iagnosis of ADHD (DSM-IV criteria). Patients were optimised to open-label lisdexamfetamine dimesylate for an extended period (at least 26 weeks) prior to entry into the 6-week randomised withdrawal period. Eligible patients were randomised to continue receiving their optimised dose of lisdexamfetamine dimesylate or to switch to placebo.
Patients were observed for relapse (treatment failure) during the 6-week double-blind phase. Treatment failure was defined as a ≥50% increase (worsening) in the ADHD-RS Total Score and a ≥2-point increase in the CGI-S score compared to scores at entry into the double-blind randomised withdrawal phase. Treatment failure was significantly lower for the lisdexamfetamine dimesylate subjects (15.8%) compared to placebo (67.5%) (p<0.001). For the majority of subjects (70.3%) who were treatment failures regardless of treatment, ADHD symptoms worsened at or before the week 2 visit following randomisation.
Abuse liability studies
In a human abuse liability study, when equivalent oral doses of 100 mg lisdexamfetamine dimesylate and 40 mg immediate-release dexamfetamine sulphate were administered to individuals with a history of drug abuse, lisdexamfetamine dimesylate 100 mg produced subjective responses on a scale of “Drug Liking Effects” (primary endpoint) that were significantly less than dexamfetamine immediate-release 40 mg. However, oral administration of 150 mg lisdexamfetamine dimesylate produced increases in positive subjective responses on this scale that were comparable to the positive subjective responses produced by 40 mg of oral immediate-release dexamfetamine and 200 mg of diethylpropion.
Intravenous administration of 50 mg lisdexamfetamine dimesylate to individuals with a history of drug abuse produced positive subjective responses on scales measuring “Drug Liking”, “Euphoria”, “Amfetamine Effects”, and "Benzedrine Effects" that were greater than placebo but less than those produced by an equivalent dose (20 mg) of intravenous dexamfetamine.
5.2 Pharmacokinetic properties
Absorption
After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the gastrointestinal tract of healthy adults and children (6 to 12 years) with ADHD, thought to be mediated by the high capacity PEPT1 transporter.
Food does not affect the observed AUC and Cmax of dexamfetamine in healthy adults after single-dose oral administration of Elvanse Adult 70 mg capsules but prolongs Tmax by approximately 1 hour (from 3.8 hours at fasted state to 4.7 hours after a high fat meal). After an 8-hour fast, the AUCs for dexamfetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.
Distribution
In 18 children (6 to 12 years) with ADHD, the Tmax of dexamfetamine was approximately 3.5 hours following single-dose oral administration of lisdexamfetamine dimesylate either 30 mg, 50 mg, or 70 mg administered after an 8-hour overnight fast. The Tmax of lisdexamfetamine dimesylate was approximately 1 hour. Linear pharmacokinetics of dexamfetamine after single-dose oral administration of lisdexamfetamine dimesylate was established over the dose range of 30 mg to 70 mg in children aged 6 to 12 years.
Weight/dose normalised AUC and Cmax were 22% and 12% lower, respectively, in adult females than in males on day 7 following a 70 mg/day dose of lisdexamfetamine for 7 days. W |
