The Medical Letter. on Drugs and Therapeutics. Objective Drug Reviews Since Volume 57 March 16, Drugs for ADHD... p 37

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1 The Medical Letter on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 March 16, 2015 ISSUE ISSUE No Volume 56 IN THIS ISSUE Drugs for ADHD... p 37 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc. publications are protected by U.S. and international copyright laws. Forwarding, copying or any distribution of this material is prohibited. Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited. By accessing and reading the attached content I agree to comply with U.S. and international copyright laws and these terms and conditions of The Medical Letter, Inc. For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: Published by The Medical Letter, Inc. A Nonprofit Organization

2 The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any other distribution of this material is strictly prohibited. For further information call: The Medical Letter on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 (Issue 1464) March 16, 2015 Take CME exams Drugs for ADHD Recommendations for Treatment of ADHD Attention-deficit/hyperactivity disorder (ADHD) is a disruptive behavior disorder that has been diagnosed in up to 10% of school-age children in the US, most often in boys, and frequently persists into adulthood. 1,2 A recent study in a large Danish cohort found that ADHD was associated with increased mortality in children, adolescents, and adults, mainly due to accidents. 3 Pharmacologic treatment of ADHD has been reported to lower the risk of serious traffic accidents and criminal behavior. 4,5 The drugs approved by the FDA for treatment of ADHD are listed in Table 1 on pages None of these agents (except for short-acting dextroamphetamine) are approved for use in children <6 years old. STIMULANTS All of the stimulants used for treatment of ADHD are classified as schedule II controlled substances by the US Drug Enforcement Administration. METHYLPHENIDATE Methylphenidate has been shown to be effective in reducing ADHD symptoms in both children and adults. 6,7 Short-Acting Immediate-release methylphenidate formulations are rapidly absorbed; effects on behavior can be seen within 30 minutes of administration and persist for 3-5 hours. Their short duration of action usually requires mid-day dosing in school or during after-school programs. Immediate-release methylphenidate tablets are sometimes used in addition to longer-acting formulations, either to provide a boost early in the morning or to smooth withdrawal in the late afternoon. Intermediate-Acting Extended-release methylphenidate formulations have a slower onset of action than immediate-release methylphenidate and a duration of action of up to 8 hours. These drugs may be better tolerated by some children who are sensitive to stimulant side effects, but they have been highly variable in duration and efficacy, and are generally Treatment of ADHD in school-age children or adults should begin with an oral stimulant, either a methylphenidatebased formulation or an amphetamine. The choice of a drug should be based on its rapidity of onset, duration of action, and effectiveness. Mixing short- and long-acting stimulants can be helpful to achieve an immediate effect for early-morning school classes or for reducing rebound irritability or overactivity, especially in the evening. An extended-release alpha 2 -adrenergic agonist may be helpful when used concurrently with a stimulant in patients who cannot tolerate usual doses of the stimulant, particularly those with tics. Atomoxetine is an alternative for patients who cannot tolerate stimulants or for whom treatment with a controlled substance is undesirable. viewed as less useful in practice than immediaterelease or long-acting methylphenidate formulations. Long-Acting Once-daily dosing with long-acting methylphenidate preparations has become the standard clinical practice. Concerta, which has a longer duration of action than Metadate CD, Ritalin LA, or their generic equivalents, has been as effective as multiple doses of immediate-release methylphenidate in reducing symptoms, but some Concerta generic equivalents have been less effective. 8,9 Transdermal methylphenidate (Daytrana) is probably as effective as oral long-acting formulations of the drug, but a 2-hour delay in its onset of action could be a major disadvantage when getting children ready for school in the morning. After application of the transdermal patch, methylphenidate is steadily absorbed and reaches peak serum concentrations after 7-9 hours. Peak methylphenidate levels are higher with chronic doses of the patch than with equivalent doses of Concerta. 10 The duration of action for a 9-hour wear period is about 11.5 hours. Adverse effects such as anorexia, insomnia, and tics have occurred more frequently with the patch formulation than with oral formulations, which may be related to the absence of first-pass metabolism, and mild skin reactions are common. 11 One advantage of the patch formulation is that it can be removed early in patients who have a problem with insomnia. Published by The Medical Letter, Inc. A Nonprofit Organization 37

