports of sudden death and hypotension in children receiving oral clonidine in combination with other therapies for attention-deficit hyperactivity disorder (ADHD) have been published, causality has not been established and not all ADHD clinical trials evaluating clonidine have reported adverse cardiac effects. Monitoring of blood pressure and heart rate prior to initiation of therapy, after dose increases, periodically during therapy, and during weaning is recommended, even when clonidine is used for psychotropic indications. In addition, the American Heart Association recommends obtaining a detailed patient and family history and physical examination prior to the therapy initiation; obtaining a baseline electrocardiogram (ECG) is also a reasonable addition to the initial evaluation. Treat patients with a history of syncope or conditions that may increase the risk of syncope such as hypotension, orthostatic hypotension, bradycardia, or dehydration with caution.

Use clonidine cautiously in patients with a history of major depression because the drug can induce depressive episodes.

Warn patients and caregivers of the potential sedative and hypotensive effects of clonidine and advise against activities requiring coordination and concentration (e.g., riding a bicycle), or performing other hazardous tasks, until they are aware of how the medication affects them. These effects may be potentiated by other CNS depressants, such as alcohol, barbiturates, and opiates.

Use clonidine cautiously in patients with Raynaud's phenomenon or thromboangiitis obliterans (Buerger's disease). Raynaud's phenomenon has been reported in patients taking clonidine and it may exacerbate these conditions.

Use clonidine cautiously in patients with diabetes mellitus because transient elevations in blood glucose have been noted. It has, however, been used safely in many diabetic patients.

Clonidine has been used safely in patients with renal impairment and renal disease. Clonidine is 45% renally excreted and drug concentrations may accumulate in renal failure. Therefore, FDA-approved labeling recommends careful monitoring and that patients with renal impairment may benefit from a lower initial dose. In clinical practice, dosage adjustments are usually not clinically needed in patients with renal failure or renal impairment; the dosage of clonidine is titrated to achieve clinical goals.

Clonidine epidural injection is contraindicated in patients receiving anticoagulant therapy or in patients with a coagulopathy. Epidural clonidine is also contraindicated in patients with an infection at the site of injection.

The inadvertent intrathecal administration of clonidine has not been associated with significantly increased adverse events; however, there are inadequate safety and efficacy data to support the use of intrathecal clonidine.

Clonidine transdermal systems (i.e., patches) should be removed prior to defibrillation (cardioversion) because the drug can alter electrical conductivity, increasing the likelihood that electrical arcing will occur. Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging (MRI) scan. Because the clonidine transdermal systems may contain aluminum or other metal components, it is recommended to remove the system before undergoing an MRI.

Absorption of transdermal clonidine can be increased in areas of skin irritation or skin abrasion, so avoid placement of the patches in these areas.

Consider carefully the scheduling of clonidine doses near the time of surgery; specific recommendations are available that are dependent on the dosage form. Continue oral administration of immediate-release clonidine to within 4 hours of surgery and resume as soon as possible thereafter. Although FDA-approved labeling for clonidine injection and extended-release clonidine for attention-deficit hyperactivity disorder (ADHD) does not provide specific recommendations regarding dosing near surgery, do not abruptly discontinue these formulations due to the risk of withdrawal symptoms. Do not interrupt therapy with transdermal clonidine during the surgical period. Carefully monitor blood pressure during surgery; have additional measures to control blood pressure readily available if necessary. If transdermal clonidine therapy is initiated during the perioperative period, clinicians must be aware that therapeutic plasma clonidine concentrations are not achieved until 2-3 days after initial application of the transdermal therapeutic system.

Clonidine is not expected to have a therapeutic effect on hypertension caused by pheochromocytoma.

