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Focalin XR (Dexmethylphenidate Hydrochloride) - Description and Clinical Pharmacology

 
 



. DESCRIPTION

Focalin XR is an extended-release formulation of dexmethylphenidate with a bi-modal release profile. Focalin XR uses the proprietary SODAS (Spheroidal Oral Drug Absorption System) technology. Each bead-filled Focalin XR capsule contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of dexmethylphenidate and a second delayed release of dexmethylphenidate. Focalin XR is available as 5, 10, 15, and 20 mg extended-release capsules. Focalin XR 5, 10, 15, and 20 mg extended-release capsules provide in a single dose the same amount of dexmethylphenidate as dosages of 2.5, 5, 7.5 or 10 mg of Focalin given b.i.d. as tablets.

Dexmethylphenidate hydrochloride, the d-threo enantiomer of racemic methylphenidate hydrochloride, is a central nervous system (CNS) stimulant.

Dexmethylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, (R,R’)-(+)-. Its empirical formula is C14H19NO2•HCl. Its molecular weight is 269.77 and its structural formula is

Note* = asymmetric carbon center

Dexmethylphenidate hydrochloride is a white to off white 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.

Inactive ingredients: ammonio methacrylate copolymer, FD&C Blue #2 (5 mg and 15 mg strengths), FDA/E172 yellow iron oxide (10 mg and 15 mg strengths), gelatin, ink Tan SW-8010, methacrylic acid copolymer, polyethylene glycol, sugar spheres, talc, titanium dioxide, and triethyl citrate.

. CLINICAL PHARMACOLOGY

  Mechanism of Action

Dexmethylphenidate hydrochloride, the active ingredient in Focalin XR, is a central nervous system stimulant. Dexmethylphenidate, the more pharmacologically active d -enantiomer of racemic 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. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.

Pharmacokinetics

Absorption

Focalin XR produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks approximately 4 hours apart) when orally administered to healthy adults. The initial rate of absorption for Focalin XR is similar to that of Focalin tablets as shown by the similar rate parameters between the two formulations, i.e., first peak concentration (Cmax1), and time to the first peak (tmax1), which is reached in 1 ½ hours (typical range 1-4 hours). The mean time to the interpeak minimum (tminip) is slightly shorter, and time to the second peak (tmax2) is slightly longer for Focalin XR given once daily (about 6.5 hours, range 4.5-7 hours) compared to Focalin tablets given in two doses 4 hours apart (see Figure 1), although the ranges observed are greater for Focalin XR.

Focalin XR given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than Focalin 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).

The AUC (exposure) after administration of Focalin XR given once daily is equivalent to the same total dose of Focalin tablets given in two doses 4 hours apart. The variability in Cmax, Cmin, and AUC is similar between Focalin XR and Focalin IR with approximately a three-fold range in each.

Radiolabeled racemic methylphenidate is well absorbed after oral administration with approximately 90% of the radioactivity recovered in urine. However, due to first pass metabolism the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22-25%.

Figure 1.      	Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration of 1 x 20 mg Focalin XR (n=24) Capsules and 2 x 10 mg Focalin Immediate-Release Tablets (n=25)

Figure 1.      Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration of 1 x 20 mg Focalin XR (n=24) Capsules and 2 x 10 mg Focalin Immediate-Release Tablets (n=25)

Dose Proportionality

Dose proportionality of Focalin XR was evaluated in a randomized, single-dose, five-period, cross-over study with administration of single doses of 5, 10, 20, 30 and 40 mg to healthy adults. Results confirmed dose proportionality within this dose range.

Food Effects  

Administration times relative to meals and meal composition may need to be individually titrated.

No food effect study was performed with Focalin XR. However, the effect of food has been studied in adults with racemic methylphenidate in the same type of extended-release formulation. The findings of that study are considered applicable to Focalin XR. After a high fat breakfast, there was 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 is no evidence of dose dumping in the presence or absence of food. There were no differences in the plasma concentration-time profile, when administered with applesauce, compared to administration in the fasting condition. The results are expected not to differ for Focalin XR.

For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered [ see Dosage a nd Administration   (2) ].

Distribution

The plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12-15%, independent of concentration. Dexmethylphenidate shows a volume of distribution of 2.65±1.11 L/kg. Plasma dexmethylphenidate concentrations decline monophasically following oral administration of Focalin XR.

Metabolism and Excretion

In humans, dexmethylphenidate is metabolized primarily to d-α -phenyl-piperidine acetic acid (also known as d -ritalinic acid) by de-esterification. This metabolite has little or no pharmacological activity. There is no in vivo interconversion to the l-threo -enantiomer, based on a finding of no levels of l-threo -methylphenidate being detectable after administration of up to 40 mg dexmethylphenidate in adults. After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic (d,l -) methylphenidate was d,l -ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose.

In vitro studies showed that dexmethylphenidate did not inhibit cytochrome P450 isoenzymes at concentrations observed after therapeutic doses.

Intravenous dexmethylphenidate was eliminated with a mean clearance of 0.40±0.12 L/kg.h-1 corresponding to 0.56±0.18 L/min. The mean terminal elimination half-life of dexmethylphenidate was just over 3 hours in healthy adults and typically varied between 2 and 4.5 hours with an occasional subject exhibiting a terminal half-life between 5 and 7 hours. Children tend to have slightly shorter half-lives with means of 2–3 hours.

