Metadate CD (Methylphenidate) - Description and Clinical Pharmacology

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Metadate CD™
(methylphenidate HCl, USP)
Extended-Release Capsules
CII

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:

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 C_max was 8.6 (±2.2) ng/mL, the later C_max was 10.9 (±3.9)* ng/mL and AUC_0-9h 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 C_max 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 (C_max) concentration of methylphenidate.

Dose Proportionality

Following single oral doses of 10-60 mg methylphenidate free base as a solution given to ten healthy male volunteers, C_max and AUC increased proportionally with increasing doses. After the 60 mg dose, t_max was reached 1.5 hours post-dose, with a mean C_max 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, C_max 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 C_max of METADATE CD by about 30% and AUC by about 17%, on average (see DOSAGE and ADMINISTRATION).

After a single dose, the bioavailability (C_max 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 (t_½) of methylphenidate following administration of METADATE CD (t_½=6.8h) is longer than the mean terminal (t_½) following administration of methylphenidate hydrochloride immediate-release tablets (t_½=2.9h) and methylphenidate hydrochloride sustained-release tablets (t_½=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.