clonidine hydrochloride
Dosage Form: tablet, extended release
FULL PRESCRIBING INFORMATION
1. INDICATIONS AND USAGE
Kapvay™ (clonidine hydrochloride) extended-release is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications.
The efficacy of Kapvay in the treatment of ADHD is based on two controlled trials (one monotherapy and one adjunctive to stimulant medication) in children and adolescents ages 6-17 who met DSM-IV criteria for ADHD hyperactive or combined hyperactive/inattentive subtypes [see Clinical Studies (14)]. In the adjunctive study, Kapvay was administered to patients who had been on a stable regimen of either methylphenidate or amphetamine (or their derivatives) and who had not achieved an optimal response. The effectiveness of Kapvay for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials.
A diagnosis of ADHD implies the presence of hyperactive-impulsive and/or inattentive symptoms that cause impairment and were present before the age of 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; "on the go"; excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met.
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV® characteristics.
Need for Comprehensive Treatment program
Kapvay is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Kapvay is not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational/vocational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe Kapvay will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms and on the level of functional impairment.
NOTE: This extended-release formulation of clonidine hydrochloride is also approved for the treatment of hypertension in adults under the trade name JENLOGA.
2. DOSAGE AND ADMINISTRATION
Kapvay is an extended-release tablet formulation of clonidine hydrochloride. While it is dosed twice a day, the same as the immediate-release clonidine formulation, it is not to be used interchangeably with the immediate-release formulation.
General Dosing Information
Kapvay is an extended-release tablet and, therefore, must be swallowed whole and never crushed, cut or chewed. Kapvay may be taken with or without food.
Due to the lack of controlled clinical trial data and differing pharmacokinetic profiles, substitution of Kapvay for other clonidine products on a mg-per-mg basis is not recommended.
Dose Selection
The dose of Kapvay, administered either as monotherapy or as adjunctive therapy to a psychostimulant, should be individualized according to the therapeutic needs and response of the patient. Dosing should be initiated with one 0.1 mg tablet at bedtime, and the daily dosage should be adjusted in increments of 0.1 mg/day at weekly intervals until the desired response is achieved. Doses should be taken twice a day, with either an equal or higher split dosage being given at bedtime (see Table 1).
| Total Daily Dose | Morning Dose | Bedtime Dose |
|---|---|---|
| 0.1 mg/day | 0.1 mg | |
| 0.2 mg/day | 0.1 mg | 0.1 mg |
| 0.3 mg/day | 0.1 mg | 0.2 mg |
| 0.4 mg/day | 0.2 mg | 0.2 mg |
Doses of Kapvay higher than 0.4 mg/day (0.2 mg twice daily) were not evaluated in clinical trials for ADHD and are not recommended.
When Kapvay is being added-on to a psychostimulant, the dose of the psychostimulant can be adjusted depending on the patient's response to Kapvay.
Maintenance Treatment
The effectiveness of Kapvay for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials. Therefore the physician electing to use Kapvay for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Discontinuation
When discontinuing Kapvay, the total daily dose should be tapered in decrements of no more than 0.1 mg every 3 to 7 days.
3. DOSAGE FORM AND STRENGTHS
Kapvay tablets are available in two strengths, 0.1 mg and 0.2 mg as an extended-release formulation. Both the 0.1 mg and 0.2 mg tablets are white, non-scored, standard convex with debossing on one side. The 0.1 mg tablets are round and the 0.2 mg tablets are oval. Kapvay tablets must be swallowed whole and never crushed, cut or chewed.
4. CONTRAINDICATIONS
Kapvay should not be used in patients with known hypersensitivity to clonidine.
5. WARNINGS AND PRECAUTIONS
Hypotension/Bradycardia
Treatment with Kapvay can cause dose related decreases in blood pressure and heart rate. In patients that completed 5 weeks of treatment in a controlled, fixed-dose monotherapy study in pediatric patients, during the treatment period the maximum placebo-subtracted mean change in systolic blood pressure was -4.0 mmHg on Kapvay 0.2 mg/day and -8.8 mmHg on Kapvay 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was -4.0 mmHg on Kapvay 0.2 mg/day and -7.3 mmHg on Kapvay 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -4.0 beats per minute on Kapvay 0.2 mg/day and -7.7 beats per minute on Kapvay 0.4 mg/day.