Special Populations

Gender

After administration of Focalin XR the first peak, (Cmax1), was on average 45% higher in women. The interpeak minimum and the second peak also tended to be slightly higher in women although the difference was not statistically significant, and these patterns remained even after weight normalization. Pharmacokinetic parameters for dexmethylphenidate after Focalin immediate-release tablets were similar for boys and girls.

Race

There is insufficient experience with the use of Focalin XR to detect ethnic variations in pharmacokinetics.

Age

The pharmacokinetics of dexmethylphenidate after Focalin XR administration have not been studied in children less than 18 years of age. When a similar formulation of racemic methylphenidate was examined in 15 children between 10 and 12 years of age and 3 children with ADHD between 7 and 9 years of age, the time to the first peak was similar, although 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 administration of the same dose to children and adults, concentrations in children were approximately twice the concentrations observed in adults. This higher exposure is almost completely due to smaller body size as no relevant age-related differences in dexmethylphenidate pharmacokinetic parameters (i.e., clearance and volume of distribution) are observed after normalization to dose and weight.

Renal Insufficiency

There is no experience with the use of Focalin XR in patients with renal insufficiency. After oral administration of radiolabeled racemic methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of racemic ritalinic acid which is pharmacologically inactive. Very little unchanged drug is excreted in the urine, thus renal insufficiency is expected to have little effect on the pharmacokinetics of Focalin XR.

Hepatic Insufficienc y

There is no experience with the use of Focalin XR in patients with hepatic insufficiency (see Drug Interactions (7)].

. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies have not been carried out with dexmethylphenidate. In a lifetime carcinogenicity study carried out in B6C3F1 mice, racemic 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. 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.

Racemic methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day.

In a 24-week study of racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Mice were fed diets containing the same concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60-74 mg/kg/day of racemic methylphenidate.

Mutagenesis

Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma cell forward mutation assay, or the in vivo mouse bone marrow micronucleus test.

Racemic methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay, and was negative in vivo in the mouse bone marrow micronucleus assay. However, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay of racemic methylphenidate in cultured Chinese Hamster Ovary (CHO) cells.

Impairment of F ertility

Racemic 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 of up to 160 mg/kg/day.

. CLINICAL STUDIES

The effectiveness of Focalin XR in the treatment of ADHD was established in randomized, double-blind, placebo-controlled studies in children and adolescents and in adults who met Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria for ADHD [ see   Indications and Usage (1) ].

Children and Adolescents

The effectiveness of Focalin XR was established in a randomized, double-blind, placebo-controlled, parallel-group study in 103 pediatric patients (ages 6 to 12, n=86; ages 13 to 17, n=17) who met DSM-IV criteria for ADHD. Patients were randomized to receive either a flexible dose of Focalin XR (5 to 30 mg/day) or placebo once daily for 7 weeks. During the first 5 weeks of treatment patients were titrated to their optimal dose and in the last 2 weeks of the study patients remained on their optimal dose without dose changes or interruption.

Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline to endpoint for Focalin XR– and placebo-treated patients using an intent-to-treat analysis of the primary efficacy outcome measure, the DSM-IV total subscale score of the Conners ADHD/DSM-IV Scales for teachers (CADS-T).

There was a statistically significant treatment effect in favor of Focalin XR. There were insufficient adolescents enrolled in this study to assess the efficacy for Focalin XR in the adolescent population. However, pharmacokinetic considerations and evidence of effectiveness of immediate-release Focalin in adolescents support the effectiveness of Focalin XR in this population.

In two additional studies in pediatric patients aged 6-12 years who received 20 mg Focalin XR or placebo in a cross-over design, Focalin XR was found to have a statistically significant treatment effect versus placebo on the Swanson, Kotkin, Agler, M-Flynn & Pelham (SKAMP) rating scale combined score at all time points after dosing in each study  (0.5, 1, 3, 4, 5, 7, 9, 10, 11 and 12 hours in one study and 1, 2, 4, 6, 8, 9, 10, 11 and 12 hours in the other study. A treatment effect was also observed 0.5 hours after administration of Focalin XR 20 mg in an additional study of ADHD patients aged 6-12 years. The SKAMP is a reliable and validated scale that assesses specific classroom behaviors related to attention (e.g., getting started, sticking with activities, completing work, and stopping for transition) and deportment or behavior (e.g., remaining quiet, remaining seated, interacting with other students, and interacting with the teacher.)  Each item is rated on a 7-point impairment scale, and an average rating per item is calculated for the subscales of Attention and Deportment.

Adults

The effectiveness of Focalin XR was established in a randomized, double-blind, placebo-controlled, parallel-group study in 221 adult patients (ages 18 to 60) who met DSM-IV criteria for ADHD. Patients were randomized to receive either a fixed dose of Focalin XR (20, 30, or 40 mg/day) or placebo once daily for 5 weeks. Patients randomized to Focalin XR were initiated on a 10 mg/day starting dose and titrated in increments of 10 mg/week to the randomly assigned fixed dose. Patients were maintained on their fixed dose (20, 30 or 40 mg/day) for a minimum of 2 weeks.

Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline to endpoint for Focalin XR– and placebo-treated patients using an intent-to-treat analysis of the primary efficacy outcome measure, the investigator-administered DSM-IV Attention-Deficit/Hyperactivity Disorder Rating Scale (DSM-IV ADHD RS).

All three Focalin XR doses were statistically significantly superior to placebo. There was no obvious increase in effectiveness with increasing dose.

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