Methylphenidate Controlled-Delivery Capsules (Equasym™XL, Metadate CD™)

Controlled-delivery methylphenidate (methylphenidate CD) [Equasym™XL, Metadate CD™], an oral stimulant, is approved in the US and EU to treat children aged ≥6 years who have been diagnosed with attention-deficit hyperactivity disorder (ADHD).

Once-daily methylphenidate CD is generally well tolerated and effective in the treatment of children and adolescents with ADHD. Methylphenidate CD resulted in superior control of ADHD symptoms compared with osmotic release oral system (OROS®) methylphenidate over a time period corresponding to that of an average school day in a laboratory classroom. In 3-week clinical trials conducted in a community setting, methylphenidate CD was superior to placebo and noninferior to methylphenidate immediate-release (IR) in the treatment of children and adolescents with ADHD. Thus, methylphenidate CD should be considered an important primary treatment on its own or in addition to behavioral and psychosocial interventions, for when a reduction in ADHD symptoms is required during the school day in preference to the evening.

Methylphenidate CD is a CNS stimulant that is thought to inhibit the reuptake of dopamine and norepinephrine (noradrenaline) into the presynaptic neuron. The increase in these monoamines in the extraneuronal space may be responsible for the improvement in ADHD symptoms observed with methylphenidate treatment. Improvements in cognitive function, behavior, accuracy, reaction time, short-term memory, vigilance, impulsivity control, and possibly learning have been observed with the use of methylphenidate.

Oral methylphenidate CD has a biphasic, dose-proportional pharmacokinetic profile, with peak plasma concentrations reached at ≈1.5 and ≈4.5 hours. The bioavailability of methylphenidate CD is ≈28% (with breakfast). Although foods such as applesauce do not affect the absorption profile of methylphenidate CD, a high-fat meal can alter the bioavailability of the stimulant. Elimination of methylphenidate CD is mainly though the urinary elimination of ritalinic acid. Methylphenidate CD has an elimination half-life of ≈6 hours.

The effect of methylphenidate CD on ADHD symptoms in children was compared with that of OROS® methylphenidate and placebo in a well designed trial conducted in a laboratory classroom (the COMACS study). In the COMACS study, significantly lower Swanson, Kotkin, Atkins, M-Flynn, and Pelham Deportment (SKAMP-D) scores were seen with methylphenidate CD than with OROS® methylphenidate from 1.5 through to 4.5 hours after drug administration, and for 7.5 hours versus placebo. A summary score averaging SKAMP-D scores over 1.5–7.5 hours post-dose revealed a significantly lower SKAMP-D score for methylphenidate CD than for OROS® methylphenidate over this time period.

The clinical efficacy of methylphenidate CD in children and/or adolescents with ADHD was also shown in two well designed, 3-week, placebo-controlled trials, one of which was also a noninferiority trial with methylphenidate IR, and a 3-week, noncomparative postmarketing study, all of which were conducted in a community setting. The noninferiority of methylphenidate CD to methylphenidate IR was shown when the lower limit of the confidence interval for the between-group difference in the inattention/overactivity (I/O) component of the Teacher’s Inattention/Overactivity With Aggression (IOWA) Conners’ rating scale was greater than the set limit (−1.5 points) at week 3. Methylphenidate CD was significantly more effective than placebo in reducing the symptoms of ADHD as seen by a significantly lower score (improvement) in the I/O component of the overall ten-item Teacher’s IOWA Conners’ rating scale in one placebo-controlled trial and a significant reduction from baseline in the Conners’ Teacher Global Index in the other placebo-controlled trial. In addition, 65% of methylphenidate CD recipients responded to treatment on the Clinical Global Index improvement subscale in the postmarketing study.

Methylphenidate CD 20–60mg once daily was generally well tolerated in children and adolescents with ADHD; adverse events were usually of mild severity. In four studies, the most commonly reported adverse events in methylphenidate CD recipients were headache, anorexia, abdominal pain, and insomnia. No clinically significant changes in parameters such as hematology, biochemistry, urinalysis, or vital signs were noted in two studies, although one study observed a small decrease in systolic blood pressure and a small increase in heart rate.