New Treatment Options for Attention-Deficit/Hyperactivity Disorder (ADHD): Part I. Transdermal Methylphenidate and Lisdexamfetamine

Marcia L. Buck, PharmD, FCCP; Kristi N. Hofer, PharmD; Michelle W. McCarthy, PharmD

Disclosures

Pediatr Pharm. 2008;14(3) 

In This Article

Lisdexamfetamine

On February 23, 2007, the FDA approved lisdexamfetamine for the treatment of ADHD in children 6 to 12 years of age. Lisdexamfetamine is a prodrug of dextroamphetamine which requires conversion in the gastrointestinal (GI) tract to release active drug. This formulation is only effective when given orally; reducing the potential for abuse through injection or inhalation.[9,10]

Clinical Studies in Children

The approval of lisdexamfetamine was based on the results of two clinical trials conducted in children.[11,12] Both were multicenter, randomized, double-blind, controlled studies supported by the original manufacturer (New River Pharmaceuticals). In the phase II crossover study, Biederman and colleagues compared the effects of lisdexamfetamine to an extended-release preparation of mixed amphetamine salts (MAS; Adderall XR™) and placebo.[11] A total of 52 children between 6 and 12 years of age were enrolled; 50 children completed the study. After a 3-week open-label dose-titration with MAS, patients were randomized to receive either lisdexamfetamine, MAS, or placebo. Doses were based on the patient's optimal MAS dose or the equivalent lisdexamfetamine dose (i.e., 30 mg lisdexamfetamine for 10 mg MAS). Patients received each treatment for 1 week. Both lisdexamfetamine and MAS produced significant improvement in SKAMP, PERMP, and CGI scores compared to placebo. Treatment effects were seen for up to 12 hours (the last time point measured).

A phase III study conducted in 290 children at 40 institutions provided similar results.[12] Patients (all between 6 and 12 years of age) received lisdexamfetamine at fixed doses of 30 mg, 50 mg, or 70 mg, or placebo daily for 4 weeks. Response was assessed by scores on the ADHDRS—IV, CGI scale, and the Conners' Parent Rating Scale (CPRS). All doses of lisdexamfetamine produced significant improvement in ADHD-RS-IV, CGI, and CPRS scores compared to placebo (p<0.001). Symptom improvement was observed for up to 12 hours. Lisdexamfetamine was well tolerated. The primary reason for discontinuation was lack of efficacy (reported in 1% of the 30 mg and 70 mg lisdexamfetamine groups and 17% of the placebo patients).

Pharmacokinetics

After oral administration, lisdexamfetamine is rapidly absorbed in the GI tract and converted to dextroamphetamine and L-lysine through both a first-pass effect and hepatic metabolism. In a pharmacokinetic study conducted in 18 children, the time to maximum serum dextroamphetamine concentration was approximately 3.5 hours after a dose. Administration with food, particularly a high fat meal, prolongs the time to maximum concentration by an hour, but does not affect the extent of absorption. Approximately 42% of a dose is eliminated as dextroamphetamine, with 25% eliminated as hippuric acid and 2% as intact lisdexamfetamine. Pharmacokinetic studies conducted in adolescents and adults have provided similar results to the pediatric data.[10]

Drug Interactions

Lisdexamfetamine should not be administered to patients taking monoamine oxidase inhibitors because of the potential for precipitating hypertensive crisis. Lisdexamfetamine may increase the effects of meperidine, norepinephrine, phenytoin, and tricyclic antidepressants. It may inhibit or reduce the response to adrenergic blockers, antihistamines, antihypertensives, and ethosuximide. When given concurrently, furazolidone and propoxyphene may increase the effects of lisdexamfetamine, while chlorpromazine, haloperidol, lithium, and urinary acidifying agents may decrease its effects.[9,10]

Contraindications/Precautions

As with other dextroamphetamine products, lisdexamfetamine is contraindicated in patients with known cardiovascular disease, hypertension, hyperthyroidism, glaucoma, or anxiety. It should be used with caution in patients with tics or Tourette syndrome.[9,10]

Adverse Effects

In the phase III placebo-controlled lisdexamfetamine study described earlier, the following adverse effects occurred in 5% or more of the children receiving lisdexamfetamine: decreased appetite (39%), insomnia (19%), abdominal pain (12%), headache (12%), irritability (10%), vomiting (9%), decreased weight (9%), nausea (6%), dry mouth (5%). Children taking lisdexamfetamine should be monitored for changes in heart rate, blood pressure, sleep patterns, and growth parameters.[12] The long-term effects of lisdexamfetamine on growth are not yet known.

Dosing Recommendations

The recommended initial dose for lisdexamfetamine is 30 mg taken once daily in the morning. If needed, the dose may be increased by 20 mg/day increments at weekly intervals. The maximum recommended dose is 70 mg/day. Lisdexamfetamine may be taken with or without food. In children unable to swallow the capsules, the capsule contents may be mixed in a glass of water. Once dissolved, the solution should be taken immediately and not stored for future use.[9,10]

Availability and Cost

Lisdexamfetamine (Vyvanse™; Shire) is available in 20, 30, 40, 50, 60, and 70 mg capsules. The average wholesale price for 100 capsules of any strength is $426.68, making the monthly cost approximately $130.[8]

Summary

These new treatment options offer patients with ADHD more alternatives to standard therapies. Although both of the products discussed are based on traditional therapies, they provide unique advantages, such as titration of effect duration or a longer-acting once-daily product. As with all newly approved products, however, prescribers should use caution when titrating the dose of these new products or evaluating patients for adverse effects, as rare events may not have been detected during premarketing clinical trials.

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