Description: Clonidine is a centrally acting alpha-2 agonist approved in an oral extended-release formulation for pediatric patients 6 years and older to treat attention-deficit hyperactivity disorder (ADHD) as monotherapy or as an adjunct to a psychostimulant. The American Academy of Pediatrics (AAP) recommends starting ADHD therapy with any FDA-approved drug, although the body of evidence supporting the use of stimulants as first-line therapy is larger than for alpha-2 agonists, and alpha-2 agonists have a slightly weaker effect size than stimulants. Some experts recommend clonidine as an adjunct to stimulants in children with ADHD and comorbid tic disorders (e.g., Tourette's syndrome), stimulant-induced insomnia, or aggressive behavior. The American Academy of Neurology practice guideline states that clonidine is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; for those with comorbid ADHD, clonidine may provide benefits for both conditions. When clonidine is used for the treatment of ADHD, the American Heart Association recommends careful cardiovascular screening and monitoring of patients. Clonidine has been used successfully off-label for a variety of pediatric conditions, including opiate or benzodiazepine withdrawal, neonatal abstinence syndrome, tic disorders (e.g., Tourette's syndrome), autism spectrum disorder, and as a diagnostic agent for growth hormone deficiency. The AAP considers oral clonidine useful for severely hypertensive patients (i.e., hypertensive urgency or emergency) without life-threatening symptoms. Clonidine is also used for the maintenance treatment of hypertension in children and adolescents 12 years and older. Epidural clonidine has orphan drug designation in children and adolescents for severe pain secondary to malignancy, including neuropathic pain. The use of epidural clonidine has resulted in decreases in opiate requirements when used in combination with epidural opiate agonists and increases the duration of response to anesthetic agents used in peripheral nerve blocks. During long-term therapy, the transdermal formulation has been used off-label after a stable oral dose has been established; however, further study is needed to determine optimal transdermal dosing regimen for select conditions.

For the treatment of hypertension*:
Oral dosage (immediate-release tablets):
Children younger than 12 years: Generally not recommended in children younger than 12 years. Initial doses of 5 to 10 mcg/kg/day PO in divided doses every 8 to 12 hours then titrated based on clinical response (Max: 25 mcg/kg/day or 0.9 mg/day) has been reported.
Children and Adolescents 12 years and older: Initially, 0.1 mg PO twice daily titrated up based on clinical response (Max: 2.4 mg/day). Increase by 0.1 mg/day at weekly intervals until desired effect is achieved (usual adult range: 0.2 to 0.6 mg/day). For unequal doses, taking the larger portion of the daily dose at bedtime may minimize adverse events.
Transdermal dosage:
Children and Adolescents: Initial dosing recommendations for pediatric patients are not available. Although not studied specifically in children with hypertension, in children with psychiatric disorders such as Tourette's and ADHD, it has been suggested that once patients are stabilized on an oral dose, they can be converted to the transdermal patch that provides an approximately equivalent daily dose. While the manufacturer recommends patches be changed once every 7 days in adult patients, it is suggested that patches may need to be changed earlier (i.e., every 5 days) in pediatric patients due to variable absorption in this population. Partial doses of patches may be administered by placing impermeable material (e.g., adhesive bandage) on the skin under the patch proportionate to the desired dose reduction.

For the treatment of hypertensive urgency* or hypertensive emergency*:
Oral dosage:
Children and Adolescents: 2 to 5 mcg/kg/dose PO every 6 to 8 hours as needed (Max: 10 mcg/kg/dose) for severely hypertensive patients with non-life-threatening symptoms. Alternatively, 0.05 to 0.1 mg/dose PO, which can be repeated hourly as needed, up to a total dose of 0.8 mg PO.

