(methylphenidate HCl) Extended-release Tablets CII
Concerta® is a central nervous system (CNS) stimulant. Concerta® is available
in two tablet strengths. Each extended-release tablet for once-a-day oral
administration contains 18 or 36 mg of methylphenidate HCl USP and is
designed to have a 12-hour duration of effect. Chemically, methylphenidate
HCl is d,l (racemic) methyl a-phenyl-2-piperidineacetate hydrochloride.
Its empirical formula is C14H19NO2·HCl.
Its structural formula is:
Methylphenidate HCl USP is
a white, odorless crystalline powder. Its solutions are acid to litmus.
It is freely soluble in water and in methanol, soluble in alcohol, and
slightly soluble in chloroform and in acetone. Its molecular weight is
Concerta® also contains the
following inert ingredients: butylated hydroxytoluene, carnauba wax, cellulose
acetate, hydroxypropyl methylcellulose, lactose, phosphoric acid, poloxamer,
polyethylene glycol, polyethylene oxides, povidone, propylene glycol,
sodium chloride, stearic acid, succinic acid, synthetic iron oxides, titanium
dioxide, and triacetin.
System Components and Performance
Concerta® uses osmotic pressure to deliver methylphenidate HCl at a controlled
rate. The system, which resembles a conventional tablet in appearance,
comprises an osmotically active trilayer core surrounded by a semipermeable
membrane with an immediate-release drug overcoat. The trilayer core is
composed of two drug layers containing the drug and excipients, and a
push layer containing osmotically active components. There is a precision-laser
drilled orifice on the drug-layer end of the tablet. In an aqueous environment,
such as the gastrointestinal tract, the drug overcoat dissolves within
one hour, providing an initial dose of methylphenidate. Water permeates
through the membrane into the tablet core. As the osmotically active polymer
excipients expand, methylphenidate is released through the orifice. The
membrane controls the rate at which water enters the tablet core, which
in turn controls drug delivery. The biologically inert components of the
tablet remain intact during gastrointestinal transit and are eliminated
in the stool as a tablet shell along with insoluble core components.
Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode
of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD)
is not known. Methylphenidate is thought to block the reuptake of norepinephrine
and dopamine into the presynaptic neuron and increase the release of these
monoamines into the extraneuronal space. Methylphenidate is a racemic
mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically
active than the l-isomer.
Methylphenidate is readily absorbed. Following oral administration of
Concerta® to adults, plasma methylphenidate concentrations increase rapidly
reaching an initial maximum at about 1 to 2 hours, then increase gradually
over the next several hours. Peak plasma concentrations are achieved at
about 6 to 8 hours after which a gradual decrease in plasma levels of
methylphenidate begins. Concerta® qd minimizes the fluctuations between
peak and trough concentrations associated with immediate-release methylphenidate
tid (see Figure 1). The relative bioavailability of Concerta® qd and methylphenidate
tid in adults is comparable.
Figure 1. Mean methylphenidate
plasma concentrations in 36 adults, following a single dose of Concerta®
18 mg qd and immediate-release methylphenidate 5 mg tid administered every
The mean pharmacokinetic parameters
in 36 adults following the administration of Concerta® 18 mg qd and methylphenidate
5 mg tid are summarized in Table 1.
Mean ± SD Pharmacokinetic Parameters
(18 mg qd)
(5 mg tid)
|3.7 ± 1.0
|6.8 ± 1.8
|3.5 ± 0.4
|4.2 ± 1.0
|6.5 ± 1.8
|3.0 ± 0.5
No differences in the pharmacokinetics
of Concerta® were noted following single and repeated qd dosing indicating
no significant drug accumulation. The AUC and t1/2 following repeated
qd dosing are similar to those following the first dose of Concerta® 18
Following administration of Concerta® in single doses of 18, 36, and 54
mg/day to adults, Cmax and AUC(0-inf) of d-methylphenidate were proportional
to dose, whereas l-methylphenidate Cmax and AUC(0-inf) increased disproportionately
with respect to dose. Following administration of Concerta®, plasma concentrations
of the l-isomer were approximately 1/40th the plasma concentrations of
Plasma methylphenidate concentrations in adults decline biexponentially
following oral administration. The half-life of methylphenidate in adults
following oral administration of Concerta® was approximately 3.5 h.
