Drug Criteria & Outcomes
Drug evaluation: Dexmethylphenidate hydrochloride tablets (Focalin)
Part 2 of 2: Clinical Studies, Cost, Application, Formulary Recommendation
By Emily K. Pauli, BS, BMS, PharmD Candidate
Harrison School of Pharmacy
Auburn (AL) University
Clinical studies
Trial 1: Wigal S, Swanson JM, Feifel D, et al. A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2004;43:1,406-1,414.
Study goal: Evaluate d-MPH relative to placebo and d,l-MPH in the treatment of ADHD, including a comparison of the duration of action.
Methods
- Randomized, prospective, multicenter (12 U.S. centers), placebo-controlled clinical trial.
- Children (ages 6-17 years) diagnosed with ADHD according to DSM-IV criteria.
- Primary outcome: Determine efficacy and safety of d-MPH relative to d,l-MPH.
- Secondary outcome: Evaluate the duration of action in clinically titrated doses of d-MPH and d,l-MPH.
- Experimental design
One-week, single-blind placebo lead-in period.
Four-week, double-blind treatment period with randomization into three groups:
- Placebo (n = 42).
- d-MPH (n = 44); initiated at 2.5 mg/day and titrated to 20 mg/day as-needed based on response; average dose = 18.25 mg/day.
- d,l-MPH (n = 46); initiated at 5 mg/day and titrated to 40 mg/day as needed based on response; average dose = 32.14 mg/day.
Treatment definition
- Oral, twice-daily dosing (separated by four hours).
Response measurement
- Primarily by Teacher SNAP rating and secondarily by Parent SNAP rating, CGI-S, and math tests.
- Inclusion criteria
- Ages 6-17 years, diagnosed with ADHD according to DSM-IV criteria, and within 30% of normal body weight.
- Enrolled in school.
- Available for the entire study duration.
- Exclusion criteria
- History or evidence of: cardiovascular, respiratory (other than asthma or allergies), renal, endocrine, central nervous system (other than ADHD), or immune system disease and disorders; or substance abuse.
- Hypersensitivity to stimulants or any MPH product component.
- Treatment with any investigational agent 30 days prior to screening.
- Treatment with antidepressants, sedative/hypnotics, mood stabilizers, anticonvulsants, beta-blockers, alpha-2 agonists, thyroid medications, or oral steroids.
- Strengths
- RCT, multicenter, intention-to-treat.
- Multiple evaluation techniques.
- Statistical power.
- Weaknesses
- Multicenter.
- Four-week treatment period; no counseling included in treatment.
- Treatment response measured primarily by nonclinical evaluator.
- Protocol violation not accounted for in analysis.
- Data reporting incomplete and questionable.
- Failed to meet all study goals.
Analysis of data
- Baseline comparison: Cochran-Mantel-Haenszel (categorical variables) and ANOVA (continuous variables).
- Outcomes →
Efficacy: Cochran-Mantel-Haenszel (categorical variables) and ANCOVA (continuous variables).
Safety (Adverse Events; AE): Fisher’s exact
Duration: ANCOVA
Results
- Primary outcome
- Efficacy: Improvement from baseline compared to placebo for d-MPH and d,l-MPH.
Teacher SNAP rating
d-MPH and d,l-MPH show significant improvement (P < 0.05).
Parent SNAP ratings
3 p.m.: d-MPH and d,l-MPH significant improvement (P < 0.05).
6 p.m.: d-MPH significant improvement (P < 0.05)
d,l-MPH not significant (P > 0.05).
CGI-S scores
Significant improvement (P < 0.05) for d-MPH; not significant for d,l-MPH (P> 0.05).
Math test
Significant (P < 0.05) for d-MPH and d,l-MPH at office exam.
Significant (P < 0.05) for d-MPH at evening/home exam; d,l-MPH not reported.
- Safety
No serious adverse events; mild to moderate only.
Similar relative frequency among all treatment groups.
