A review of modafinil film-coated tablets for attention-deficit/hyperactivity disorder in children and adolescents

Abstract

Modafinil, a wakefulness-promoting agent unrelated to classical sympathomimetic stimulants, has been studied in a total of 933 children and adolescents as a treatment for attention-deficit/hyperactivity disorder (ADHD). Several studies, including three double-blind, placebo-controlled studies with intent-to-treat analyses, have demonstrated the efficacy of modafinil film-coated tablets in reducing symptoms of ADHD and associated problem behaviors in children and adolescents. Modafinil is generally well tolerated, with adverse events (such as insomnia, headache, loss of appetite, weight loss, and gastrointestinal discomfort) that are generally mild to moderate, rarely leading to medication discontinuation. To minimize treatment-emergent side effects, titration to the target dose of 355-425 mg once a day should take place over 2-3 weeks. Due to reports of skin rash (including one case of possible erythema multiforme/Stevens Johnson Syndrome during pivotal studies), additional studies have been requested to better evaluate the risks of developing severe cutaneous adverse reactions.

Keywords: adolescents; attention-deficit/hyperactivity disorder; behavior; children; modafinil; treatment.

Figure 1

Chemical structures of modafinil, methylphenidate, amphetamine, and pemoline.

Figure 2

Indirect activation of the cerebral cortex by modafinil action on the tuberomammillary nucleus. Adapted from Swanson et al (1998). Abbreviations: SN, suprachiasmatic nucleus; TMN, tuberomammilary nucleus; VTA, ventral tegmental area.

Figure 3a

ADHD Rating Scale total scores as a function of time in a flexible-dose study of efficacy of modafinil for children and adolescents with attention-deficit/hyperactivity disorder (n = 194). *p values <0.05; endpoint represents the last obtained value carried forward Reproduced from Cephalon, Inc. 2006. Modafinil (CEP-1538) tablets Supplemental NDA 20-717/S-019 ADHD indication. Briefing document for Psychopharmacologic Drugs Advisory Committee Meeting March 26, 2006. Frazer, PA: Cephalon, Inc.

Figure 3b

ADHD Rating Scale total scores as a function of time for a flexible-dose study of modafinil efficacy for children and adolescents with attention-deficit/hyperactivity disorder (n = 244). *p values <0.05; endpoint represents the last obtained value carried forward. Reproduced from: Cephalon, Inc. 2006. Modafinil (CEP-1538) tablets Supplemental NDA 20-717/S-019 ADHD indication. Briefing document for Psychopharmacologic Drugs Advisory Committee Meeting March 26, 2006. Frazer, PA: Cephalon, Inc.

Figure 3c

ADHD Rating Scale total scores as a function of time for a fixed-dose study of efficacy of modafinil for children and adolescents with attention-deficit/hyperactivity disorder (n = 183). *p values <0.05; endpoint represents the last obtained value carried forward Reproduced from Cephalon, Inc. 2006. Modafinil (CEP-1538) tablets Supplemental NDA 20-717/S-019 ADHD indication. Briefing document for Psychopharmacologic Drugs Advisory Committee Meeting March 26, 2006. Frazer, PA: Cephalon, Inc.

Figure 4a

Percentage responders as a function of time for a flexible-dose study of efficacy of modafinil for children and adolescents with attention-deficit/hyperactivity disorder (n = 194). Response is defined as having a Clinical Global Impressions of Change score of 1 (“very much improved”) or 2 (“much improved”). *p values <0.05; EP = endpoint, which represents the last obtained value carried forward. Reproduced from Cephalon, Inc. 2006. Modafinil (CEP-1538) tablets Supplemental NDA 20-717/S-019 ADHD indication. Briefing document for Psychopharmacologic Drugs Advisory Committee Meeting March 26, 2006. Frazer, PA: Cephalon, Inc.

Figure 4b

Percentage responders as a function of time for a flexible-dose study of efficacy of modafinil for children and adolescents with attention-deficit/hyperactivity disorder (n = 244). Response is defined as having a Clinical Global Impressions of Change score of 1 (“very much improved”) or 2 (“much improved”). *p values <0.05; EP = endpoint, which represents the last obtained value carried forward. Reproduced from Cephalon, Inc. 2006. Modafinil (CEP-1538) tablets Supplemental NDA 20-717/S-019 ADHD indication. Briefing document for Psychopharmacologic Drugs Advisory Committee Meeting March 26, 2006. Frazer, PA: Cephalon, Inc.

Figure 4c

Percentage responders as a function of time for a fixed-dose study of efficacy of modafinil for children and adolescents with attention-deficit/hyperactivity disorder (n = 183). Response is defined as having a Clinical Global Impressions of Change score of 1 (“very much improved”) or 2 (“much improved”). *p values <0.05; EP = endpoint, which represents the last obtained value carried forward. Reproduced from Cephalon, Inc. 2006. Modafinil (CEP-1538) tablets Supplemental NDA 20-717/S-019 ADHD indication. Briefing document for Psychopharmacologic Drugs Advisory Committee Meeting March 26, 2006. Frazer, PA: Cephalon, Inc.