Ritalin LA®
(methylphenidate hydrochloride)
extended-release capsules
Rx only
Prescribing Information
DESCRIPTION
Methylphenidate hydrochloride is a central nervous system (CNS) stimulant.
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is an extended-release
formulation of methylphenidate with a bi-modal release profile. Ritalin LA® uses the proprietary
SODAS® (Spheroidal Oral Drug Absorption System) technology. Each bead-filled Ritalin LA capsule
contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads,
thus providing an immediate release of methylphenidate and a second delayed release of
methylphenidate. Ritalin LA 10, 20, 30, and 40 mg capsules provide in a single dose the same amount
of methylphenidate as dosages of 5, 10, 15, or 20 mg of Ritalin® tablets given b.i.d.
The active substance in Ritalin LA is methyl α-phenyl-2-piperidineacetate hydrochloride, and its
structural formula is
Methylphenidate hydrochloride USP is a white, odorless, fine 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 269.77.
Inactive ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules
only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules
only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg
capsules only).
CLINICAL PHARMACOLOGY
Pharmacodynamics
Methylphenidate hydrochloride, the active ingredient in Ritalin LA® (methylphenidate hydrochloride)
extended-release capsules, 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
Reference ID: 3321241
release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture
comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active
than the l-threo enantiomer.
Pharmacokinetics
Absorption
Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks
approximately four hours apart) when orally administered to children diagnosed with ADHD and to
healthy adults. The initial rate of absorption for Ritalin LA is similar to that of Ritalin tablets as shown
by the similar rate parameters between the two formulations, i.e., initial lag time (Tlag), first peak
concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1-3 hours. The mean time
to the interpeak minimum (Tminip), and time to the second peak (Tmax2) are also similar for Ritalin LA
given once daily and Ritalin tablets given in two doses 4 hours apart (see Figure 1 and Table 1),
although the ranges observed are greater for Ritalin LA.
Ritalin LA given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak
minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin tablets given in
two doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the
delayed-release beads (see Figure 1 and Table 1).
The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of
Ritalin tablets given in two doses 4 hours apart in both children and in adults.
Figure 1. Mean plasma concentration time-profile of methylphenidate after a single dose of
Ritalin LA® 40 mg q.d. and Ritalin® 20 mg given in two doses four hours apart
Table 1. Mean ± SD and range of pharmacokinetic parameters of methylphenidate after a single
dose of Ritalin LA® and Ritalin® given in two doses 4 hours apart
Population Children Adult Males
Formulation Ritalin® Ritalin LA® Ritalin® Ritalin LA®
Dose 10 mg & 10 mg 20 mg 10 mg & 10 mg 20 mg
N 21 18 9 8
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Tlag (h) 0.24 ± 0.44 0.28 ± 0.46 1.0 ± 0.5 0.7 ± 0.2
0 - 1 0 - 1 0.7 - 1.3 0.3 - 1.0
Tmax1 (h) 1.8 ± 0.6 2.0 ± 0.8 1.9 ± 0.4 2.0 ± 0.9
1 - 3 1 - 3 1.3 - 2.7 1.3 - 4.0
Cmax1 (ng/mL) 10.2 ± 4.2 10.3 ± 5.1 4.3 ± 2.3 5.3 ± 0.9
4.2 - 20.2 5.5 - 26.6 1.8 - 7.5 3.8 - 6.9
Tminip (h) 4.0 ± 0.2 4.5 ± 1.2 3.8 ± 0.4 3.6 ± 0.6
4 - 5 2 - 6 3.3 - 4.3 2.7 - 4.3
Cminip (ng/mL) 5.8 ± 2.7 6.1 ± 4.1 1.2 ± 1.4 3.0 ± 0.8
3.1 - 14.4 2.9 - 21.0 0.0 - 3.7 1.7 - 4.0
Tmax2 (h) 5.6 ± 0.7 6.6 ± 1.5 5.9 ± 0.5 5.5 ± 0.8
5 - 8 5 - 11 5.0 - 6.5 4.3 - 6.5
Cmax2 (ng/mL) 15.3 ± 7.0 10.2 ± 5.9 5.3 ± 1.4 6.2 ± 1.6
6.2 - 32.8 4.5 - 31.1 3.6 - 7.2 3.9 - 8.3
AUC(0-∞) 102.4 ± 54.6 86.6 ± 64.0a 37.8 ± 21.9 45.8 ± 10.0
(ng/mL x h-1) 40.5 - 261.6 43.3 - 301.44 14.3 - 85.3 34.0 - 61.6
t1/2 (h) 2.5 ± 0.8 2.4 ± 0.7a 3.5 ± 1.9 3.3 ± 0.4
1.8 - 5.3 1.5 - 4.0 1.3 - 7.7 3.0 - 4.2
a N = 15
Dose Proportionality
After oral administration of Ritalin LA 20 mg and 40 mg capsules to adults there is a slight upward
trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and
Cmax2).