- Secondary outcome
Duration of action: Change from baseline compared to placebo for d-MPH only
- 6 p.m. data: Parent SNAP and math test.
- Possible six-hour duration for d-MPH.
Conclusion
- Authors’ conclusion
No difference in efficacy and safety between d-MPH and d,l-MPH.
Results suggest slightly longer duration of efficacy for d-MPH over d,l-MPH.
- Emily Pauli’s conclusion
Since d-MPH is the active enantiomer of d,l-MPH, it is not surprising that equivalence in efficacy is established between the active treatment groups. However, a four-week trial is insufficient to draw conclusions regarding safety of a medication.
Data reporting is equivocal and incomplete. It is scientifically indecorous to suggest that d-MPH may have a longer duration of action than d,l-MPH based on reported data in this trial.
Additionally, clinical significance of a six-hour duration of action is questionable with the availability of longer-acting formulations of d,l-MPH.
Trial 2: Arnold LE, Lindsay RL, Conners CK, et al. A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2004;14:542-554.
- Arnold et al have studied 89 adolescents (ages 6-17 years) in a six-week open-label titration of d-MPH followed by a two-week randomized, placebo-controlled withdrawal period designed to determine the efficacy and safety of d-MPH after 7-8 weeks of treatment, and secondarily, to retest the hypothesis that d-MPH has a six-hour duration of action.
- Only 75 adolescents completed the study — evaluation techniques were identical to those used by Wigal et al; the sole determinant for duration of action was the 6 p.m. math test administered on Saturday and Sundays of the last two weeks of the study.
- The authors’ results and conclusions are similar to Wigal et al in that d-MPH is efficacious and safe in treatment of ADHD and that based on the 6 p.m. math score, it shows a duration of six hours compared to placebo (P < 0.05).
Cost
Cost comparisons are presented in Table 2.
Application
- d-MPH is an additional option for the treatment of ADHD in children 6-17 years of age. The efficacy and safety of d-MPH is equal that of the racemic mixture products (d,l-MPH).
- Adverse events are no more common or less frequent with d-MPH.
- All of the studies available regarding clinical use of d-MPH are pre-marketing, Phase III trials. Novartis Pharmaceuticals (which also markets Ritalin) has recently purchased the rights to Focalin from Celgene.
- A head-to-head trial of d-MPH and d,l-MPH that controls for severity of disease and reports all data is needed. Additionally, further investigation into the pharmacology of d-MPH is needed in determining it distinct from methylphenidate.
Formulary recommendation
An automatic formulary interchange is recommended for any child 6-17 years of age that is admitted and requires ADHD treatment with methylphenidate; he or she should be given eqimolar doses of the current methylphenidate formulary agent in lieu of d-MPH or Focalin XR, unless otherwise stated by the prescribing physician.
Recommended reading
- Arnold LE, Lindsay RL, Conners CK, et al. A double-blind, placebo-controlled withdrawal trial of dexmethyl-phenidate hydrochloride in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2004;14:542-554.
- Ding YS, Fowler JS, Volkow ND, et al. Chiral drugs: Comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain. Psychopharmacology 1997;131:71-78.
- Methylphenidate HCl. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc., pp. 773-775.
- MICROMEDEX Healthcare Series. Greenwood Village, CO: MICROMEDEX; (edition expired July 2005).
- National Institute of Mental Health. Attention Deficit Hyperactivity Disorder: An Update. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services; 2003 [cited July 12, 2005]. NIMH Pub No. 3572. Available at: www.nimh.nih.gov/publicat/adhd.cfm#ref.
- Novartis Pharmaceuticals Corp. Focalin package insert. East Hanover, NJ; May 2005.
- Novartis Pharmaceuticals Corp. Focalin XR package insert. East Hanover, NJ; May 2005.
- Red Book Pharmacy’s Fundamental Reference, Thomson Physicians’ Desk Reference. Montvale, NJ; 2005.
- Wigal S, Swanson JM, Feifel D, et al. A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2004;43:1,406-1,414.
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