The U.S. Food and Drug Administration (FDA) has issued an approvable letter
to Shire for its extended-release formulation of guanfacine (Intuniv), a
selective alpha-2A-receptor agonist, for the treatment of
attention-deficit/hyperactivity disorder (ADHD) in children and adolescents.
This letter indicates that the FDA expects to approve the product if certain
questions or requests are addressed to its satisfaction.
The manufacturer of the product, Shire, submitted a new drug application in
August 2006 on the basis of data from two placebo-controlled clinical trials
in ADHD patients aged 6 to 17.
Various animal and human studies have shown that norepinephrine and
alpha-2A-adrenergic receptor activation play an important role in cognitive
functions and impulse control. Alpha-2A-receptor agonists such as clonidine
and guanfacine enhance the neurological activity in the prefrontal cortex, a
region of the brain involved in planning, impulse control, and organization.
Prefrontal cortex dysfunction is consistently detected on structural and
functional brain imaging in people with ADHD. In addition, genetic research
has found evidence to support the link between the alpha-2A-adrenergic
receptor gene (ADRA2A) and patients' response to methylphenidate, especially
in the inattentive dimension of ADHD symptoms.
Agonists of the alpha-2A-adrenergic receptors such as clonidine and
guanfacine (immediate-release) have been used to treat ADHD symptoms in
clinical practice, often as an adjunct to stimulants.
The side effects of alpha-2A agonists include drowsiness, drop in blood
pressure, irritability, dry mouth, constipation, dizziness, and sleep
disturbance. Guanfacine may have fewer severe side effects in the central
nervous system than clonidine because it is more selective than clonidine in
binding with alpha-2A-adrenergic receptors, said Amy Arnstern, Ph.D., a
professor of neurobiology at Yale University School of Medicine, in a review
of the biochemistry of ADHD published in the September 2000 Journal of the
American Academy of Child and Adolescent Psychiatry.
The therapeutic position statement put forth by the American Society of
Health-System Pharmacists on the treatment of ADHD in children recommends that
patients' vital signs be monitored. Electrocardiogram monitoring is
recommended but "controversial." The guidelines recommend that
patients be started on a lower dose and gradually increased. Tapering over
several weeks may be necessary when a drug is discontinued, as rebound
symptoms associated with abrupt cessation of central 2-adrenergic agonists,
such as nervousness, anxiety, and increases in blood pressure, may occur,
according to guanfacine prescribing information.
Guanfacine is currently available in immediate-release formulation (1 mg
and 2 mg tablets) by various manufacturers for the indication of hypertension.
It is taken once or twice daily. Shire's application for guanfacine
extended-release is intended for once-daily use with dosage ranging from 1 mg
to 4 mg.
If approved, guanfacine extended-release will be an addition to the
nonstimulant ADHD treatment with FDA-approved labeling. Atomoxetine
(Strattera), a selective norepinephrine reuptake inhibitor that also increases
the action of norepinephrine in the prefrontal cortex, was the first
nonstimulant drug approved to treat ADHD in children, adolescents, and adults.▪