For the treatment of attention-deficit hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to a psychostimulant:
Oral dosage (extended-release; Kapvay):
Children and Adolescents 6 to 17 years: 0.1 mg PO once daily at bedtime, initially. Increase the dose by 0.1 mg/day at weekly intervals based on clinical response. Max: 0.4 mg/day. Administer doses more than 0.1 mg/day in 2 divided doses, with either an equal or higher split dosage being given at bedtime. When extended-release clonidine is added to a psychostimulant, the dosage of the psychostimulant may be adjusted according to response. When discontinuing clonidine, taper the dose by no more than 0.1 mg/day every 3 to 7 days to avoid rebound hypertension. Due to the lack of controlled clinical trial data and differing pharmacokinetic profiles, substitution of extended-release clonidine for other clonidine products on a mg-per-mg basis is not recommended.
Oral dosage (immediate-release)*:
Children and Adolescents 6 to 17 years weighing 27 to 40.4 kg: 0.05 mg PO once daily at bedtime, initially. Increase the dose by 0.05 mg/day to 0.05 mg PO twice daily, then 0.05 mg PO 3 times daily, and then 0.05 mg PO 4 times daily. Max: 0.2 mg/day. In a 16-week, multicenter, randomized, controlled clinical trial of children with ADHD and a chronic tic disorder (n = 136), clonidine doses were 0.25 mg/day PO as monotherapy and 0.28 mg/day PO with methylphenidate. The greatest ADHD benefit and improved tic severity compared to baseline was seen with the combined treatment of clonidine plus methylphenidate. Worsening of tics occurred in 20% to 26% of each treatment group, including placebo. Sedation was common (28%) with clonidine.
Children and Adolescents 6 to 17 years weighing 40.5 to 45 kg: 0.05 mg PO once daily at bedtime, initially. Increase the dose by 0.05 mg/day to 0.05 mg PO twice daily, then 0.05 mg PO 3 times daily, and then 0.05 mg PO 4 times daily. Max: 0.3 mg/day. In a 16-week, multicenter, randomized, controlled clinical trial of children with ADHD and a chronic tic disorder (n = 136), clonidine doses were 0.25 mg/day PO as monotherapy and 0.28 mg/day PO with methylphenidate. The greatest ADHD benefit and improved tic severity compared to baseline was seen with the combined treatment of clonidine plus methylphenidate. Worsening of tics occurred in 20% to 26% of each treatment group, including placebo. Sedation was common (28%) with clonidine.
Children and Adolescents 6 to 17 years weighing more than 45 kg: 0.1 mg PO once daily at bedtime, initially. Increase the dose by 0.1 mg/day to 0.1 mg PO twice daily, then 0.1 mg PO 3 times daily, and then 0.1 mg PO 4 times daily. Max: 0.4 mg/day. In a 16-week, multicenter, randomized, controlled clinical trial of children with ADHD and a chronic tic disorder (n = 136), clonidine doses were 0.25 mg/day PO as monotherapy and 0.28 mg/day PO with methylphenidate. The greatest ADHD benefit and improved tic severity compared to baseline was seen with the combined treatment of clonidine plus methylphenidate. Worsening of tics occurred in 20% to 26% of each treatment group, including placebo. Sedation was common (28%) with clonidine.
Transdermal dosage*:
Children and Adolescents 6 to 17 years: Initial dosing recommendations are not available; however, it has been suggested that once children are stabilized on an oral dose they may be converted to the transdermal patch that provides an approximately equivalent daily dose (e.g., 0.1, 0.2, or 0.3 mg/day). Patches are changed once every 7 days in adults; however, due to variable absorption in children, patches may need to be changed earlier (i.e., every 5 days). Partial doses of patches may be administered by placing impermeable material (e.g., adhesive bandage) on the skin under the patch proportionate to the desired dose reduction.

For the treatment of severe pain secondary to malignancy including neuropathic pain:
NOTE: Clonidine has been designated an orphan drug by the FDA for this indication.
Epidural dosage:
Children and Adolescents: Initially, 0.5 mcg/kg/hour by continuous epidural infusion and adjusted cautiously based upon pain relief and incidence of side effects. It is recommended that epidural clonidine be restricted to pediatric patients with severe intractable pain from malignancy that is unresponsive to epidural or spinal opiates or other more conventional analgesic techniques. Epidural clonidine has been effective primarily in the subgroup of patients with neuropathic pain.

For the treatment of opiate agonist withdrawal* and/or benzodiazepine withdrawal*:
Oral dosage:
Infants, Children, and Adolescents: Limited data available; 2 to 4 mcg/kg/dose PO every 4 to 6 hours as needed has been recommended to manage withdrawal symptoms in patients being weaned from opioids and benzodiazepines.

For the treatment of neonatal abstinence syndrome*:
Oral dosage:
Neonates: 0.5 to 1 mcg/kg/dose PO every 3 to 6 hours (Max: 8 mcg/kg/day PO) is recommended by the American Academy of Pediatrics (AAP). Dosages of 2 to 6 mcg/kg/day PO given in divided doses every 4 to 6 hours have been effective in treating opiate agonist withdrawal symptoms in neonates addicted to opiates secondary to intrauterine exposure to methadone or heroin and in neonates being weaned from opiate infusions. Premature neonates (n = 11, gestational age 24 to 35 weeks) were included in 1 small study.