During the taper period of the fixed-dose monotherapy study the maximum placebo-subtracted mean change in systolic blood pressure was +3.4 mmHg on Kapvay 0.2 mg/day and -5.6 mmHg on Kapvay 0.4 mg/day. The maximum placebo-subtracted mean change in diastolic blood pressure was +3.3 mmHg on Kapvay 0.2 mg/day and -5.4 mmHg on Kapvay 0.4 mg/day. The maximum placebo-subtracted mean change in heart rate was -0.6 beats per minute on Kapvay 0.2 mg/day and -3.0 beats per minute on Kapvay 0.4 mg/day.
Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use Kapvay with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use Kapvay with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated.
Sedation and Somnolence
Somnolence and sedation were commonly reported adverse reactions in clinical studies. In patients that completed 5 weeks of therapy in a controlled fixed dose pediatric monotherapy study, 31% of patients treated with 0.4 mg/day and 38% treated with 0.2 mg/day vs 7% of placebo treated patients reported somnolence as an adverse event. In patients that completed 5 weeks of therapy in a controlled flexible dose pediatric adjunctive to stimulants study, 19% of patients treated with Kapvay+stimulant vs 8% treated with placebo+stimulant reported somnolence. Before using Kapvay with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with Kapvay. Advise patients to avoid use with alcohol.
Abrupt Discontinuation
No studies evaluating abrupt discontinuation of Kapvay in children with ADHD have been conducted. In children and adolescents with ADHD, physicians should gradually reduce the dose of Kapvay in decrements of no more than 0.1 mg every 3 to 7 days. Patients should be instructed not to discontinue Kapvay therapy without consulting their physician due to the potential risk of withdrawal effects.
In adults with hypertension, sudden cessation of clonidine hydrochloride extended-release formulation treatment in the 0.2 to 0.6 mg/day range resulted in reports of headache, tachycardia, nausea, flushing, warm feeling, brief lightheadedness, tightness in chest, and anxiety.
In adults with hypertension, sudden cessation of treatment with immediate-release clonidine has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.
Allergic Reactions
In patients who have developed localized contact sensitization to clonidine transdermal system, continuation of clonidine transdermal system or substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash.
In patients who develop an allergic reaction from clonidine transdermal system, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).
Patients with Vascular Disease, Cardiac Conduction Disease, or Renal Failure
Clonidine hydrochloride should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal failure.
Other Clonidine-Containing Products
Clonidine, the active ingredient in Kapvay, is also approved as an antihypertensive. Do not use Kapvay in patients concomitantly taking other clonidine-containing products, (e.g. Catapres®).
6. ADVERSE REACTIONS
Clinical Trial Experience
Two Kapvay ADHD clinical studies evaluated 256 patients who received active therapy, in one of the two placebo-controlled studies (Studies 1 and 2) with primary efficacy end-points at 5-weeks.
Study 1: Fixed-dose Kapvay Monotherapy
Study 1 was a multi-center, randomized, double-blind, placebo-controlled study with primary efficacy endpoint at 5 weeks, of two fixed doses (0.2 mg/day or 0.4 mg/day) of Kapvay in children and adolescents (6 to 17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes.
Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the treatment period are listed in Table 2.
