ADHD prodrug may help high-risk patients.

Lisdexamfetamine dimesylate is the newest extended-release stimulant for treating attention-deficit/hyperactivity disorder in young children.

It was recently approved by the Food and Drug Administration for treatment of attention-deficit/hyperactivity disorder (ADHD) in patients aged 6-12 years.

Lisdexamfetamine (Vyvanse, Shire/New River Pharmaceuticals) is a prodrug of D-amphetamine. In this unique formulation, D-amphetamine is covalently linked to L-lysine, an amino acid, and remains inactive until metabolized by the gastrointestinal tract. This metabolism is a rate-limiting effect that provides sustained release: Unlike other extended-release stimulants for ADHD, the active ingredient is not encapsulated in a matrix or bead formulation.

In clinical studies, children with ADHD taking the agent in the morning still had control of symptoms at 6:00 p.m. This sustained release is not unique. "Depending on how you use them, Concerta, Adderall, and Focalin will last somewhere from 10 to 12 hours. So if you give a child a dose at 6:00 a.m., it will usually last until about 6:00 p.m. at night," said Dr. Raul Silva, vice chairman of the department of child and adolescent psychiatry at New York University, New York.

"We do have several extended-release or long-acting medications, so this joins that group," Dr. Oscar Bukstein said in an interview. "By virtue of it being long-acting, there is a certain protection against reinforcement versus a more immediate release medication." In other words, there is no immediate high for someone who tries to abuse lisdexamfetamine.

"The whole purpose of the prodrug seems to be it is less addictive," Dr. Silva said in an interview.

The prodrug is inert outside the body. "If you grind it and stick it up your nose or stick it in your veins, it's not active," said Dr. Bukstein, who is on the psychiatry faculty at the University of Pittsburgh.

The manufacturer conducted two studies in known substance abusers. Participants reported a lower preference for lisdexamfetamine, compared with equivalent doses of D-amphetamine using a "Drug Liking Effects" scale.

However, "you have to wonder about the doses in those studies," Dr. Silva said. "Were the doses comparable to what people who abuse these drugs use?"

Dr. Silva has no affiliation with Shire/New River Pharmaceuticals.

Dr. Bukstein is a consultant and speaker for Shire/New River Pharmaceuticals.

The U.S. Drug Enforcement Administration accepted the FDA recommendation for a Schedule II controlled substance designation for lisdexamfetamine. However, a final decision is still pending. Other stimulants for ADHD have a Schedule II designation, including Adderall XR (mixed salts of a single entity amphetamine product, Shire), Concerta (methylphenidate HCl, Johnson & Johnson), and Focalin XR (dexmethylphenidate HCl, Novartis).

"It's an advancement for several reasons, but not an earth-shattering advancement," Dr. Bukstein said. "If they price it like Adderall, there is no reason not to use it." He added that "once Adderall and the other long-acting agents become generic, it's going to be harder to justify use in an average school age kid."

Lisdexamfetamine might make more sense in high-risk populations, such as substance abusers with ADHD, Dr. Bukstein said.

Dr. Silva agreed. "There will be information that will make it appealing for folks who have a predisposition to substance abuse, such as people with a strong family history of addiction. It may also be used by people whose children have failed a nonstimulant like Strattera [atomoxetine HCl, Lilly] and who may have hesitated to use a stimulant before."

Clinical trials demonstrated statistically significant improvements in ADHD symptoms, compared with placebo at all once-daily doses (30 mg, 50 mg and 70 mg). A phase II study showed both Vyvanse and Adderall XR improved classroom behavior ratings, compared with placebo using the Swanson, Kotkin, Agler, M. Flynn and Pelham (SKAMP) deportment rating scale. Also, both drugs significantly improved academic productivity, compared with placebo on the Permanent Product Measure of Performance (PERMP) instrument, an age-adjusted collection of math problems that measures a child's ability to pay attention and stay on task.

In a phase III, randomized, double-blind placebo-controlled study, lisdexamfetamine significantly improved the 18-item ADHD Rating Scale (ADHD-RS-IV) scores, compared with placebo after 4 weeks.

Lisdexamfetamine improved ADHD symptom rating scale scores by 60% among children aged 6-12 years who received 6 months of treatment in an open-label, phase III study. Clinicians reported a "much improved" or "very much improved" rating on the Clinical Global Impressions-Improvement score scale for 95% of children.

Lisdexamfetamine should not be prescribed for patients with arteriosclerosis, symptomatic heart disease, moderate to severe hypertension, hyperthyroidism, seizures, glaucoma, agitated states, a history of substance abuse problems, a known allergy or unusual reactions to sympathomimetic amines, or for patients who have taken a monoamine oxidase inhibitor (MAOI) within the last 14 days.

Advise parents and patients to watch for development of any symptoms that suggest heart problems, such as chest pain or fainting, and monitor children for blurred vision.

BY DAMIAN MCNAMARA

Miami Bureau