Metadate CD, Page 1

Metadate CD (methylphenidate HCl, USP) Extended-Release Capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The efficacy of Metadate CD in the treatment of ADHD was established in one controlled trial.

METADATE CD — methylphenidate hydrochloride capsule, extended release
Physicians Total Care, Inc.

Once Daily

DESCRIPTION

METADATE CD is a central nervous system (CNS) stimulant. The extended-release capsules comprise both immediate-release (IR) and extended-release (ER) beads such that 30% of the dose is provided by the IR component and 70% of the dose is provided by the ER component. METADATE CD is available in six capsule strengths containing 10 mg (3 mg IR; 7 mg ER), 20 mg (6 mg IR; 14 mg ER), 30 mg (9 mg IR; 21 mg ER), 40 mg (12 mg IR; 28 mg ER), 50 mg (15 mg IR; 35 mg ER), or 60 mg (18 mg IR; 42 mg ER) of methylphenidate hydrochloride for oral administration.

Chemically, methylphenidate HCl is d,l (racemic)-threo-methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C14H19NO2•HCl. Its structural formula is:

Chemical Structure

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 269.77.

METADATE CD also contains the following inert ingredients: Sugar spheres, povidone, hydroxypropylmethylcellulose and polyethylene glycol, ethylcellulose aqueous dispersion, dibutyl sebacate, gelatin, and titanium dioxide.

The individual capsules contain the following color agents:

10 mg capsules: FD&C Blue No. 2, FDA/E172 Yellow Iron Oxide
20 mg capsules: FD&C Blue No. 2
30 mg capsules: FD&C Blue No. 2, FDA/E172 Red Iron Oxide
40 mg capsules: FDA/E172 Yellow Iron Oxide
50 mg capsules: FD&C Blue No. 2, FDA/E172 Red Iron Oxide

CLINICAL PHARMACOLOGY

Pharmacodynamics

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-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer.

Pharmacokinetics

The pharmacokinetics of the METADATE CD methylphenidate hydrochloride formulation have been studied in healthy adult volunteers and in children with Attention Deficit Hyperactivity Disorder (ADHD).

Absorption And Distribution

Methylphenidate is readily absorbed. METADATE CD has a plasma/time concentration profile showing two phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet, and a second rising portion approximately three hours later, followed by a gradual decline. (See Figure 1 below.)

Comparison Of Immediate Release (IR) And METADATE CD Formulations After Repeated Doses Of Methylphenidate HCl In Children With ADHD

METADATE CD was administered as repeated once-daily doses of 20 mg or 40 mg to children aged 7-12 years with ADHD for one week. After a dose of 20 mg, the mean (±SD) early Cmax was 8.6 (±2.2) ng/mL, the later Cmax was 10.9 (±3.9)* ng/mL and AUC0-9h was 63.0 (±16.8) ng•h/mL. The corresponding values after a 40 mg dose were 16.8 (±5.1) ng/mL, 15.1 (±5.8)* ng/mL and 120 (±39.6) ng•h/mL, respectively. The early peak concentrations (median) were reached about 1.5 hours after dose intake, and the second peak concentrations (median) were reached about 4.5 hours after dose intake. The means for Cmax and AUC following a dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at 0 and 4 hours.

*25-30% of the subjects had only one observed peak (Cmax) concentration of methylphenidate.

Figure
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Dose Proportionality

Following single oral doses of 10-60 mg methylphenidate free base as a solution given to ten healthy male volunteers, Cmax and AUC increased proportionally with increasing doses. After the 60 mg dose, tmax was reached 1.5 hours post-dose, with a mean Cmax of 31.8 ng/mL (range 24.7-40.9 ng/mL).

Following one week of repeated once-daily doses of 20 mg or 40 mg METADATE CD to children aged 7-12 years with ADHD, Cmax and AUC were proportional to the administered dose.

Food Effects

In a study in adult volunteers to investigate the effects of a high-fat meal on the bioavailability of a dose of 40 mg, the presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay). The plasma levels rose rapidly following the food-induced delay in absorption. Overall, a high-fat meal increased the Cmax of METADATE CD by about 30% and AUC by about 17%, on average (see DOSAGE and ADMINISTRATION).