| Percentage of Patients Reporting Event | |||
|---|---|---|---|
| Preferred Term | Kapvay 0.4 mg/day N=78 | Kapvay 0.2 mg/day N=76 | Placebo (N=76) |
| |||
| Somnolence* | 31% | 38% | 5% |
| Headache | 19% | 29% | 18% |
| Upper Abdominal Pain | 13% | 20% | 17% |
| Fatigue† | 13% | 16% | 1% |
| Upper Respiratory Tract Infection | 6% | 11% | 4% |
| Irritability | 6% | 9% | 3% |
| Throat Pain | 6% | 8% | 3% |
| Nausea | 8% | 5% | 4% |
| Nightmare | 9% | 3% | 0 |
| Dizziness | 3% | 7% | 5% |
| Insomnia | 6% | 4% | 1% |
| Emotional Disorder | 5% | 4% | 1% |
| Constipation | 6% | 1% | 0 |
| Dry Mouth | 5% | 0 | 1% |
| Nasal Congestion | 5% | 3% | 1% |
| Body Temperature Increased | 1% | 5% | 3% |
| Gastrointestinal Viral | 0% | 7% | 4% |
| Diarrhea | 1% | 4% | 3% |
| Ear Pain | 0 | 5% | 1% |
| Nasopharyngitis | 3% | 3% | 1% |
| Abnormal Sleep-Related Event | 1% | 3% | 0 |
| Aggression | 1% | 3% | 1% |
| Asthma | 1% | 3% | 1% |
| Bradycardia | 4% | 0 | 0 |
| Enuresis | 4% | 0 | 0 |
| Influenza like Illness | 3% | 1% | 1% |
| Tearfulness | 3% | 1% | 0 |
| Thirst | 3% | 1% | 0 |
| Tremor | 3% | 1% | 0 |
| Epistaxis | 0 | 3% | 0 |
| Lower Respiratory Tract Infection | 0 | 3% | 1% |
| Pollakiuria | 0 | 3% | 0 |
| Sleep Terror | 0 | 3% | 0 |
Commonly observed adverse reactions (incidence of ≥ 2% in either active treatment group and greater than the rate on placebo) during the taper period are listed in Table 3.
| Percentage of Patients Reporting Event | |||
|---|---|---|---|
| Preferred Term | Kapvay 0.4 mg/day N=78 | Kapvay 0.2 mg/day N=76 | Placebo (N=76) |
| |||
| Abdominal Pain Upper | 6% | 0 | 3% |
| Headache | 2% | 5% | 3% |
| Gastrointestinal Viral | 5% | 0 | 0 |
| Somnolence | 3% | 2% | 0 |
| Heart Rate Increased | 3% | 0 | 0 |
| Otitis Media Acute | 0 | 3% | 0 |
Study 2: Flexible-dose Kapvay as Adjunctive Therapy to Psychostimulants
Study 2 was a multi-center, randomized, double-blind, placebo-controlled study, with primary efficacy endpoint at 5 weeks, of a flexible dose of Kapvay as adjunctive therapy to a psychostimulant in children and adolescents (6 to 17 years) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes. Kapvay was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. Most Kapvay treated patients (75.5%) were escalated to the maximum dose of 0.4 mg/day.
Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the treatment period are listed in Table 4.
| Percentage of Patients Reporting Event | ||
|---|---|---|
| Preferred Term | Kapvay+STM (N=102) | PBO+STM (N=96) |
| ||
| Somnolence* | 19% | 8% |
| Fatigue† | 16% | 4% |
| Abdominal Pain Upper | 12% | 7% |
| Nasal Congestion | 6% | 5% |
| Throat Pain | 6% | 3% |
| Decreased Appetite | 5% | 4% |
| Body Temperature Increased | 4% | 2% |
| Dizziness | 4% | 2% |
| Insomnia | 4% | 2% |
| Epistaxis | 3% | 0 |
| Rhinorrhea | 3% | 0 |
| Abdominal Pain | 2% | 1% |
| Anxiety | 2% | 0 |
| Pain in Extremity | 2% | 0 |
Commonly observed adverse reactions (incidence of ≥ 2% in the treatment group and greater than the rate on placebo) during the taper period are listed in Table 5.
| Percentage of Patients Reporting Event | ||
|---|---|---|
| Preferred Term | Kapvay+STM (N=102) | PBO+STM (N=96) |
| ||
| Nasal Congestion | 4% | 2% |
| Headache | 3% | 1% |
| Irritability | 3% | 2% |
| Throat Pain | 3% | 1% |
| Gastroenteritis Viral | 2% | 0 |
| Rash | 2% | 0 |
Most common adverse reactions, defined as events that were reported in at least 5% of drug-treated patients and at least twice the rate as in placebo patients, during the treatment period were somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain. The most common adverse reactions that were reported during the taper phase were upper abdominal pain and gastrointestinal virus.