For use in peripheral nerve block* in combination with local anesthetics:
Peripheral nerve block dosage:
Children and Adolescents 2 years and older: Limited data available; 1 mcg/kg/dose (Max: 100 mcg/dose) as a single-shot nerve block in combination with a local anesthetic significantly prolonged the mean duration of sensory blockade (17.2 hours vs. 13.2 hours) and the mean duration of analgesia (10 hours vs. 6.8 hours) compared to nerve block with a local anesthetic alone in patients undergoing various surgeries.

For the treatment of Tourette's syndrome* and tic disorders*:
Oral dosage (immediate-release tablets):
Children and Adolescents 6 years and older: Initially, 0.025 to 0.05 mg/day PO; titrate gradually in increments of 0.025 mg to the target dose of 0.2 to 0.3 mg/day PO given in 3 to 4 divided doses. Max: 0.4 mg/day. In a 16-week, multicenter, randomized, controlled clinical trial of patients with ADHD and a chronic tic disorder (n = 136), clonidine doses were 0.25 mg/day PO (alone) and 0.28 mg/day PO (with methylphenidate about 26 mg/day PO). The greatest ADHD benefit and improved tic severity compared to baseline were seen with the combined treatment of clonidine plus methylphenidate. Worsening of tics occurred in 20% to 26% of each treatment group, including placebo. The American Academy of Neurology practice guideline states that clonidine is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; weigh the benefits of treatment against the risks (e.g., sedation, hypotension). For those with comorbid attention-deficit hyperactivity disorder (ADHD), clonidine may provide benefits for both conditions. The effect size of clonidine on tics appears larger in children with tics and ADHD compared to individuals with tics and without ADHD.
Oral dosage (extended-release tablets):
Children and Adolescents 6 years and older: Initially 0.1 mg/day PO at bedtime. Increase the dose in 0.1 mg/day increments weekly as needed to attain the desired response (Max: 0.4 mg/day). Divide doses larger than 0.1 mg/day into 2 doses taken in the morning and at bedtime. If the morning and bedtime doses are not equal, the larger dose should be given at bedtime. The American Academy of Neurology practice guideline states that clonidine is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; weigh the benefits of treatment against the risks (e.g., sedation, hypotension). For those with comorbid attention-deficit hyperactivity disorder (ADHD), clonidine may provide benefits for both conditions.
Transdermal dosage:
Children and Adolescents 6 years and older: Initial dosing recommendations for pediatric patients are not available; however, some patients stabilized on an oral dose may then be converted to the transdermal patch that provides an approximately equivalent daily dose (i.e., 0.1, 0.2, or 0.3 mg/day). Patches are changed once every 7 days in adults; however, due to variable absorption, patches may need to be changed earlier (i.e., every 5 days) in pediatric patients. Partial doses of patches may be administered by placing impermeable material (e.g., adhesive bandage) on the skin under the patch proportionate to the desired dose reduction. The American Academy of Neurology practice guideline states that clonidine is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; weigh the benefits of treatment against the risks (e.g., sedation, hypotension). For those with comorbid attention-deficit hyperactivity disorder (ADHD), clonidine may provide benefits for both conditions. The effect size of clonidine on tics appears larger in children with tics and ADHD compared to individuals with tics and without ADHD.

For the treatment of aggressive behavior and hyperactivity/inattentiveness in patients with autistic disorder*:
Oral dosage (immediate-release):
Children and Adolescents 5 to 17 years: 0.05 mg PO once daily in the evening for 3 days, then increase the dose to 0.05 mg PO twice daily. May further increase the dose by 0.05 mg/day every 3 days as needed. Usual dose: 0.1 to 0.4 mg/day in 3 to 4 divided doses. Max: 0.4 mg/day.
Transdermal dosage:
Children and Adolescents 5 to 17 years: Initial doses of 0.005 mg/kg/day rounded to the nearest available patch strength (patches are available in 3 strengths delivering doses of approximately 0.1, 0.2, or 0.3 mg/day over 7 days) were used in a small study including 7 pediatric patients (age range 5 to 12 years, weight range 19.1 to 52.7 kg). Patients weighing less than 25 kg were started on half a 0.1 mg/day patch for 3 days to minimize adverse reactions. The mean dose of clonidine used in the study was 0.16 +/- 0.09 mg/day. Although patches in this study were changed every 7 days, other authors have suggested that pediatric patients may require patches be changed earlier (i.e., every 5 days) due to variable absorption. Partial doses of patches may be administered by placing impermeable material (e.g., adhesive bandage) on the skin under the patch proportionate to the desired dose reduction.