Distribution
Binding to plasma proteins is low (10%-33%). The volume of distribution was 2.65±1.11 L/kg for d
methylphenidate and 1.80±0.91 L/kg for l-methylphenidate.
Metabolism
The absolute oral bioavailability of methylphenidate in children was 22±8% for d-methylphenidate and
5±3% for l-methylphenidate, suggesting pronounced presystemic metabolism. Biotransformation of
methylphenidate by the carboxylesterase CES1A1 is rapid and extensive leading to the main, de
esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid). Only small amounts of
hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in
plasma. Therapeutic activity is principally due to the parent compound.
Elimination
In studies with Ritalin LA and Ritalin tablets in adults, methylphenidate from Ritalin tablets is
eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 - 7.7 hours). In children
the average half-life is about 2.5 hours, with a range of about 1.5 - 5.0 hours. The rapid half-life in both
children and adults may result in unmeasurable concentrations between the morning and mid-day doses
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with Ritalin tablets. No accumulation of methylphenidate is expected following multiple once a day
oral dosing with Ritalin LA. The half-life of ritalinic acid is about 3-4 hours.
The systemic clearance is 0.40±0.12 L/h/kg for d-methylphenidate and 0.73±0.28 L/h/kg for l
methylphenidate. After oral administration of an immediate release formulation of methylphenidate,
78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within
48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of
the dose is excreted in the urine as ritalinic acid (60%-86%), the remainder being accounted for by
minor metabolites.
Food Effects
Administration times relative to meals and meal composition may need to be individually titrated.
When Ritalin LA was administered with a high fat breakfast to adults, Ritalin LA had a longer lag time
until absorption began and variable delays in the time until the first peak concentration, the time until
the interpeak minimum, and the time until the second peak. The first peak concentration and the extent
of absorption were unchanged after food relative to the fasting state, although the second peak was
approximately 25% lower. The effect of a high fat lunch was not examined.
There were no differences in the pharmacokinetics of Ritalin LA when administered with applesauce,
compared to administration in the fasting condition. There is no evidence of dose dumping in the
presence or absence of food.
For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and
administered (see DOSAGE AND ADMINISTRATION).
Alcohol Effect
Alcohol may exacerbate the adverse CNS effects of psychoactive drugs, including Ritalin. It is
therefore advisable for patients to abstain from alcohol during treatment. An in vitro study was
conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the
Ritalin LA® 40 mg capsule dosage form. At an alcohol concentration of 40% there was a 98% release
of methylphenidate in the first hour. The results with the 40 mg capsule are considered to be
representative of the other available capsule strengths.
Special Populations
Age: The pharmacokinetics of Ritalin LA was examined in 18 children with ADHD between 7 and 12
years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between
peak minimum, and the time until the second peak were delayed and more variable in children
compared to adults. After a 20-mg dose of Ritalin LA, concentrations in children were approximately
twice the concentrations observed in 18 to 35 year old adults. This higher exposure is almost
completely due to the smaller body size and total volume of distribution in children, as apparent
clearance normalized to body weight is independent of age.