Metabolism and Excretion
In humans, methylphenidate is metabolized primarily by de-esterification
to a-phenyl-piperidine acetic acid (PPA) which has little or no pharmacologic
activity. In adults the metabolism of Concerta® qd as evaluated by metabolism
to PPA is similar to that of methylphenidate tid. The metabolism of single
and repeated qd doses of Concerta® is similar.
After oral dosing of radiolabeled
methylphenidate in humans, about 90% of the radioactivity was recovered
in urine. The main urinary metabolite was PPA, accounting for approximately
80% of the dose.
In patients, there were no differences in either the pharmacokinetics
or the pharmacodynamic performance of Concerta® when administered after
a high fat breakfast. There is no evidence of dose dumping in the presence
or absence of food.
In healthy adults, the mean dose-adjusted AUC(0-inf) values for Concerta®
were 36.7 ng·h/mL in men and 37.1 ng·h/mL in women, with no differences
noted between the two groups.
In adults receiving Concerta®, dose-adjusted AUC(0-inf) was consistent
across ethnic groups; however, the sample size may have been insufficient
to detect ethnic variations in pharmacokinetics.
The pharmacokinetics of Concerta® has not been studied in children less
than 6 years of age.
There is no experience with the use of Concerta® in patients with renal
insufficiency. After oral administration of radiolabeled methylphenidate
in humans, methylphenidate was extensively metabolized and approximately
80% of the radioactivity was excreted in the urine in the form of PPA.
Since renal clearance is not an important route of methylphenidate clearance,
renal insufficiency is expected to have little effect on the pharmacokinetics
There is no experience with the use of Concerta® in patients with hepatic
Concerta® was demonstrated to be effective in the treatment of Attention
Deficit Hyperactivity Disorder (ADHD) in three double-blind, active- and
placebo-controlled studies in 416 children 6 to 12 years old. The controlled
studies compared Concerta® given qd (18, 36, or 54 mg), methylphenidate
given tid over 12 hours (15, 30, or 45 mg total daily dose), and placebo
in two single-center, 3-week crossover studies (Studies 1 and 2) and in
a multicenter, 4-week, parallel-group comparison (Study 3). The primary
comparison of interest in all three trials was Concerta® versus placebo.
The Diagnostic and Statistical
Manual, 4th edition, of the American Psychiatric Association (DSM-IV)
provides criteria for three subtypes of ADHD (Combined Type, Predominantly
Inattentive Type, or Predominantly Hyperactive-Impulsive Type). These
criteria were used for diagnosis in all three studies.
Symptoms of ADHD were evaluated
by community school teachers using the Inattention/Overactivity with Aggression
(IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity
subscale versus placebo was shown consistently across all three controlled
studies for Concerta® qd. The scores for Concerta® and placebo for the
three studies are presented in Figure 2.
Figure 2: Mean
Community School Teacher IOWA Conners Inattention/Overactivity Scores
with CONCERTA qd (18, 36, or 54 mg) and placebo. Studies 1 and 2
involved a 3-way crossover of 1 week per treatment arm. Study 3 involved
4 weeks of parallel group treatments with a Last Observation Carried Forward
analysis at week 4. Error bars represent the mean plus standard error
of the mean.
INDICATION AND USAGE
Attention Deficit Hyperactivity Disorder (ADHD)
Concerta® is indicated for the treatment of Attention Deficit Hyperactivity
The efficacy of Concerta® in
the treatment of ADHD was established in three controlled trials of children
aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY).
