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Home , Dextroamphetamine, Lisdexamfetamine

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Lisdexamfetamine for ADHD Timothy E. Wilens, MD

isdexamfetamine—FDA-approved Table 1 Extended-action to treat -defi cit/hyperactiv- : Fast facts psychostimulant ity disorder (ADHD) in children ages L Brand name: Vyvanse off ers daylong 6 to 12 (Table 1)—reduces ADHD symp- coverage and has toms during and after school and may be Indication: ADHD in children ages 6 to 12 comparatively low less likely to be abused than other psycho- Approval date: February 23, 2007 abuse potential , particularly immediate-release Manufacturers: New River Pharmaceuticals preparations, clinical data suggest. and Shire Dosing forms: 30-, 50-, and 70-mg capsules Clinical implications Recommended dosage: Start at 30 mg/d. ® Dowden HealthIf necessary, Media titrate by 20 mg every 3 to 7 Because it is effective for about 12 hours, days to a maximum 70 mg/d. lisdexamfetamine might improve the child’s abilityCopyright to completeFor homework personal and partici- use only pate in extracurricular activities, which in Lisdexamfetamine requires turn might enhance academic performance metabolism (in the GI tract) to its active and/or socialization skills. constituent d-. As a result, Lisdexamfetamine could help the child the medication will not produce high d- with ADHD who shows no contraindica- amphetamine blood levels—and should tions to the drug (page 105)—particularly if not cause or other reinforcing he or she needs daylong coverage. effects—if injected or snorted. Its abuse potential is lower overall compared with immediate-release psychostimulant How it works formulations. Lisdexamfetamine—a derivative—is rapidly absorbed and con- verted to dextroamphetamine, which is believed to exert therapeutic effect by: Dextroamphetamine’s plasma elimination 1 • blocking and half-life is approximately 9 ⁄2 hours—which into presynaptic neurons accounts for lisdexamfetamine’s extended • increasing the ’ re- action. The drug reaches steady-state con- lease into the extraneuronal space. centrations in 2 to 3 days. The medication’s amphetamine release Food does not affect absorption and is highly predictable, which contributes to delays maximum concentration by 1 hour its therapeutic benefi t in ADHD. Amphet- or less, so taking lisdexamfetamine dur- is released through GI metabolism ing breakfast should not slow its thera- of lisdexamfetamine, which produces the peutic effect. Because dextroamphet- active d-amphetamine moiety that reaches the bloodstream. The medication is de- Dr. Wilens is associate professor of psychiatry, Harvard Medical School and director, services, rived from d-amphetamine, with negligi- Current Psychiatry Clinical and Research Program in Pediatric Pharmacology, 96 June 2007 ble amounts of cleaved. Massachusetts General Hospital, Boston.

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amine reaches maximum concentration in children were started at 30 mg/d; some 1 approximately 3 ⁄2 hours, the medication received dosages titrated at random to 50 should take effect by the time the child or 70 mg/d in weekly 20-mg increments. gets to school. In one randomized, phase- Over 4 weeks, ADHD Rating Scale Ver- 2 trial, children with ADHD who received sion IV (ADHD-RS-IV) scores fell 50% to lisdexamfetamine, 30 to 70 mg/d, showed 59% among the 3 lisdexamfetamine dos- overall improvement within 2 hours after age groups, compared with a 15% reduc- dosing.1 tion in the placebo group. Substantial ADHD-RS-IV score improvements after 1 week of lisdexamfetamine were main- Effi cacy tained throughout the trial, suggesting Lisdexamfetamine reduced ADHD symp- the medication sustains ADHD symp- toms in 2 double-blind studies: a phase-2 tom improvement. Controlled trials have crossover study and a phase-3 random- not addressed lisdexamfetamine use >4 dose trial. weeks, however. Clinical Point Phase-2 crossover study.2 Fifty-two Based on parents’ and guardians’ re- IInn oneone sstudy,tudy, children ages 6 to 12 with combined or ports, treatment-group patients’ ADHD cchildrenhildren wwithith hyperactive-impulsive type ADHD re- symptoms were notably less severe at AADHDDHD showedshowed ceived extended-release mixed amphet- 10 am, 2 pm, and 6 pm compared with amine salts (MAS) for 3 weeks. Subjects re- placebo-group children.3 This suggests iimprovementmprovement ceived 10 mg/d or dosages titrated to 20 or that lisdexamfetamine offers a daylong wwithinithin 2 hourshours 30 mg/d based on response to medication. therapeutic effect. aafterfter receivingreceiving The youths then were divided into 3 llisdexamfetamineisdexamfetamine groups based on optimal MAS dosage and received 3 treatments for 1 week each: Tolerability • group 1: placebo; MAS, 10 mg/d; In the phase-3 study,3 162 of 218 (74%) lisdexamfetamine, 30 mg/d children receiving any dosage of lisdex- • group 2: placebo; MAS, 20 mg/d; amfetamine reported an adverse event, lisdexamfetamine, 50 mg/d compared with 34 of 72 (47%) children • group 3: placebo; MAS, 30 mg/d; in the placebo group. Overall, 39% of lis- lisdexamfetamine, 70 mg/d. dexamfetamine-group patients reported While taking lisdexamfetamine or MAS, decreased appetite. Also common were subjects showed similar improvement , headaches, , upper in behavior, based on Swanson, Kotkin, , vomiting, and weight Agler, M-Flynn, and Pelham (SKAMP) loss (Table 2, page 98). scores, and inattention, based on SKAMP Although most adverse events were and Permanent Product Measure of Per- mild to moderate, 9.2% of treatment-group formance scores. children dropped out because of intoler- Both psychostimulants outperformed ability, compared with 1.4% of the placebo placebo in both measures, and both im- group. The investigators increased dosages proved behavior more decisively than quickly, regardless of effi cacy or tolerabili- inattention. Based on post-hoc analysis, ty,3 which might have increased side-effect improvement 12 hours after dosing was incidence among the treatment groups. more substantial with lisdexamfetamine than with MAS. Phase-3 random-dose trial.3 A total of Read about other new 290 children ages 6 to 12 with combined or drugs and innovations at hyperactive-impulsive type ADHD were CurrentPsychiatry.com “washed out” from prior medications over u Click on ‘Browse Back Issues’ 1 week, then received lisdexamfetamine u Then click on ‘Out of the Pipeline’ under Current Psychiatry or placebo for 4 weeks. Treatment-group ‘Browse by Category’ Vol. 6, No. 6 97 continued Out of the Pipeline