Gender: There were no apparent gender differences in the pharmacokinetics of methylphenidate
between healthy male and female adults when administered Ritalin LA.
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Renal Insufficiency: Ritalin LA has not been studied in renally-impaired patients. Renal insufficiency
is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a
radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic
acid), has little or no pharmacologic activity.
Hepatic Insufficiency: Ritalin LA has not been studied in patients with hepatic insufficiency. Hepatic
insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is
metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely
distributed throughout the body.
CLINICAL STUDIES
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules was evaluated in a
randomized, double-blind, placebo-controlled, parallel group clinical study in which 134 children, ages
6 to 12, with DSM-IV diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) received a single
morning dose of Ritalin LA in the range of 10-40 mg/day, or placebo, for up to 2 weeks. The doses
used were the optimal doses established in a previous individual dose titration phase. In that titration
phase, 53 of 164 patients (32%) started on a daily dose of 10 mg and 111 of 164 patients (68%) started
on a daily dose of 20 mg or higher. The patient’s regular schoolteacher completed the Conners
ADHD/DSM-IV Scale for Teachers (CADS-T) at baseline and the end of each week. The CADS-T
assesses symptoms of hyperactivity and inattention. The change from baseline of the (CADS-T) scores
during the last week of treatment was analyzed as the primary efficacy parameter. Patients treated with
Ritalin LA showed a statistically significant improvement in symptom scores from baseline over
patients who received placebo. (See Figure 2.) This demonstrates that a single morning dose of Ritalin
LA exerts a treatment effect in ADHD.
Figure 2. CADS-T total subscale - Mean change from baseline*
INDICATIONS AND USAGE
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is indicated for the treatment
of Attention Deficit Hyperactivity Disorder (ADHD).
The efficacy of Ritalin LA in the treatment of ADHD was established in one controlled trial 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.
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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 Program
Ritalin LA 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.
Long-Term Use
The effectiveness of Ritalin LA for long-term use, i.e., for more than 2 weeks, has not been
systematically evaluated in controlled trials. Therefore, the physician who elects to use Ritalin LA for
extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual
patient (see DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS
Agitation
Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is contraindicated in marked
anxiety, tension, and agitation, since the drug may aggravate these symptoms.
Hypersensitivity to Methylphenidate
Ritalin LA is contraindicated in patients known to be hypersensitive to methylphenidate or other
components of the product.
Glaucoma
Ritalin LA is contraindicated in patients with glaucoma.
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Tics
Ritalin LA is contraindicated in patients with motor tics or with a family history or diagnosis of
Tourette’s syndrome. (See ADVERSE REACTIONS.)
Monoamine Oxidase Inhibitors
Ritalin LA is contraindicated during treatment with monoamine oxidase inhibitors, and also within a
minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor
(hypertensive crises may result).
WARNINGS
Serious Cardiovascular Events
Sudden Death and Pre-Existing Structural Cardiac Abnormalities or Other Serious Heart Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses in children
and adolescents with structural cardiac abnormalities or other serious heart problems. Although some
serious heart problems alone carry an increased risk of sudden death, stimulant products generally
should not be used in children or adolescents with known serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place
them at increased vulnerability to the sympathomimetic effects of a stimulant drug.
Adults
Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at
usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults
have a greater likelihood than children of having serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac
problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.
Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2-4 mmHg) and
average heart rate (about 3-6 bpm), and individuals may have larger increases. While the mean changes
alone would not be expected to have short-term consequences, all patients should be monitored for
larger changes in heart rate and blood pressure. 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 pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular
arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications
Children, adolescents, or adults who are being considered for treatment with stimulant medications
should have a careful history (including assessment for a family history of sudden death or ventricular
arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further
cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram).
Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other
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symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac
evaluation.
Psychiatric Adverse Events
Pre-Existing Psychosis
Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder
in patients with a pre-existing psychotic disorder.
Bipolar Illness
Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar
disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to
initiating treatment with a stimulant, patients with comorbid depressive symptoms should be
adequately screened to determine if they are at risk for bipolar disorder; such screening should include
a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
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