Novartis Pharmaceuticals won approval from
the Food and Drug Administration last month to market its
improved version of methylphenidate, the standard medication
prescribed for attention deficit/hyperactivity disorder for
nearly 50 years.
The new version, dexmethylphenidate, will be
marketed under the trade name Focalin. Novartis expects Focalin
to be available in pharmacies in late January.
Dexmethylphenidate is the latest drug to be approved
in a string of medications either in the late stages of
development or under current FDA review for the treatment of
Dexmethylphenidate is the d- , or
"right-handed," isomer of the racemic mixture found
in d,l-methylphenidate (Ritalin). It is one of several examples
of medications designed through advancing technology aimed at
isolating single active isomers (see
story below). It was separated and developed for Novartis by
Cellgene Corporation. Because dexmethylphenidate is the more active
of the two isomers, doses are half that recommended for methyl-phenidate.
The recommended starting dose for new patients is 2.5 mg, and
patients being switched from methylphenidate should be started
at half their final methylphenidate dose, according to
In company-sponsored clinical trials reviewed by the
FDA, the drug was found to be effective in lowering scores on
the Teacher SNAP-ADHD assessment rating scale. SNAP assessments
by parents of children in the study supported the improvements
indicated by teachers. In addition, patients receiving
dexmethylphenidate significantly improved on Clinical Global
Impression of Improvement scores. Interestingly, in the
clinical trials there appeared to be a slight but statistically
significant advantage in improvements reported with
dexmethylphenidate compared with methylphenidate.
Overall, the side-effect profile appears to be the
same as for methylphenidate, with the most commonly reported
complaints being stomach upset and insomnia.
Like other stimulant medications used for ADHD,
dexmethylphenidate is a Schedule II controlled substance.
While dexmethylphenidate, like its parent compound,
must still be prescribed in multiple daily doses, the
pharmaceutical industry has been pursuing ways to allow
patients with ADHD to take only one daily dose. For children,
this would eliminate the stigmatizing need to take medication
during the school day. In addition, sustained or
controlled-release formulations are generally believed to give
patients more consistent control of their symptoms throughout the
On November 5 Shire Pharmaceuticals launched its
latest version of its mixed amphetamine salts product (Adderall).
The new formulation, Adderall XR, is a new use of existing drug
technology that encapsulates the active medication in coated
beads within the capsule. In Adderall XR, half of the beads
dissolve immediately, releasing a first dose of medication into
the bloodstream, followed by the remaining half dissolving
approximately four to six hours later. The formulation
eliminates the need for patients to take a second, mid-day dose
and allows for symptom control for eight to 10 hours.
The regular form of Adderall is the most prescribed
ADHD medication, according to data from NDCHealth, an
Atlanta-based independent firm that tracks drug sales.
NDCHealth data for the 30 days ended November 1 showed Adderall
with a 33 percent market share. Preliminary data from NDCHealth
for the new formulation showed Adderall XR with a 5.4 percent
market share by the end of its first four weeks on the market.
Adderall XR enters a market already strongly
competitive with three other longer-acting methylphenidate
modified-release products: Celltech Pharmaceutical’s Metadate
CD; Concerta, marketed by Alza Pharmaceuticals; and
Novartis’s Ritalin-SR. Each product uses slightly different
patented technology to sustain the release of the active
medication over the course of the day.
A number of studies have compared the newer
long-acting medications, according to Laurence Greenhill, M.D.,
a professor of clinical psychiatry at Columbia University and
the New York State Psychiatric Institute. Greenhill reviewed
the comparisons recently at the annual meeting of the American
Academy of Child and Adolescent Psychiatry (AACAP) in Honolulu.
Greenhill emphasized that medication can be an
effective adjunct in a comprehensive treatment plan for ADHD
patients, which, he said, should include educational,
behavioral, psychological, and family therapies, as well as
In studies presented at the AACAP meeting and those
reviewed by Greenhill, Metadate CD and Concerta were roughly
comparable in terms of efficacy and safety of the two products;
however, differences are apparent, Greenhill said.
Although the overall exposure to methylphenidate
from the two products appears comparable, higher blood levels
are achieved quicker with Metadate CD than with Concerta, he
said. Blood levels of methylphenidate achieved with Metadate CD
continued to be higher compared with Concerta through the
six-hour time point in several published studies, according to
Greenhill. However, at later time points, between eight and 12
hours, concentrations were higher with Concerta.
The seemingly minor difference in the amount of
methylphenidate released with the two preparations over time
does lead to a practical difference in how Greenhill uses the
"Concerta is the longest-acting
preparation," Greenhill told those attending his AACAP
presentation, "and I use it in children who have no sleep
problems on prior treatment [with stimulants and who have] a
big problem with homework."
The higher concentrations later in the day help
patients to focus and complete homework tasks, but they can
lead to insomnia. Nonetheless, "if I have a child who has
a poor appetite, won’t eat dinner, and on past treatment has
been sensitive to the anorexic effects [of stimulants], and is
sleeping poorly, then I’d use something shorter like Metadate
CD or Ritalin SR."
Greenhill noted, however, that Ritalin SR has
generally not been highly prescribed. Patients do not appear to
achieve relief from symptoms as quickly with Ritalin-SR as they
do with immediate-release methylphenidate and relief of
symptoms throughout the patient population using Ritalin-SR has
been shown to be not as consistent or as robust as compared
with two doses of immediate-release methylphenidate. Although
spokespersons for Novartis would not comment, it is widely
believed by many clinicians that these studies were the impetus
for Novartis’s development of its new Ritalin-LA.
If the patient is experiencing dysphoria, a side
effect of long-acting stimulant therapy, then Greenhill prefers
to use Adderall XR, which he says does not seem to cause
Although Greenhill generally initiates stimulant
therapy with an immediate-release preparation—to check for
any allergic reactions or immediate adverse events—he
strongly urges clinicians to move more patients to long-acting
forms of medication therapy.
"There is enough strong evidence in the
literature now to suggest they are effective," he said.
"It gets the medication out of the school and under the
control of the parents."
Several additional ADHD medications are either in
the late stages of development or are pending FDA approval.
"I’m looking forward to having important new
options in the armamentarium. Increasing options for patients
is always a good thing," he said.