Table 2 Rates of commonly reported adverse eff ects during phase-3 lisdexamfetamine (LDX) study Adverse LDX LDX LDX LDX effect 30 mg/d 50 mg/d* 70 mg/d* all dosages Placebo All adverse 72% 68% 84% 74% 47% effects

Decreased 37% 31% 49% 39% 4% appetite

Insomnia 16% 16% 25% 19% 3%

Upper 14% 7% 15% 12% 6% abdominal pain

Headache 10% 10% 16% 12% 10% Clinical Point Irritability 11% 8% 10% 10% 0% ADHD Rating Scale Vomiting 7% 5% 14% 9% 4% score decreases 6% 3% 19% 9% 1% after 1 and 4 *Dosages were randomly titrated regardless of effi cacy or tolerability. weeks suggest that Source: Reference 3 lisdexamfetamine sustains symptom In the phase-2 crossover trial,2 adverse Abuse potential improvement event rates were similar among the lis- As with other psychostimulants indicated dexamfetamine, extended-release MAS, for ADHD, the Drug Enforcement Admin- and placebo groups (15% to 18%). Among istration has classifi ed lisdexamfetamine youths receiving lisdexamfetamine, 8% as a schedule II drug, which applies to ad- reported insomnia and 6% reported appe- dictive prescription-only medications with tite loss, compared with 2% and 4% of the an accepted medical use. MAS group, respectively. Clinical data suggest, however, that lisdexamfetamine might be less “enjoy- able”—and less likely to be abused in- Safety travenously, orally, or intranasally—than Findling et al4 found a larger change in equipotent d-amphetamine. In an abuse corrected QT interval with lisdexamfet- liability study,6 12 adults with histories of amine (7 to 14 msec) than with extended- abuse received intravenous im- 1 release MAS (5 to 10 msec) 5 and 10 ⁄2 mediate-release (IR) d-amphetamine, 10 hours after dosing. The authors reasoned or 20 mg. Two days later, they received a that these fi ndings are atypical, and no comparable dose of IV lisdexamfetamine, children suffered serious adverse events 25 or 50 mg. The researchers found that: during the trial. Nonetheless, more re- • Plasma d-amphetamine peaked with- search on whether lisdexamfetamine in- in 5 minutes after injection, compared creases cardiac risk is needed. with 2 to 3 hours after lisdexamfetamine In a lethal-dose study in rats,5 oral lis- dosing. dexamfetamine doses up to 1,000 mg/kg • Subjects who received IR d-amphet- did not result in death, suggesting the amine said they felt euphoria within 15 min- medication might undergo saturation utes of injection. By contrast, no one report- kinetics in the GI tract that may protect ed euphoria or amphetamine-like subjective against overdose or abuse at higher dosag- effects after receiving lisdexamfetamine. es. By comparison, the median lethal oral When asked which medication they would dosage of d-amphetamine in rats was 96.8 try again, 9 of 12 subjects chose IR d-amphet- Current Psychiatry 98 June 2007 mg/kg.5 amine and 1 chose lisdexamfetamine. continued on page 105 Out of the Pipeline

