FDA Approves Extended-Release Clonidine for Pediatric ADHD

The US Food and Drug Administration (FDA) has approved clonidine hydrochloride, 0.1-mg and 0.2-mg, extended-release tablets (Kapvay; Shionogi Inc) alone or with stimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD) in pediatric patients aged 6 to 17 years.

The product is the first formulation of clonidine to be approved by the FDA for ADHD and also represents the first and only adjunctive treatment to stimulant therapy for the condition.

“ADHD is a complex disorder that requires individualized treatment. While there are prescription treatment options available, many ADHD patients on stimulants do not achieve adequate control of symptoms,” explained Rakesh Jain, MD, MPH, director of psychiatric drug research for R/D Clinical Research in Lake Jackson, Texas, in a company news release. “Kapvay, when added to a stimulant, addresses an unmet need and improves ADHD symptoms beyond what is achieved by stimulants alone. This is a significant step forward for the treatment of ADHD to have an approved product for add-on therapy in our treatment armamentarium.”

FDA approval was based on clinical data from 2 phase 3 studies, showing that twice-daily use of extended-release clonidine alone or with stimulants (methylphenidate or amphetamine) significantly improved ADHD symptoms in children and teenagers aged 6 to 17 years at 5 weeks relative to placebo or stimulants alone, respectively, as evaluated using the ADHD Rating Scale IV–Parent Version, which included hyperactive/impulsivity and inattentive subscales.

Adverse events most commonly reported with use of extended-release clonidine (incidence ≥5% and twice the rate of placebo) included somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain.

Treatment with extended-release clonidine should be initiated with a single 0.1-mg tablet at bedtime and adjusted upward in increments of 0.1 mg/day at weekly intervals until the desired response is achieved (maximum dose, 0.4 mg/day). Doses should be taken twice a day, with either an equal or higher split dosage administered at bedtime.

A slower rate of up-titration is recommended when treating patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease, or chronic renal failure.

Because of the risk for hypotension/bradycardia, heart rate and blood pressure should be measured before initiation of therapy, following dose increases, and periodically thereafter. Patients should be advised to avoid becoming dehydrated or overheated.

Caution is advised with coadministration of antihypertensive drugs and agents known to affect sinus node function or atrioventricular nodal conduction, such as digitalis, calcium channel blockers, and β-blockers. Concomitant use of other clonidine products (eg, Catapres; Boehringer Ingelheim) should be avoided.

Extended-release clonidine may also cause somnolence or sedation — an effect augmented by concomitant use of central nervous system depressants, such as alcohol, barbiturates, and benzodiazepines. Patients should be warned against operating heavy equipment or driving until they know how the medication will affect them.

In patients who have developed localized contact sensitization or other allergic reactions to transdermal clonidine, substitution of oral clonidine may cause generalized rash, urticaria, or angioedema.

Abrupt discontinuation of clonidine use can lead to withdrawal symptoms; dosage should be slowly titrated in decrements of no more than 0.1 mg every 3 to 7 days.

The FDA notes that long-term efficacy (>5 weeks) of extended-release clonidine has not been systematically evaluated in clinical trials and recommends periodic assessment of the drug’s usefulness during maintenance therapy. This drug has also not been studied in children younger than 6 years.

Extended-release clonidine tablets previously were approved for the treatment of hypertension (Jenloga; Shionogi Inc).

Clinical Implications

• The FDA has approved clonidine HCl 0.1-mg and 0.2-mg extended-release tablets alone or with stimulants for the twice-daily treatment of ADHD in pediatric patients aged 6 to 17 years.
• Treatment with extended-release clonidine should start with a 0.1-mg nightly dose and increase by 0.1 mg/day at weekly intervals to a maximum of 0.4 mg/day, given in 2 divided doses. Caution and slow up-titration is advised for patients with vascular disease, cardiac conduction disease, or renal failure.
• Because of the risk for hypotension and bradycardia, heart rate and blood pressure should be measured before initiation of therapy, after dose increases, and periodically thereafter. Caution is advised with use of antihypertensive drugs and agents known to affect sinus node function or atrioventricular node conduction. Concomitant use of central nervous system depressants can increase somnolence/sedation.