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2/5/2002

Methylphenidate Isomer Approved by FDA

Cheryl A. Thompson

Novartis Pharmaceuticals Corp. has received FDA approval to market dexmethylphenidate (Focalin), the more pharmacologically active isomer of methylphenidate, for the treatment of attention-deficit hyperactivity disorder (ADHD).

The efficacy of dexmethylphenidate in the treatment of ADHD was shown in two multicenter, double-blind, parallel-group, placebo-controlled studies involving 207 patients, ages 6–17 years, with ADHD who may have previously received therapy for the condition. For both studies, the diagnosis of ADHD was made on the basis of the criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.

In the larger study, which lasted four weeks, methylphenidate 5, 10, or 20 mg/day, taken in two divided doses 3.5–5.5 hours apart, improved patients' teacher-assessed scores on the Swanson, Nolan, and Pelham rating scale of ADHD symptoms significantly more than placebo did. The scale is composed of 18 items describing ADHD-related psychopathology (e.g., often talks excessively); the relative presence of each item is rated as 0, 1, 2, or 3; and the overall score is reported as the average of the 18 items' scores. Treatment was started at 5 mg/day, and, depending on a patient's clinical response to and tolerance of therapy, the dose could have been doubled at one-week intervals. Although a group of patients was assigned to take methylphenidate (the racemic mixture), the results from that part of the study are not reported in the labeling for dexmethylphenidate.

The smaller study, which began with six weeks of open-label treatment with dexmethylphenidate and eliminated patients whose symptoms did not improve, found that 17% of the children assigned to continue therapy with methylphenidate for two weeks were rated "much worse" or "very much worse" on the investigator-assessed Clinical Global Impression scale for improvement. That level of response was found in 63% of the children who were switched to placebo for two weeks after the initial six weeks.

Dexmethylphenidate has essentially the same contraindications, warnings, and precautions as methylphenidate. The most commonly reported adverse effects that emerged during the double-blind studies of dexmethylphenidate were abdominal pain (15%), nausea (9%), anorexia (6%), and fever (5%).

The labeling for dexmethylphenidate does not compare its pharmacokinetic properties with those of the racemic mixture but does report that the values are similar in boys and girls.

In fasting patients with ADHD, the plasma concentration of dexmethylphenidate rises quickly and reaches a maximum after 1 to 1.5 hours. Ingestion of the drug with a high-fat breakfast, instead of during a fasting state, delays by 1.4 hours the time of the maximum plasma concentration in adults.

For the most part, the metabolism of dexmethylphenidate occurs by removal of an ester group. The resulting compound has little or no pharmacologic activity. Little or no drug is converted in vivo to the opposite isomer. The mean elimination half-life of dexmethylphenidate is about 2.2 hours.

Regardless of the total daily dose, dexmethylphenidate should be administered twice daily in equal doses, with at least four hours between doses. The medication can be taken with or without food.

The recommended starting dosage of dexmethylphenidate in patients not taking the racemic mixture is 5 mg/day. This starting dosage should also be used by patients who are already receiving a stimulant. Adjustments of 2.5–5 mg may be made about once a week, with the total dosage not to exceed 20 mg/day.

For patients already using the racemic mixture, the recommended starting dosage of dexmethylphenidate is half the dose of methylphenidate, and the final dosage should not exceed 20 mg/day.

Focalin is available in three strengths of tablets—2.5 mg (blue), 5 mg (yellow), and 10 mg (white, dye-free)—in bottles of 100, accompanied by an information sheet for patients, parents, and caregivers. The tablets are made by Mikart, a contract drug manufacturer in Atlanta.

Dexmethylphenidate is a Schedule II controlled substance. Unlike methylphenidate, dexmethylphenidate is not indicated for the treatment of narcolepsy.