For growth hormone deficiency diagnosis*:
Oral dosage:
Children and Adolescents: 5 mcg/kg/dose PO as a single dose (Max: 250 mcg PO). Maximal growth hormone secretion usually occurs 60 minutes after the dose. Blood should be drawn at 0, 30, 60, and 90 minutes after the dose of clonidine is given. Similarly, blood pressure should be measured at these same time intervals.

For the treatment of insomnia* and sleep disturbance* associated with neurodevelopmental disorders, including autism spectrum disorder:
Oral dosage (immediate-release):
Children and Adolescents 4 to 17 years weighing less than 27 kg: 0.002 to 0.003 mg/kg/dose (Minimum: 0.025 mg/dose) PO at bedtime, initially. Increase the dose by 0.005 to 0.01 mg/kg/day every 1 to 2 weeks as needed and tolerated. Max: 0.01 mg/kg/day or 0.2 mg/day.
Children and Adolescents 4 to 17 years weighing 27 to 40.5 kg: 0.025 to 0.05 mg PO at bedtime, initially. Increase the dose by 0.025 mg/day every 1 to 2 weeks as needed and tolerated. Max: 0.2 mg/day.
Children and Adolescents 4 to 17 years weighing 40.6 kg to 45 kg: 0.025 to 0.05 mg PO at bedtime, initially. Increase the dose by 0.025 mg/day every 1 to 2 weeks as needed and tolerated. Max: 0.3 mg/day.
Children and Adolescents 4 to 17 years weighing more than 45 kg: 0.025 to 0.05 mg PO at bedtime, initially. Increase the dose by 0.025 mg/day every 1 to 2 weeks as needed and tolerated. Max: 0.4 mg/day.

Maximum Dosage Limits:
-Neonates
Premature Neonates: Safety and efficacy have not been established; however, doses up to 8 mcg/kg/day PO have been used off-label for the management of neonatal abstinence syndrome.
Neonates: Safety and efficacy have not been established; however, doses up to 12 mcg/kg/day PO have been used off-label for the management of neonatal abstinence syndrome.
-Infants
Safety and efficacy have not been established; however, doses up to 4 mcg/kg/dose PO have been recommended for the management of the symptoms of opioid or benzodiazepine withdrawal.
-Children
1 to 5 years: Safety and efficacy have not been established; however, doses up 0.9 mg/day PO for the treatment of hypertension have been recommended. Maximum doses of transdermal or epidural clonidine in pediatric patients have not been established.
6 to 11 years: 0.4 mg/day PO extended-release tablets for ADHD; safety and efficacy of immediate-release tablets have not been established; however, doses up to 0.9 mg/day PO for the treatment of hypertension have been recommended. Maximum doses of transdermal or epidural clonidine in pediatric patients have not been established.
12 years: 0.4 mg/day PO extended-release tablets for ADHD; safety and efficacy of immediate-release tablets have not been established; however, doses up to 2.4 mg/day for the treatment of hypertension have been recommended. Maximum doses of transdermal or epidural clonidine in pediatric patients have not been established.
-Adolescents
0.4 mg/day PO extended-release tablets for ADHD; safety and efficacy of immediate-release tablets have not been established; however, doses up to 2.4 mg/day for hypertension have been recommended. Maximum doses of transdermal and epidural clonidine in pediatric patients have not been established.

Patients with Hepatic Impairment Dosing
No quantitative recommendations are available. Because clonidine is substantially metabolized by the liver, monitor patients for sedation and hypotension and adjust the dose if necessary.

Patients with Renal Impairment Dosing
A lower initial dose may be beneficial; monitor patients carefully for bradycardia, sedation, and hypotension.

Intermittent hemodialysis
Clonidine is minimally removed by hemodialysis. In general, no supplemental dosage is needed following hemodialysis. Adjust dosage based on clinical response.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Clonidine is an agonist at presynaptic alpha2-receptors in the medulla, specifically, the nucleus tractus solitarius (i.e., the depressor area of the vasomotor center of the medulla oblongata). Stimulation of these receptors results in the inhibition of sympathetic outflow and tone. Suppression of efferent sympathetic pathways decreases vascular tone in the heart, kidneys, and peripheral vasculature; lowers peripheral resistance; and reduces blood pressure. Reflex tachycardia usually does not occur. Instead, stimulation of the central alpha-receptors by clonidine results in a reciprocal increase in vagal tone, causing an increase in baroreceptor activity and bradycardia. Clonidine is also a partial agonist at presynaptic alpha2-adrenergic receptors of peripheral nerves in vascular smooth muscle, however, this site of action contributes little, if anything, to its antihypertensive effects. Doses higher than those required to lower blood pressure are necessary to demonstrate agonism at this peripheral site. Agonism at peripheral presynaptic alpha2-receptors may interfere with the peripheral regulation of norepinephrine.