A diagnosis of Attention Deficit
Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive
or inattentive symptoms that caused impairment and were present before
age 7 years. The symptoms must cause clinically significant impairment,
e.g., in social, academic, or occupational functioning, and be present
in two or more settings, e.g., school (or work) and at home. The symptoms
must not be better accounted for by another mental disorder. For the Inattentive
Type, at least six of the following symptoms must have persisted for at
least 6 months: lack of attention to details/careless mistakes; lack of
sustained attention; poor listener; failure to follow through on tasks;
poor organization; avoids tasks requiring sustained mental effort; loses
things; easily distracted; forgetful. For the Hyperactive-Impulsive Type,
at least six of the following symptoms must have persisted for at least
6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing;
difficulty with quiet activities; "on the go;" excessive talking; blurting
answers; can't wait turn; intrusive. The Combined Types requires both
inattentive and hyperactive-impulsive criteria to be met.
Special Diagnostic Considerations
Specific etiology of this syndrome is unknown, and there is no single
diagnostic test. Adequate diagnosis requires the use not only of medical
but of special psychological, educational, and social resources. Learning
may or may not be impaired. The diagnosis must be based upon a complete
history and evaluation of the child and not solely on the presence of
the required number of DSM-IV characteristics.
Need for Comprehensive Treatment
Concerta® is indicated as an integral part of a total treatment program
for ADHD that may include other measures (psychological, educational,
social) for patients with this syndrome. Drug treatment may not be indicated
for all children with this syndrome. Stimulants are not intended for use
in the child who exhibits symptoms secondary to environmental factors
and/or other primary psychiatric disorders, including psychosis. Appropriate
educational placement is essential and psychosocial intervention is often
helpful. When remedial measures alone are insufficient, the decision to
prescribe stimulant medication will depend upon the physician's assessment
of the chronicity and severity of the child's symptoms.
The effectiveness of Concerta® for long-term use, i.e., for more than
4 weeks, has not been systematically evaluated in controlled trials. Therefore,
the physician who elects to use Concerta® for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Concerta® is contraindicated in patients with marked anxiety, tension,
and agitation, since the drug may aggravate these symptoms.
Hypersensitivity to Methylphenidate
Concerta® is contraindicated in patients known to be hypersensitive to
methylphenidate or other components of the product.
Concerta® is contraindicated in patients with glaucoma.
Concerta® is contraindicated in patients with motor tics or with a family
history or diagnosis of Tourette's syndrome (see ADVERSE REACTIONS).
Monoamine Oxidase Inhibitors
Concerta® is contraindicated during treatment with monoamine oxidase inhibitors,
and also within a minimum of 14 days following discontinuation of a monoamine
oxidase inhibitor (hypertensive crises may result).
Concerta® should not be used to treat severe depression.
Concerta® should not be used for the prevention or treatment of normal
Long-Term Suppression of
Sufficient data on the safety of long-term use of methylphenidate in children
are not yet available. Although a causal relationship has not been established,
suppression of growth (i.e., weight gain, and/or height) has been reported
with the long-term use of stimulants in children. Therefore, patients
requiring long-term therapy should be carefully monitored. Patients who
are not growing or gaining weight as expected should have their treatment
Clinical experience suggests that in psychotic patients, administration
of methylphenidate may exacerbate symptoms of behavior disturbance and
There is some clinical evidence that methylphenidate may lower the convulsive
threshold in patients with prior history of seizures, in patients with
prior EEG abnormalities in absence of seizures, and, very rarely, in absence
of history of seizures and no prior EEG evidence of seizures. In the presence
of seizures, the drug should be discontinued.
Potential for Gastrointestinal
Because the Concerta® tablet is nondeformable and does not appreciably
change in shape in the GI tract, Concerta® should ordinarily not be administered
to patients with preexisting severe gastrointestinal narrowing (pathologic
or iatrogenic, for example: small bowel inflammatory disease, "short gut"
syndrome due to adhesions or decreased transit time, past history of peritonitis,
cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum).
There have been rare reports of obstructive symptoms in patients with
known strictures in association with the ingestion of other drugs in nondeformable
controlled-release formulations. Due to the controlled-release design
of the tablet, Concerta® should only be used in patients who are able
to swallow the tablet whole (see PRECAUTIONS: Information for Patients).