continued from page 98 In a double-blind, randomized, placebo- Related Resource 7 controlled study, oral lisdexamfetamine, • Lisdexamfetamine Web site. www.vyvanse.com. 50 or 100 mg, was not more “likeable” Drug Brand Names than placebo. Subjects reported “liking” Extended-release mixed amphetamine salts • XR effects with 150 mg of lisdexamfetamine, Lisdexamfetamine • Vyvanse however, suggesting the medication could Disclosure be misused or abused at higher-than- Dr. Wilens receives research/grant support from Abbott therapeutic dosages. Laboratories, Eli Lilly and Company, National Institute on Drug Abuse, NeuroSearch, Ortho-McNeil, and Shire; is a speaker for Novartis Pharmaceuticals Corp., Ortho-McNeil, and Shire; and is a consultant to Abbott Laboratories, Eli Lilly and Company, GlaxoSmithKline, National Institute on Drug Contraindications Abuse, Novartis Pharmaceuticals Corp., Ortho-McNeil, Pfi zer, As with other psychostimulants, do not and Shire. give lisdexamfetamine to youths with pre- existing serious structural cardiac abnor- malities or other heart problems. Assess Clinical Point References patient and family history of heart disease 1. Lopez FA, Boellner SW, Childress A, et al. ADHD symptom DDoo notnot prescribeprescribe before prescribing this medication. improvement in children treated with lisdexamfetamine dimesylate (LDX). Poster presented at: Annual Meeting of llisdexamfetamineisdexamfetamine Do not prescribe lisdexamfetamine to the American Academy of Child and Adolescent Psychiatry; October 24-29, 2006; San Diego, CA. ttoo ppatientsatients ttakingaking patients taking a in- 2. Biederman J, Boellner SW, Childress A, et al. Improvements hibitor (MAOI). By slowing amphetamine in symptoms of attention-defi cit/hyperactivity disorder in aann MAOIMAOI oror wwhoho school-aged children with lisdexamfetamine (NRP 104) and metabolism, these inten- mixed amphetamine salts, extended-release versus placebo. hhaveave takentaken oonene sify ’ effect on monoamine Poster presented at: Annual Meeting of the American Psychiatric Association; May 20-25, 2006; Toronto, Canada. wwithinithin 2 weeksweeks ooff release, which can cause headaches and 3. Biederman J, Krishnan S, Zhang Y, et al. Effi cacy and tolerability ppresentationresentation lead to hypertensive crisis. Before start- of lisdexamfetamine dimesylate (NRP 104) in children with attention-defi cit/hyperactivity disorder: a phase III, multicenter, ing lisdexamfetamine, ask if the patient is randomized, double-blind, forced-dose, parallel-group study. taking an MAOI or has taken one within 2 Clin Ther 2007;29:450-63. 4. Findling FL, Biederman J, Wilens TE, et al. Short- and long- weeks of presentation. term cardiovascular effects of mixed amphetamine salts Use caution when prescribing lisdexam- extended release in children. J Pediatr 2005;147:348-54. 5. Krishnan S. Toxicity profi le of lisdexamfetamine dimesylate fetamine to patients with: (LDX NRP104) in three independent rat toxicology studies. • a comorbid eating disorder or sleep dis- Basic Clin Phamacol Toxicol. In press. turbance. Determine whether to address the 6. Jasinski DR. Abuse liability of intravenous L-lysine-d- amphetamine (NRP 104). Poster presented at: Annual Meeting comorbidity before treating ADHD symp- of the College on Problems of Drug Dependence; June 17-22, 2006; Scottsdale, AZ. Available at: http://xml.10kwizard. toms, and make sure lisdexamfetamine is com/fi ling_raw.php?repo=tenk&ipage=4234033. Accessed not worsening the comorbid symptoms. April 5, 2007. 7. Jasinski D, Krishnan S. A double-blind, randomized, placebo • untreated or other cardio- and active-controlled, six-period crossover study to evaluate vascular conditions, as stimulant medica- the likeability, safety, and abuse liability of NRP 104 in healthy adult volunteers with histories of stimulant abuse (NRP104. tions can increase and heart A03). Poster presented at: Annual Meeting of the College on Problems of Drug Dependence; June 17-22, 2006; Scottsdale, rate. Watch for signifi cant heart rate and AZ. Available at: http://www.secinfo.com/d12Pk6.v9Ac. blood pressure changes in patients taking d.htm. Accessed May 14, 2007. 8. Wilens TE, Zusman RM, Hammerness PG, et al. An open- lisdexamfetamine, which probably would label study of the tolerability of mixed amphetamine salts not cause sustained blood pressure increase in adults with attention-defi cit/hyperactivity disorder and treated primary essential hypertension. J Clin Psychiatry in patients taking antihypertensives.8 2006;67:696-702. Bottom Line IInn clinicalclinical trials,trials, lisdexamfetaminelisdexamfetamine reducedreduced children’schildren’s ADHDADHD symptomssymptoms andand waswas eeffff eectivective iintonto tthehe eevening,vening, ssuggestinguggesting a ddaylongaylong bbenefienefi t.t. SStarttart aatt 3300 mmg/d;g/d; iiff nnecessary,ecessary, titratetitrate bbyy 2200 mmgg eeveryvery 3 ttoo 7 ddaysays ttoo a mmaximumaximum 7700 mmg/d.g/d. MMonitoronitor Current Psychiatry reresponsesponse monthly,monthly, tthenhen llessess frequentlyfrequently aafterfter ssymptomsymptoms areare underunder control.control. Vol. 6, No. 6 105