Intravenous administration or large oral doses of clonidine also can stimulate alpha1-receptors in peripheral vascular smooth muscle, resulting in acute vasoconstriction and a transient increase in blood pressure. An accurate correlation between clonidine's plasma concentrations and its antihypertensive effects is evident only at lower plasma concentrations. Higher plasma concentrations of clonidine will result in reduced antihypertensive activity because of the increased contribution of the pressor effect.

Inhibition of sympathetic outflow by clonidine results in a variety of pharmacodynamic effects. In the supine position, decreased sympathetic tone reduces heart rate (HR), mean arterial pressure (MAP), cardiac output (CO), and stroke volume (SV), with essentially no change in the total peripheral resistance (TPR), renal blood flow (RBF), renal plasma flow (RPF), glomerular filtration rate (GFR), urinary potassium excretion, or renal vascular resistance (RVR). Urinary sodium and chloride excretion are increased, however. Thus, the principal antihypertensive effect in the supine position is related to the reduction in cardiac output secondary to the reduced stroke volume and heart rate.

In the erect position (45-degree tilt), clonidine reduces MAP, CO, HR, and TPR, with no significant change in stroke volume. Cardiac output due to clonidine decreases less in hypertensive patients than in normal patients, and the antihypertensive effects of the drug appear to be related to a reduction in both cardiac output and TPR, with the effects of the reduced TPR predominating in the erect position. Renin and aldosterone output are reduced. Clonidine appears to decrease catecholamine excretion during prolonged therapy, but it does not deplete catecholamine stores. As an antihypertensive, clonidine reduces LVH and does not cause detrimental effects on glucose tolerance.

Because of clonidine's ability to inhibit sympathetic outflow, it has been used successfully to manage withdrawal from opiate agonists and benzodiazepines. The inhibition of sympathetic outflow results in decreased circulating concentrations of epinephrine and norepinephrine thereby preventing symptoms of excessive catecholamine release associated with withdrawal. Clonidine also acts centrally to produce mild sedation and a calming effect, which helps to lessen the symptoms of withdrawal.

Although the exact mechanism of clonidine for the treatment of attention-deficit hyperactivity disorder (ADHD) is unknown, it is thought to be related to the centrally mediated effects. Clonidine is thought to block the release of norepinephrine from central catecholaminergic nerve terminals and reduce the turnover rate of norepinephrine. The drug also affects several alpha-2 receptor subtypes located in the prefrontal cortex leading to increased blood flow and improved neuropsychological functioning.

Clonidine administered epidurally produces a dose-dependent analgesia that is not antagonized by opiate antagonists. By preventing pain signal transmission to the brain, clonidine produces analgesia at presynaptic and postjunctional alpha2-adrenoceptors in the spinal cord. Yohimbine, an alpha2-adrenoreceptor antagonist, will partially reverse the analgesic and sedation effects of epidural clonidine with no effect on clonidine-induced changes in blood pressure or heart rate. Clonidine-induced analgesia occurs only in body regions innervated by spinal segments where analgesic concentrations of clonidine are present. Clonidine enhances epidural or peripheral nerve blocks by blocking the conduction of C and A delta fibers and increasing potassium conductance in neurons and causing local vasoconstriction decreasing the elimination of the local anesthetic.

Pharmacokinetics: Clonidine is administered orally, via transdermal patch, and epidurally. Fifty percent (50%) of a circulating dose is metabolized in the liver to inactive compounds. Unchanged drug (40-60%) and its metabolites are excreted in the urine and feces.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Immediate- and extended-release clonidine have different pharmacokinetic characteristics; dose substitution on a mg-for-mg basis will result in differences in exposure. Food does not influence the pharmacokinetics of oral clonidine. The pharmacokinetics of clonidine are dose-proportional in the range of 100-600 mcg. Elimination half-life of clonidine is approximately 12-16 hours.