Hypertension and other Cardiovascular
Use cautiously in patients with hypertension. Blood pressure should be
monitored at appropriate intervals in patients taking Concerta®, especially
patients with hypertension. In the laboratory classroom clinical trials
(Studies 1 and 2), both Concerta® and methylphenidate tid increased resting
pulse by an average of 2-6 bpm and produced average increases of systolic
and diastolic blood pressure of roughly 1-4 mm Hg during the day, relative
to placebo. Therefore, caution is indicated in treating patients whose
underlying medical conditions might be compromised by increases in blood
pressure or heart rate, e.g., those with preexisting hypertension, heart
failure, recent myocardial infarction, or hyperthyroidism.
Symptoms of visual disturbances have been encountered in rare cases. Difficulties
with accommodation and blurring of vision have been reported.
Use in Children Under Six
Years of Age
Concerta® should not be used in children under six years, since safety
and efficacy in this age group have not been established.
Concerta® should be given cautiously to patients with a history of
drug dependence or alcoholism. Chronic abusive use can lead to marked
tolerance and psychological dependence with varying degrees of abnormal
behavior. Frank psychotic episodes can occur, especially with parenteral
abuse. Careful supervision is required during withdrawal from abusive
use since severe depression may occur. Withdrawal following chronic
therapeutic use may unmask symptoms of the underlying disorder that
may require follow-up.
Periodic CBC, differential, and platelet counts are advised during prolonged
Information for Patients
Patients should be informed that Concerta® should be swallowed whole with
the aid of liquids. Tablets should not be chewed, divided, or crushed.
The medication is contained within a nonabsorbable shell designed to release
the drug at a controlled rate. The tablet shell, along with insoluble
core components, is eliminated from the body; patients should not be concerned
if they occasionally notice in their stool something that looks like a
Patient information is printed
at the end of this insert. To assure safe and effective use of Concerta®,
the information and instructions provided in the patient information section
should be discussed with patients.
Because of possible effects on blood pressure, Concerta® should be used
cautiously with pressor agents.
Human pharmacologic studies
have shown that methylphenidate may inhibit the metabolism of coumarin
anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone),
and some antidepressants (tricyclics and selective serotonin reuptake
inhibitors). Downward dose adjustment of these drugs may be required when
given concomitantly with methylphenidate. It may be necessary to adjust
the dosage and monitor plasma drug concentrations (or, in the case of
coumarin, coagulation times), when initiating or discontinuing concomitant
Serious adverse events have
been reported in concomitant use with clonidine, although no causality
for the combination has been established. The safety of using methylphenidate
in combination with clonidine or other centrally acting alpha-2 agonists
has not been systematically evaluated.
and Impairment of Fertility
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate
caused an increase in hepatocellular adenomas and, in males only, an increase
in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This
dose is approximately 30 times and 4 times the maximum recommended human
dose of Concerta® on a mg/kg and mg/m2 basis, respectively. Hepatoblastoma
is a relatively rare rodent malignant tumor type. There was no increase
in total malignant hepatic tumors. The mouse strain used is sensitive
to the development of hepatic tumors, and the significance of these results
to humans is unknown.
Methylphenidate did not cause
any increases in tumors in a lifetime carcinogenicity study carried out
in F344 rats; the highest dose used was approximately 45 mg/kg/day, which
is approximately 22 times and 5 times the maximum recommended human dose
on a mg/kg and mg/m2 basis, respectively.
In a 24-week carcinogenicity
study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic
carcinogens, there was no evidence of carcinogenicity. Male and female
mice were fed diets containing the same concentration of methylphenidate
as in the lifetime carcinogenicity study; the high-dose groups were exposed
to 60 to 74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic
in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma
cell forward mutation assay. Sister chromatid exchanges and chromosome
aberrations were increased, indicative of a weak clastogenic response,
in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate
was negative in vivo in males and females in the mouse bone marrow micronucleus
Methylphenidate did not impair
fertility in male or female mice that were fed diets containing the drug
in an 18-week Continuous Breeding study. The study was conducted at doses
up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended
human dose of Concerta® on a mg/kg and mg/m2 basis, respectively.