After a single dose, the bioavailability (Cmax and AUC) of methylphenidate in 26 healthy adults was unaffected by sprinkling the capsule contents on applesauce as compared to the intact capsule. This finding demonstrates that a 20 mg METADATE CD Capsule, when opened and sprinkled on one tablespoon of applesauce, is bioequivalent to the intact capsule.

Metabolism And Excretion

In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid). The metabolite has little or no pharmacologic activity.

In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes, and did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations.

The mean terminal half-life (t½) of methylphenidate following administration of METADATE CD (t½=6.8h) is longer than the mean terminal (t½) following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9h) and methylphenidate hydrochloride sustained-release tablets (t½=3.4h) in healthy adult volunteers. This suggests that the elimination process observed for METADATE CD is controlled by the release rate of methylphenidate from the extended-release formulation, and that the drug absorption is the rate-limiting process.

Special Populations

Gender

The pharmacokinetics of methylphenidate after a single dose of METADATE CD were similar between adult men and women.

Race

The influence of race on the pharmacokinetics of methylphenidate after METADATE CD administration has not been studied.

Age

The pharmacokinetics of methylphenidate after METADATE CD administration have not been studied in children less than 6 years of age.

Renal Insufficiency

There is no experience with the use of METADATE CD 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 ritalinic acid. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of METADATE CD.

Hepatic Insufficiency

There is no experience with the use of METADATE CD in patients with hepatic insufficiency.

CLINICAL STUDIES

METADATE CD was evaluated in a double-blind, parallel-group, placebo-controlled trial in which 321 untreated or previously treated pediatric patients with a DSM-IV diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), 6 to 15 years of age, received a single morning dose for up to 3 weeks. Patients were required to have the combined or predominantly hyperactive-impulsive subtype of ADHD; patients with the predominantly inattentive subtype were excluded. Patients randomized to the METADATE CD group received 20 mg daily for the first week. Their dosage could be increased weekly to a maximum of 60 mg by the third week, depending on individual response to treatment.

The patient’s regular school teacher completed the teachers’ version of the Conners’ Global Index Scale (TCGIS), a scale for assessing ADHD symptoms, in the morning and again in the afternoon on three alternate days of each treatment week. The change from baseline of the overall average (i.e., an average of morning and afternoon scores over 3 days) of the total TCGIS scores during the last week of treatment was analyzed as the primary efficacy parameter. Patients treated with METADATE CD showed a statistically significant improvement in symptom scores from baseline over patients who received placebo. (See Figure 2.) Separate analyses of TCGIS scores in the morning and afternoon revealed superiority in improvement with METADATE CD over placebo during both time periods. (See Figure 3.) This demonstrates that a single morning dose of METADATE CD exerts a treatment effect in both the morning and the afternoon.

Figure
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Figure
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INDICATION AND USAGE

Attention Deficit Hyperactivity Disorder (ADHD)

METADATE CD (methylphenidate HCl, USP) Extended-Release Capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

The efficacy of METADATE CD in the treatment of ADHD was established in one controlled trial of children aged 6 to 15 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 Program

METADATE CD 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 METADATE CD for long-term use, i.e., for more than 3 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use METADATE CD for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE and ADMINISTRATION).

CONTRAINDICATIONS

Agitation

METADATE CD is contraindicated in patients with marked anxiety, tension and agitation, since the drug may aggravate these symptoms.

Hypersensitivity To Methylphenidate Or Other Excipients

METADATE CD is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product.

METADATE CD contains sucrose. Therefore, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine.

Glaucoma

METADATE CD is contraindicated in patients with glaucoma.

Tics

METADATE CD is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome (see ADVERSE REACTIONS).

Monoamine Oxidase Inhibitors

METADATE CD 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).

Hypertension And Other Cardiovascular Conditions

METADATE CD is contraindicated in patients with severe hypertension, angina pectoris, cardiac arrhythmias, heart failure, recent myocardial infarction, hyperthyroidism or thyrotoxicosis (see WARNINGS).

Halogenated Anesthetics

There is a risk of sudden blood pressure increase during surgery. If surgery is planned, METADATE CD should not be taken on the day of the surgery.

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 (see CONTRAINDICATIONS).

Adults

Sudden deaths, 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 (see CONTRAINDICATIONS).

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 (see CONTRAINDICATIONS).

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 symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

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