May 25, 2017
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"The US Food and Drug Administration (FDA) has approved the amphetamine Dyanavel XR (Tris Pharma Inc), a once-daily extended-release oral liquid, for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children aged 6 years "...




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.


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.


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 7 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.

Table 7 : Pharmacokinetic Parameters of Clonidine in Healthy Adult Volunteers

Parameter CATAPRES-Fasted
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
T½ (hr) 12.57 3.11 12.67 3.76 12.65 3.56

Figure 1 : Mean Clonidine Concentration-Time Profiles after Single Dose Administration

Mean Clonidine Concentration-Time Profiles - Illustration

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.

Animal Toxicology And/Or Pharmacology

In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid. In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.

In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 adult patients before, and periodically after, the start of clonidine therapy for hypertension. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged.

Clinical Studies

Efficacy of KAPVAY in the treatment of ADHD was established in children and adolescents (6 to 17 years) in:

  • One short-term, placebo-controlled monotherapy trial (Study 1)
  • One short-term adjunctive therapy to psychostimulants trial (Study 2)
  • One randomized withdrawal trial as monotherapy (Study 3)
Short-term Monotherapy and Adjunctive Therapy to Psychostimulant Studies for ADHD

The efficacy of KAPVAY in the treatment of ADHD was established in 2 (one monotherapy and one adjunctive therapy) placebo-controlled trials in pediatric patients aged 6 to 17, who met DSM-IV criteria of ADHD hyperactive or combined hyperactive/inattentive subtypes. Signs and symptoms of ADHD were evaluated using the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS-IV) total score including hyperactive/impulsivity and inattentive subscales.

Study 1 (CLON-301), was an 8-week randomized, double-blind, placebo-controlled, fixed dose study of children and adolescents aged 6 to 17 (N=236) with a 5-week primary efficacy endpoint. Patients were randomly assigned to one of the following three treatment groups: KAPVAY (CLON) 0.2 mg/day (N=78), KAPVAY 0.4 mg/day (N=80), or placebo (N=78). Dosing for the KAPVAY groups started at 0.1 mg/day and was titrated in increments of 0.1 mg/week to their respective dose (as divided doses). Patients were maintained at their dose for a minimum of 2 weeks before being gradually tapered down to 0.1 mg/day at the last week of treatment. At both doses, improvements in ADHD symptoms were statistically significantly superior in KAPVAY-treated patients compared with placebo-treated patients at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).

Study 2 (CLON-302) was an 8-week randomized, double-blind, placebo-controlled, flexible dose study in children and adolescents aged 6 to 17 (N=198) with a 5-week primary efficacy end point. Patients had been treated with a psychostimulant (methylphenidate or amphetamine) for four weeks with inadequate response. Patients were randomly assigned to one of two treatment groups: KAPVAY adjunct to a psychostimulant (N=102) or psychostimulant alone (N=96). The KAPVAY dose was initiated at 0.1 mg/day and doses were titrated in increments of 0.1 mg/week up to 0.4 mg/day, as divided doses, over a 3-week period based on tolerability and clinical response. The dose was maintained for a minimum of 2 weeks before being gradually tapered to 0.1 mg/day at the last week of treatment. ADHD symptoms were statistically significantly improved in KAPVAY plus stimulant group compared with the stimulant alone group at the end of 5 weeks as measured by the ADHDRS-IV total score (Table 8).

Table 8 : Short-Term Trials

Study Number Treatment Group Primary Efficacy Measure: ADHDRS-IV Total Score
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea(95% CI)
Study 1 KAPVAY (0.2 mg/day) 43.8
(-12.2, - 4.8)
KAPVAY (0.4 mg/day) 44.6
(-12.8, - 5.5)
Placebo 45.0
Study 2 KAPVAY (0.4 mg/day) + Psychostimulant 38.9
(-7.8, -1.1)
Psychostimulant alone 39.0
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
aDifference (drug minus placebo) in least-squares mean change from baseline.

Maintenance Monotherapy for ADHD

Study 3 (SHN-KAP-401), was a double-blind, placebo-controlled, randomized-withdrawal study in children and adolescents aged 6 to 17 years (n=253) with DSM-IV-TR diagnosis of ADHD. The study consisted of a 10-week, open-label phase (4 weeks of dose optimization and 6 weeks of dose maintenance), a 26-week double-blind phase, and a 4-week taper-down and follow-up phase. All patients were initiated at 0.1 mg/day and increased at weekly intervals in increments of 0.1 mg/day until reaching personalized optimal dose (0.1, 0.2, 0.3 or 0.4 mg/day, as divided doses). Eligible patients had to demonstrate treatment response as defined by ≥ 30% reduction in ADHD-RS-IV total score and a Clinical Global Impression-Improvement score of 1 or 2 during the open label phase. Patients who sustained treatment response (n=135) until the end of the open label phase were randomly assigned to one of the two treatment groups, KAPVAY (N=68) and Placebo (N=67), to evaluate the long-term efficacy of maintenance dose of KAPVAY in the double-blind phase. The primary efficacy endpoint was the percentage of patients with treatment failure defined as a ≥ 30% increase (worsening) in ADHD-RS-IV total score and ≥ 2 points increase (worsening) in Clinical Global Impression – Severity Scale in 2 consecutive visits or early termination for any reason. A total of 73 patients experienced treatment failure in the double-blind phase: 31 patients (45.6%) in the KAPVAY group and 42 patients (62.7%) in the placebo group, with a statistically significant difference in the primary endpoint favoring KAPVAY (Table 9). The cumulative proportion of patients with treatment failure over time during the double-blind phase is displayed in Figure 2.

Table 9 : Treatment Failure: Double-Blind Full Analysis Set (Study 3)

Study 3 Double-Blind Full Analysis Set
Kapvay Placebo
Number of subjects 68 67
Number of treatment failures 31 (45.6%) 42 (62.7%)
Basis of Treatment Failure
Clinical criteriaa,b 11 (16.2%) 9 (13.4%)
Lack of efficacyc 1 (1.5%) 3 (4.5%)
Withdrawal of informed assent/consent 4 (5.9%) 20 (29.9%)
Other early terminations 15 (22.1%) 10 (14.9%)
ADHD-RS-IV = Attention Deficit Hyperactivity Disorder-Rating Scale-4th edition; CGI-S = Clinical Global Impression-Severity
aAt the same 2 consecutive visits a (1) 30% or greater reduction in ADHD-RS-IV, and (2) 2-point or more increase in CGI-S.
bTwo subjects (1 placebo and 1 KAPVAY) withdrew consent, but met the clinical criteria for treatment failure.
cThree subjects (all placebo) discontinued the study due to treatment failure, but met only the criterion for ADHD-RS-IV.

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure (Study 3)

Kaplan-Meier Estimation of Cumulative Proportion of Patients with Treatment Failure - Illustration

Last reviewed on RxList: 1/26/2017
This monograph has been modified to include the generic and brand name in many instances.

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