Pregnancy: Teratogenic Effects
Pregnancy Category C: Methylphenidate has been shown to
have teratogenic effects in rabbits when given in doses of 200 mg/kg/day,
which is approximately 100 times and 40 times the maximum recommended
human dose on a mg/kg and mg/m2 basis, respectively.
A reproduction study in rats
revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day,
approximately 15-fold and 3-fold the maximum recommended human dose of
Concerta® on a mg/kg and mg/m2 basis, respectively. The approximate plasma
exposure to methylphenidate plus its main metabolite PPA in pregnant rats
was 2 times that seen in trials in volunteers and patients with the maximum
recommended dose of Concerta® based on the AUC.
There are no adequate and well-controlled
studies in pregnant women. Concerta® should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
It is not known whether methylphenidate is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised if
Concerta® is administered to a nursing woman.
The safety and efficacy of Concerta® in children under 6 years old have
not been established. Long-term effects of methylphenidate in children
have not been well established (see WARNINGS).
The premarketing development program for Concerta® included exposures
in a total of 755 participants in clinical trials (469 patients, 286 healthy
adult subjects). These participants received Concerta® 18, 36, and/or
54 mg/day. The 469 patients (ages 6 to 13) were evaluated in three controlled
clinical studies (Studies 1, 2, and 3), two uncontrolled clinical studies
(including a long-term safety study), and one clinical pharmacology study
in children with ADHD. Of the 469 patients in this program, 68 Concerta®-treated
patients in one uncontrolled dose-initiation study were naïve to any pharmacologic
therapy for their ADHD. Safety data on all patients are included in the
discussion that follows. Adverse reactions were assessed by collecting
adverse events, results of physical examinations, vital signs, weights,
laboratory analyses, and ECGs.
Adverse events during exposure
were obtained primarily by general inquiry and recorded by clinical investigators
using terminology of their own choosing. Consequently, it is not possible
to provide a meaningful estimate of the proportion of individuals experiencing
adverse events without first grouping similar types of events into a smaller
number of standardized event categories. In the tables and listings that
follow, COSTART terminology has been used to classify reported adverse
The stated frequencies of adverse
events represent the proportion of individuals who experienced, at least
once, a treatment-emergent adverse event of the type listed. An event
was considered treatment emergent if it occurred for the first time or
worsened while receiving therapy following baseline evaluation.
Adverse Findings in Clinical
Trials with Concerta®
Adverse Events Associated with Discontinuation of Treatment
In the 4-week placebo-controlled, parallel-group trial one Concerta®-treated
patient (0.9%; 1/106) and one placebo-treated patient (1.0%; 1/99) discontinued
due to an adverse event (sadness and increase in tics, respectively).
In uncontrolled studies up
to 12 months with Concerta®, 6.6% (29/441) patients discontinued for adverse
events. Those events associated with discontinuation of Concerta® in more
than one patient included the following: twitching (tics, 1.8%); anorexia
(loss of appetite, 0.9%); aggravation reaction (0.7%); hostility (0.7%);
insomnia (0.7%); and somnolence (0.5%).
Adverse Events Occurring
at an Incidence of 1% or more Among Concerta®-Treated Patients
Table 2 enumerates, for a 4-week placebo-controlled, parallel-group trial
in children with ADHD at Concerta® doses of 18, 36, or 54 mg/day, the
incidence of treatment-emergent adverse events. The table includes only
those events that occurred in 1% or more of patients treated with Concerta®
where the incidence in patients treated with Concerta® was greater than
the incidence in placebo-treated patients.
The prescriber should be aware
that these figures cannot be used to predict the incidence of adverse
events in the course of usual medical practice where patient characteristics
and other factors differ from those which prevailed in the clinical trials.
Similarly, the cited frequencies cannot be compared with figures obtained
from other clinical investigations involving different treatments, uses,
and investigators. The cited figures, however, do provide the prescribing
physician with some basis for estimating the relative contribution of
drug and non-drug factors to the adverse event incidence rate in the population