Immediate-release (IR) formulations
After oral administration of IR clonidine tablets, peak plasma concentrations are reached in approximately 1-5 hours. The absolute oral bioavailability is 70-80%. Blood pressure begins to decrease within 30-60 minutes, with maximal hypotensive effects occurring in 2-4 hours. Mean single-dose pharmacokinetic parameters in healthy adult patients (fasted-state; n = 15) during clinical trials were as follows: Cmax = 443 pg/ml; AUC = 7313 pg/ml x hr; Tmax = 2.07 hours; half-life = 12.57 hours.

Extended-release (ER) formulations
After oral administration of ER formulation, peak clonidine concentrations were approximately 50% of those achieved with the IR formulation and occurred approximately 5 hours later. Similar half-lives were observed and total systemic bioavailability after the ER formulation was approximately 89% of that after the IR formulation. Mean single-dose pharmacokinetic parameters in healthy adult patients (fasted-state; n = 14) during clinical were as follows: Cmax = 258 pg/ml; AUC = 6729 pg/ml x hr; Tmax = 6.5 hours; half-life = 12.65 hours.

Other Route(s)
Transdermal Route
The clonidine transdermal system consists of a patch, or 0.2 mm thick film, that contains four layers of a microporous polypropylene membrane. This patch holds a reservoir of clonidine that is released and absorbed across the skin at a constant rate over a 7-day period. The absolute bioavailability of clonidine from the transdermal patch is approximately 60%. Steady-state clonidine plasma concentrations are reached within 3 days after transdermal application to the upper outer arm and increase linearly with increasing size of the transdermal patch. Mean steady-state plasma concentrations with the 3.5 cm2 (0.1 mg clonidine/day), 7 cm2 (0.2 mg clonidine/day) and 10.5 cm2 (0.3 mg clonidine/day) systems are approximately 0.4 ng/mL, 0.8 ng/mL, and 1.1 ng/mL, respectively. Similar clonidine steady-state concentrations are reached after application to the chest. Steady-state clonidine plasma concentrations remain constant after removal of one system and application of a new system of the same size. After removal of the transdermal system, clonidine plasma concentrations decline slowly with a half-life of approximately 20 hours.

Epidural Route
After epidural administration, peak clonidine plasma and cerebrospinal fluid concentrations were achieved in 19 and 26 minutes, respectively. Epidurally administered clonidine distributes into plasma via the epidural veins. Clonidine is highly lipid soluble and distributes widely throughout the body tissues, including the central nervous system. The cerebrospinal fluid (CSF) elimination half-life of clonidine is 1.3 hours. After an epidural dose of clonidine, women had a lower mean plasma clearance, longer mean plasma half-life, and higher mean peak concentration of clonidine in the plasma and CSF compared to men. The pharmacokinetics of epidural clonidine in children 1-9 years of age are similar to adults.


-Special Populations
Pediatrics
Neonates
The half-life of clonidine is prolonged in neonatal patients (44-72 hours) compared to adult patients (12-16 hours). However, a pharmacokinetic study in 36 neonatal patients (postnatal age 1-25 days, mean gestational age 38.7 +/- 1.4 weeks) showed that clearance increases rapidly with age, achieving 70% of adult values by 1 month of age.

Children and Adolescents
The pharmacokinetics of epidural clonidine in children 1-9 years of age are similar to adults. After oral administration of extended-release tablets at doses of 0.1-0.2 mg PO twice daily, plasma clonidine concentrations are higher in children and adolescents with ADHD than those of adults with hypertension with the pediatric patients receiving higher doses on a mg/kg basis. Body weight normalized clearance (CL/F) in children and adolescents was higher than observed in adults with hypertension. Clonidine plasma concentrations increased with increases in dose over the dose range of 0.2 to 0.4 mg/day of the extended-release tablets. Clonidine CL/F was independent of dose administered over the 0.2 to 0.4 mg/day dose range and appeared to decrease slightly with increases in age over the range of 6-17 years. CL/F was 23% lower in females than males. Clonidine CL/F was also 11% higher in patients who were also receiving methylphenidate and 44% lower in those receiving amphetamine compared to subjects not on adjunctive therapy.

Renal Impairment
The half-life of clonidine increases up to 41 hours in patients with severe renal impairment.