Methylphenidate Hydrochloride

METHYLPHENIDATE HYDROCHLORIDE- methylphenidate hydrochloride capsule, extended release
Amneal Pharmaceuticals of New York LLC

DESCRIPTION

Methylphenidate hydrochloride extended-release capsules are a central nervous system (CNS) stimulant. The extended-release capsules comprise beads each with both immediate-release (IR) and extended-release (ER) components such that 30% of the dose is provided by the IR component and 70% of the dose is provided by the ER component. Methylphenidate hydrochloride extended-release capsules are available in six 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 hydrochloride is d ,l (racemic)-threo -methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C14 H19 NO2 •HCl. Its structural formula is:

The chemical structure for methylphenidate HCl
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Methylphenidate hydrochloride, 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.

Methylphenidate hydrochloride extended-release capsules also contain the following inert ingredients: Sugar spheres, povidone, hydroxypropylmethylcellulose and polyethylene glycol, ethyl cellulose, cetyl alcohol, sodium lauryl sulfate, 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: D&C Red No. 28, FD&C Blue No. 1, FD&C Green No. 3
30 mg capsules: FDA/E172 Black Iron Oxide, FDA/E172 Red Iron Oxide, FDA/E172 Yellow
Iron Oxide
40 mg capsules: D&C Yellow No. 10, FD&C Red No. 4050 mg capsules: D&C Red No. 28, FD&C Green No. 3, FDA/E172 Black Iron Oxide

CLINICAL PHARMACOLOGY

Pharmacodynamics

Methylphenidate hydrochloride 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 methylphenidate hydrochloride extended-release capsule 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. Methylphenidate hydrochloride extended-release capsules have 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 Methylphenidate Hydrochloride Extended-release Capsules Formulations after Repeated Doses of Methylphenidate Hydrochloride in Children with ADHD

Methylphenidate hydrochloride extended-release capsules were administered as repeated once-daily doses of 20 mg or 40 mg to children aged 7 to 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% to 30% of the subjects had only one observed peak (Cmax ) concentration of methylphenidate.

FIGURE 1: Comparison of Immediate Release (IR) and Methylphenidate Hydrochloride Extended-release Capsule Formulations After Repeated Doses of Methylphenidate Hydrochloride in Children with ADHD

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Dose Proportionality

Following single oral doses of 10 mg to 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 ng/mL to 40.9 ng/mL).

Following one week of repeated once-daily doses of 20 mg or 40 mg methylphenidate hydrochloride extended-release capsules to children aged 7 to 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 methylphenidate hydrochloride extended-release capsules 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 methylphenidate hydrochloride extended-release 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 methylphenidate hydrochloride extended-release capsules (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 methylphenidate hydrochloride extended-release capsules is controlled by the release rate of methylphenidate from the extended-release formulation, and that the drug absorption is the rate-limiting process.

Alcohol Effect

An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hydrochloride extended-release 60 mg capsule dosage form. At an alcohol concentration of 40% there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths. Patients should be advised to avoid alcohol while taking methylphenidate hydrochloride extended-release capsules.

Special Populations

Gender

The pharmacokinetics of methylphenidate after a single-dose of methylphenidate hydrochloride extended-release capsules were similar between adult men and women.

Race

The influence of race on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride extended-release capsules administration has not been studied.

Age

The pharmacokinetics of methylphenidate after methylphenidate hydrochloride extended-release capsules administration have not been studied in children less than 6 years of age.

Renal Insufficiency

There is no experience with the use of methylphenidate hydrochloride extended-release capsules 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 methylphenidate hydrochloride extended-release capsules.

Hepatic Insufficiency

There is no experience with the use of methylphenidate hydrochloride extended-release capsules in patients with hepatic insufficiency.

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