Methylphenidate Hydrochloride (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a lifetime carcinogenicity study carried out in B6C3F1 mice, 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. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day 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.

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) on a mg/m2 basis.

Mutagenesis

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

Impairment of Fertility

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 maximum recommended human dose of 60 mg/day given to adolescents on a mg/m2 basis.

14 CLINICAL STUDIES

The efficacy of Methylphenidate Hydrochloride Extended-Release Capsules for the treatment of ADHD was established in a randomized, double-blind, single center, placebo-controlled, flexible-dose, cross-over trial in pediatric patients aged 6 to 12 years and a second randomized, double-blind, multicenter, placebo-controlled, fixed–dose trial in pediatric patients 6 to 17 years.

Pediatric Patients

A randomized, double-blind, placebo-controlled, flexible-dose, cross-over, analog classroom study (Study 1) was conducted in pediatric patients ages 6 to 12 years (N=26) who met DSM-IV-TR criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes.

Following a 2 to 4 week open-label dose optimization phase in which patients received flexible-dose Methylphenidate Hydrochloride Extended-Release Capsules 15 mg, 20 mg, 30 mg, or 40 mg administered once daily in the morning, patients were randomly assigned to Methylphenidate Hydrochloride Extended-Release Capsules (dose from open-label phase) or placebo. After 1-week of treatment, patients were evaluated over a period of 12 hours. Subsequently, patients were given the opposite treatment for 1-week and returned for the second evaluation. Patients could then enter an open-label extension phase for up to 21 months.

Efficacy assessments were conducted at 1, 2, 3, 4.5, 6, 7.5, 9, 10.5 and 12 hours post-dose using the Swanson, Kotkin, Agler, M. Flynn, and Pelham Total score (SKAMP). The primary efficacy endpoint was the average SKAMP Total Score, comparing Methylphenidate Hydrochloride Extended-Release Capsules to placebo. SKAMP is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting.

The SKAMP Total Scores were statistically significantly better (lower) for Methylphenidate Hydrochloride Extended-Release Capsules than for placebo at the test day average and at all time points (1, 2, 3, 4.5, 6, 7.5, 9, 10.5 and 12 hours) post-dosing (see Figure 2).

Figure 2: Absolute SKAMP- Total Score after treatment with Methylphenidate Hydrochloride Extended-Release Capsules or Placebo (Study 1).

Figure 2
(click image for full-size original)

A randomized, double-blind, multicenter, placebo-controlled, parallel-group, fixed-dose study (Study 2) was conducted in pediatric patients age 6 to 17 years (N=230) who met DSM-IV-TR criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes.

The ADHD-RS-IV is an 18-item questionnaire with a score range of 0 to 54 points that measures the core symptoms of ADHD and includes both hyperactive/impulsive and inattentive subscales.

Patients were randomized to a daily morning dose of Methylphenidate Hydrochloride Extended-Release Capsules 10 mg, 15 mg, 20 mg, or 40 mg, or placebo for 1 week. An 11-week open label phase followed the double-blind phase. Patients could then enter another open-label phase for up to 21 months.

The primary efficacy endpoint was the mean decrease from baseline to the end of Week 1 in the ADHD-RS-IV Total Score. Each of the four Methylphenidate Hydrochloride Extended-Release Capsules doses (10 mg, 15 mg, 20 mg, and 40 mg/day) was compared to placebo at the end of week 1. For both the 20 mg/day and the 40 mg/day doses, Methylphenidate Hydrochloride Extended-Release Capsules was superior to placebo in reduction of the ADHD-RS-IV Total Score, but not for the 10 mg/day or the 15 mg/day doses.

A total of 221 patients completed the 1-week double-blind phase. Among those, 200 (90.5%) completed the 11-week open label phase and 173 (86.5%) patients continued into the 21-month open-label extension phase.

Table 3: Summary of Parallel-Group Study
Study NumberTreatment GroupPrimary Efficacy Measure: ADHD-RS-IV Total Score
Mean Baseline Score (SD)LS Mean Reduction from Baseline (SE)Placebo-subtracted Difference * (95% CI)
Note: SD: standard deviation; SE: standard error; LS Mean: least-squares mean;
CI: confidence interval, not adjusted for multiple comparisons.
*
Difference (placebo minus drug) in least-squares mean change from baseline. Positive numbers indicate reduction (improvement).
Doses that are demonstrated to be effective.
Study 2(Pediatric)Methylphenidate Hydrochloride Extended-Release Capsules 10 mg/day37.6 (8.32)9.1 (1.40)3.7 (-0.31, 7.66)
Methylphenidate Hydrochloride Extended-Release Capsules 15 mg/day38.0 (8.64)10.3 (1.59)4.9 (0.63, 9.07)
Methylphenidate Hydrochloride Extended-Release Capsules 20 mg/day 36.2 (8.46)11.4 (1.49)6.0 (1.92, 10.02)
Methylphenidate Hydrochloride Extended-Release Capsules 40 mg/day 35.6 (9.16)12.8 (1.49)7.4 (3.38, 11.45)
Placebo33.4 (11.01)5.4 (1.48)

16 HOW SUPPLIED/STORAGE AND HANDLING

Methylphenidate Hydrochloride Extended-Release Capsules are available as follows:

10 mg Extended-Release Capsules white opaque body & light turquoise blue opaque cap containing white spherical beads. Body Imprinting “910”. Cap imprinting “RP”
Bottles of 90 NDC 42858-075-45
15 mg Extended-Release Capsules white opaque body and orange cap containing white spherical beads. Body imprinting “915”. Cap imprinting “RP”
Bottles of 90 NDC 42858-076-45
20 mg Extended-Release Capsules – white opaque body and yellow opaque cap containing white spherical beads. Body imprinting “920”. Cap imprinting “RP”
Bottles of 90 NDC 42858-077-45
30 mg Extended-Release Capsules – white opaque body and blue violet cap containing white spherical beads. Body imprinting “930”. Cap imprinting “RP”
Bottles of 90 NDC 42858-078-45
40 mg Extended-Release Capsules white opaque body and pink opaque cap containing white spherical beads. Body imprinting “940”. Cap imprinting “RP”
Bottles of 90 NDC 42858-079-45
50 mg Extended-Release Capsules white opaque body and green opaque cap containing white spherical beads. Body imprinting “950”. Cap Imprinting “RP”
Bottles of 90 NDC 42858-080-45
60 mg Extended-Release Capsules – white opaque body and gray opaque cap containing white spherical beads. Body imprinting “960”. Cap imprinting “RP”
Bottles of 90 NDC 42858-081-45

Storage and Handling

Methylphenidate Hydrochloride Extended-Release Capsules should be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

Dispense in tight container (USP).

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired Methylphenidate Hydrochloride Extended-Release Capsules by a medicine takeback program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix Methylphenidate Hydrochloride Extended-Release Capsules with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard Methylphenidate Hydrochloride Extended-Release Capsules in the household trash.

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