Adverse Reactions Leading to Discontinuation
Thirteen percent (13%) of patients receiving Kapvay discontinued from the pediatric monotherapy study due to adverse events, compared to 1% in the placebo group. The most common adverse reactions leading to discontinuation of Kapvay monotherapy treated patients were from somnolence/sedation (5%) and fatigue (4%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: formication, vomiting, prolonged QT, increased heart rate, and rash. In the pediatric adjunctive treatment to stimulants study, one patient discontinued from Kapvay + stimulant group because of bradyphrenia.
Effects on Laboratory Tests, Vital Signs, and Electrocardiograms
Kapvay treatment was not associated with any clinically important effects on any laboratory parameters in either of the placebo-controlled studies.
Mean decreases in blood pressure and heart rate were seen [see Warnings and Precautions (5.1)].
There were no changes on ECGs to suggest a drug-related effect.
7. DRUG INTERACTIONS
No drug interaction studies have been conducted with Kapvay in children. The following have been reported with other oral immediate release formulations of clonidine.
Interactions with CNS-depressant Drugs
Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs.
Interactions with Tricyclic Antidepressants
If a patient is receiving clonidine hydrochloride and also taking tricyclic antidepressants the hypotensive effects of clonidine may be reduced.
Interactions with Drugs Known to Affect Sinus Node Function or AV Nodal Conduction
Due to a potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium channel blockers and beta-blockers).
Use with other products containing clonidine
Do not use Kapvay concomitantly with other products containing clonidine (e.g. Catapres®).
Antihypertensive Drugs
Use caution when Kapvay is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope) [see Warnings and Precautions (5.2)].
8. USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C: Oral administration of clonidine hydrochloride to pregnant rabbits during the period of embryo/fetal organogenesis at doses of up to 80 mcg/kg/day (approximately 3 times the oral maximum recommended daily dose [MRHD] of 0.4 mg/day on a mg/m2 basis) produced no evidence of teratogenic or embryotoxic potential. In pregnant rats, however, doses as low as 15 mcg/kg/day (1/3 the MRHD on a mg/m2 basis) were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating and throughout gestation. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRHD) when treatment of the dams was restricted to gestation days 6-15. Increases in resorptions were observed in both rats and mice at 500 mcg/kg/day (10 and 5 times the MRHD in rats and mice, respectively) or higher when the animals were treated on gestation days 1-14; 500 mcg/kg/day was the lowest dose employed in this study. No adequate and well-controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed.
Nursing Mothers
Since clonidine hydrochloride is excreted in human milk, caution should be exercised when Kapvay is administered to a nursing woman.
Pediatric Use
A study was conducted in which young rats were treated orally with clonidine hydrochloride from day 21 of age to adulthood at doses of up to 300 mcg/kg/day, which is approximately 3 times the maximum recommended human dose (MRHD) of 0.4 mg/day on a mg/m2 basis. A slight delay in onset of preputial separation was seen in males treated with the highest dose (with a no-effect dose of 100 mcg/kg/day, which is approximately equal to the MRHD), but there were no drug effects on fertility or on other measures of sexual or neurobehavioral development.
Kapvay has not been studied in children with ADHD less than 6 years old.
Patients with Renal Impairment
The impact of renal impairment on the pharmacokinetics of clonidine in children has not been assessed. The initial dosage of Kapvay should be based on degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental Kapvay following dialysis.
Adult Use in ADHD
Kapvay has not been studied in adult patients with ADHD.
9.0 DRUG ABUSE AND DEPENDENCE
Controlled Substance
Kapvay is not a controlled substance and has no known potential for abuse or dependence.
10. OVERDOSAGE
Symptoms
Clonidine overdose: hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure.
Treatment
Consult with a Certified Poison Control Center for up-to-date guidance and advice.
11. DESCRIPTION
Kapvay (clonidine hydrochloride) extended-release is a centrally acting alpha2-adrenergic agonist available as 0.1 mg or 0.2 mg extended-release tablets for oral administration. Each 0.1 mg and 0.2 mg tablet is equivalent to 0.087 mg and 0.174 mg, respectively, of the free base.
