Focalin XR produces a bi-modal plasma concentration-time profile (i.e., 2 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 2 formulations, i.e., first peak concentration (Cmax1 ), and time to the first peak (tmax1 ), which is reached in 1.5 hours (typical range 1 to 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 to 7 hours) compared to Focalin tablets given in 2 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 fewer peak and trough fluctuations than Focalin tablets given in 2 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 ratio of geometric mean of AUC(0-inf) and Cmax after administration of Focalin XR given once daily are 1.02 and 0.86 respectively, to the same total dose of Focalin tablets given in 2 doses 4 hours apart. The variability in Cmax , Cmin , and AUC is similar between Focalin XR and Focalin immediate-release tablets with approximately a 3-fold range in each.
Approximately 90% of the dose is absorbed after oral administration of radiolabeled racemic methylphenidate. However, due to first pass metabolism, the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22% to 25%.
Figure 1. Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration 1 x 20 mg Focalin XR (n = 24) Capsules and 2 x 10 mg Focalin Immediate-Release Tablets (n = 25)
After single dose administration, Focalin XR demonstrated dose proportional pharmacokinetics (PK) in the range of 5 mg to 40 mg.
For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered [see Dosage and Administration (2)].
The plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12% to 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. The mean terminal elimination half-life of dexmethylphenidate was about 3 hours in healthy adults. Pediatric patients tend to have slightly shorter half-lives with means of 2 to 3 hours. Dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 L/hr/kg after intravenous administration.
In humans, dexmethylphenidate is metabolized primarily via de-esterification to d-α -phenyl-piperidine acetic acid (also known as d -ritalinic acid). This metabolite has little or no pharmacological activity. There is no in vivo interconversion to the l-threo -enantiomer.
After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic dl- methylphenidate was dl- ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose.
Studies in Specific Populations
Male and Female Patients
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.
Racial or Ethnic Groups
There is insufficient experience with the use of Focalin XR to detect ethnic variations in pharmacokinetics.
The pharmacokinetics of dexmethylphenidate after Focalin XR administration have not been studied in pediatrics less than 18 years of age. When a similar formulation of racemic methylphenidate was examined in 15 patients between 10 and 12 years of age, and 3 patients 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 pediatric patients compared to adults. After administration of the same dose to pediatric patients and adults, concentrations in pediatric patients 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.
Patients with Renal Impairment
There is no experience with the use of Focalin XR in patients with renal impairment. Since renal clearance is not an important route of methylphenidate elimination, renal impairment is expected to have little effect on the pharmacokinetics of Focalin XR.
Patients with Hepatic Impairment
There is no experience with the use of Focalin XR in patients with hepatic impairment.
Drug Interaction Studies
Methylphenidate is not metabolized by cytochrome P450 (CYP) isoenzymes to a clinically relevant extent. Inducers or inhibitors of CYPs are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d — and l- enantiomers of methylphenidate did not relevantly inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A. Clinically, methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.
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 was seen at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day of racemic methylphenidate given to children on a mg/m2 basis. 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, which is approximately 4 times the MRHD (children) of 60 mg/day of racemic methylphenidate in children on a mg/m2 basis.
In a 24-week carcinogenicity study with racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60 to 74 mg/kg/day of racemic methylphenidate.
Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vivo mouse bone marrow micronucleus test. In an in vitro assay using cultured Chinese Hamster Ovary cells treated with racemic methylphenidate, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response.
Impairment of Fertility
No human data on the effect of methylphenidate on fertility are available.
Fertility studies have not been conducted with dexmethylphenidate. 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, approximately 10 times the MRHD of 60 mg/day of racemic methylphenidate given to adolescents on a mg/m2 basis.
A randomized, double-blind, placebo-controlled, parallel-group study (Study 1) was conducted in 103 pediatric patients (ages 6 to 12, n = 86; ages 13 to 17, n = 17) who met DSM-IV criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes (Study 1).
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 remained on this optimal dose for the last 2 weeks of the study 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). The CADS-T includes the ADHD Index (12 items) and the DSM-IV total subscale (18 items, total score range: 0 to 54); the latter is divided into inattentive (9 items) and hyperactive-impulsive (9 items) subscales. Teachers assessed behavior observed during the school day by completing the CADS-T weekly. A decrease in the CADS-T DSM-IV total subscale score from baseline indicates improvement.
The CADS-T total scores showed a statistically significant treatment effect in favor of Focalin XR than placebo (Table 6). 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.
|Abbreviations: ADHD, attention deficit hyperactivity disorder; SD, standard deviation; SE, standard error; LS Mean, least-squares mean; CI, confidence interval, not adjusted for multiple comparisons.a Difference (drug minus placebo) in least-squares mean change from baseline.|
|Study Number||Treatment Group||Primary Efficacy Measure: CADS-T Total Score|
|Mean Baseline Score (SD)||LS Mean Change from Baseline (SE)||Placebo-subtracted Differencea (95% CI)|
|Study 1||Focalin XR 5-30 mg/day(n = 52)||33.3 (9.18)||16.41 (1.8)||10.64 (5.38, 15.91)|
|Placebo(n = 45)||34.9 (10.03)||5.77 (1.93)||—|
In 2 additional cross-over studies (Studies 2 and 3) in pediatric patients ages 6 to 12 years, who received 20 mg Focalin XR or placebo, Focalin XR was found to have a statistically significant treatment effect versus placebo on the Swanson, Kotkin, Agler, M-Flynn & Pelham (SKAMP) rating scale total scores at all-time points after dosing in each study (0.5, 1, 3, 4, 5, 7, 9, 10, 11, and 12 hours in Study 2 and 1, 2, 4, 6, 8, 9, 10, 11, and 12 hours in the Study 3). SKAMP is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting. A treatment effect was also observed 0.5 hours after administration of Focalin XR 20 mg in an additional study of ADHD patients ages 6 to 12 years.
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