The inactive ingredients are sodium lauryl sulfate, lactose monohydrate, hypromellose type 2208, partially pregelatinized starch, colloidal silicon dioxide, and magnesium stearate. The formulation is designed to delay the absorption of active drug in order to decrease peak to trough plasma concentration differences. Clonidine hydrochloride is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula:
C9H9Cl2N3•HCl Mol. Wt. 266.56
Clonidine hydrochloride is an odorless, bitter, white, crystalline substance soluble in water and alcohol.
Kapvay - Clinical Pharmacology
Mechanism of Action
Clonidine stimulates alpha2-adrenergic receptors in the brain. Clonidine is not a central nervous system stimulant. The mechanism of action of clonidine in ADHD is not known.
Pharmacodynamics
Clonidine is a known antihypertensive agent. By stimulating alpha2-adrenergic receptors in the brain stem, clonidine reduces sympathetic outflow from the central nervous system and decreases peripheral resistance, renal vascular resistance, heart rate, and blood pressure.
Pharmacokinetics
Single-dose Pharmacokinetics in Adults
Immediate-release clonidine hydrochloride and Kapvay have different pharmacokinetic characteristics; dose substitution on a milligram for milligram basis will result in differences in exposure. A comparison across studies suggests that the Cmax is 50% lower for Kapvay compared to immediate-release clonidine hydrochloride.
Following oral administration of an immediate release formulation, plasma clonidine concentration peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver. Although studies of the effect of renal impairment and studies of clonidine excretion have not been performed with Kapvay, results are likely to be similar to those of the immediate release formulation.
The pharmacokinetic profile of Kapvay administration was evaluated in an open-label, three-period, randomized, crossover study of 15 healthy adult subjects who received three single dose regimens of clonidine: 0.1 mg of Kapvay under fasted conditions, 0.1 mg of Kapvay following a high fat meal, and 0.1 mg of clonidine immediate-release (Catapres®) under fasted conditions. Treatments were separated by one-week washout periods.
Mean concentration-time data from the 3 treatments are shown in Table 6 and Figure 1. After administration of Kapvay, maximum clonidine concentrations were approximately 50% of the Catapres maximum concentrations and occurred approximately 5 hours later relative to Catapres. Similar elimination half-lives were observed and total systemic bioavailability following Kapvay was approximately 89% of that following Catapres.
Food had no effect on plasma concentrations, bioavailability, or elimination half-life.
| CATAPRES-Fasted n=15 | Kapvay-Fed n=15 | Kapvay-Fasted n=14 | ||||
|---|---|---|---|---|---|---|
| Parameter | Mean | SD | Mean | SD | MEAN | SD |
| Cmax (pg/mL) | 443 | 59.6 | 235 | 34.7 | 258 | 33.3 |
| AUCinf (hr*pg/mL) | 7313 | 1812 | 6505 | 1728 | 6729 | 1650 |
| hTmax (hr) | 2.07 | 0.5 | 6.80 | 3.61 | 6.50 | 1.23 |
| T1/2 (hr) | 12.57 | 3.11 | 12.67 | 3.76 | 12.65 | 3.56 |
| Figure 1 Mean Clonidine Concentration-Time Profiles after Single Dose Administration |
Multiple-dose Pharmacokinetics in Children and Adolescents
Plasma clonidine concentrations in children and adolescents (0.1 mg bid and 0.2 mg bid) with ADHD are greater than those of adults with hypertension with children and adolescents receiving higher doses on a mg/kg basis. Body weight normalized clearance (CL/F) in children and adolescents was higher than CL/F observed in adults with hypertension. Clonidine concentrations in plasma increased with increases in dose over the dose range of 0.2 to 0.4 mg/day. Clonidine CL/F was independent of dose administered over the 0.2 to 0.4 mg/day dose range. Clonidine CL/F appeared to decrease slightly with increases in age over the range of 6 to 17 years, and females had a 23% lower CL/F than males. The incidence of "sedation-like" AEs (somnolence and fatigue) appeared to be independent of clonidine dose or concentration within the studied dose range in the titration study. Results from the add-on study showed that clonidine CL/F was 11% higher in patients who were receiving methylphenidate and 44% lower in those receiving amphetamine compared to subjects not on adjunctive therapy.
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