3 The Medical Letter Vol. 57 (1464) March 16, 2015 Table 1. Some Drugs for ADHD Some Available Duration Pediatric Dosage 1 Adult Dosage Drug Formulations of Action Initial/Usual Initial/Usual Cost 2 Stimulants Dexmethylphenidate generic 2.5, 5, 10 mg tabs 5-6 h 2.5 mg bid/10 mg bid 5 mg bid/15 mg bid Focalin (Novartis) extended-release generic 5, 10, 15, 20, 30, 12 h 5 mg qam/10-20 mg qam 10 mg qam/30 mg qam Focalin XR 3,4 35, 40 mg ER caps Methylphenidate short-acting generic 5, 10, 20 mg tabs; 5 mg/ 3-5 h 5 mg bid or tid/10 mg tid 10 mg bid or tid/20 mg tid ml, 10 mg/5 ml soln Ritalin (Novartis) 5, 10, 20 mg tabs Methylin Chewable 2.5, 5, 10 mg tabs Tablets (Mallinckrodt) Methylin Oral Solution 5 mg/5 ml, (Mallinckrodt) 10 mg/5 ml soln 7 intermediate-acting generic 10, 20 mg ER tabs h 20 mg qam/40 mg qam 20 mg qam/80 mg qam Metadate ER (Upstate) 20 mg ER tabs long-acting generic 10, 20, 30, 40, 8-12 h 20 mg qam/30 mg qam 20 mg qam/80 mg qam Metadate CD 9,10 (UCB) 50, 60 mg ER caps generic 20, 30, 40 mg ER caps h mg qam/30 mg qam mg qam/80 mg Ritalin LA 3,4,9 (Novartis) 10, 20, 30, 40 mg ER caps 5 qam generic 11,12 18, 27, 36, 54 mg ER tabs h 18 mg qam/36 mg qam 18 or 36 mg qam/72 mg Concerta 12 (Janssen) qam Daytrana 13 (Noven) 12.5, 18.75, 25, 37.5 cm h 10 mg patch on 9 hrs, 30 mg patch on 9 hrs, off transdermal patch 14 off 15 hrs/30 mg patch 15 hrs/60 mg patch on on 9 hrs, off 15 hrs 9 hrs, off 15 hrs Quillivant XR 15 (Pfizer) 25 mg/5 ml ER susp h 20 mg qam/30-40 mg qam No data ER = extended-release; SR = sustained-release 1. Dosage for children 6 years old. 2. Approximate WAC for 30 days' treatment with the lowest usual pediatric dosage. WAC = wholesaler acquisition cost or manufacturer s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource Monthly. March 5, Reprinted with permission by First Databank, Inc. All rights reserved Should not be taken with antacids or other drugs that decrease gastric acidity. 4. Contains 50% immediate-release beads and 50% enteric-coated, delayed-release beads. 5. The contents of the capsule may be sprinkled on a small amount of applesauce or ice cream to disguise the bitter taste and given immediately. Pharmacokinetics are identical whether the beads are swallowed whole inside a capsule or sprinkled on food. 6. Cost of one 10 mg/5 ml 500-mL bottle. 7. Available in bottles containing 500 ml. 8. Must be swallowed whole, not crushed or chewed. 9. Alcohol consumption may increase the rate of release of methylphenidate and should be avoided. 10. Contains 30% immediate-release and 70% delayed-release beads. 11. Some generic formulations (manufactured by Mallinckrodt and Kudco) may not be therapeutically equivalent to the brand name product. The generic formulation that is manufactured by Janssen and marketed by Actavis is bioequivalent ( 12. Osmotic-release delivery system that contains 20% of the dose for immediate release and 80% sequestered inside the tablet for release over 6-7 hours. 13. FDA-approved only for use in children 6-17 years old. 14. The four patch sizes deliver 10, 15, 20, or 30 mg over 9 hours, respectively. Daytrana is supplied in sealed trays containing 10 or 30 patches in individual pouches. Quillivant XR is the first liquid formulation of methylphenidate to be approved for once-daily use; how it compares to other long-acting methylphenidate products is unclear. 12 AMPHETAMINES Amphetamines generally have been as effective as methylphenidate in decreasing overactivity, impulsivity, and inattention in children with ADHD. Some children who have not responded to methylphenidate may respond to an amphetamine, and vice versa. Dextroamphetamine The onset of action of immediaterelease dextroamphetamine occurs within one hour of ingestion, and its duration of action is 4-6 hours, somewhat longer than that of methylphenidate. Twice-daily administration can extend the therapeutic effect throughout the school day, but children may dislike taking the second dose in school. Long-acting formulations can be taken once daily. Mixtures Adderall and Adderall XR are mixtures of amphetamine salts. Adderall XR, which contains both immediate-release and extended-release beads, has a hour duration of action. There is no evidence that mixed amphetamine salts offer any advantage over methylphenidate or dextroamphetamine, but some patients may respond to one and not to another. Lisdexamfetamine Lisdexamfetamine dimesylate (Vyvanse) is an oral prodrug that is converted to d-amphetamine and l-lysine by enzymatic hydrolysis

4 The Medical Letter Vol. 57 (1464) March 16, 2015 Table 1. Some Drugs for ADHD (continued) Some Available Duration Pediatric Dosage 1 Adult Dosage Drug Formulations of Action Initial/Usual Initial/Usual Cost 2 Stimulants (continued) Dextroamphetamine 3,17,18 short-acting generic 5, 10 mg tabs; 5 mg/5 ml 4-6 h 5 mg qam or bid 19 /10 mg bid soln Dexedrine (Amedra) 5, 10 mg tabs Zenzedi (Arbor) 2.5, 5, 7.5, 10, 15, 20, mg tabs long-acting generic 5, 10, 15 mg SR caps h 5 mg qam or bid/15 mg qam Dexedrine Spansule (Amedra) Mixed amphetamine salts 3,17 short-acting generic 5, 7.5, 10, 12.5, 4-6 h 5 mg bid/10 mg bid 5 mg bid/15 mg bid Adderall (Teva) 15, 20, 30 mg tabs long-acting generic 5, 10, 15, 20, 25, h 5-10 mg qam/30 mg qam 20 mg qam/60 mg qam Adderall XR (Shire) 30 mg caps Lisdexamfetamine Vyvanse 17 10, 20, 30, 40, 50, 60, h mg qam/30-70 mg qam 30 mg qam/30-70 mg qam (Shire) 70 mg caps Non-Stimulants Guanfacine extended-release 13 generic 1, 2, 3, 4 mg ER tabs h 20 1 mg once daily/1-4 mg Intuniv (Shire) once daily Clonidine extended-release 13 generic 0.1 mg ER tabs 8 12 h mg once daily at bedtime/ Kapvay (Shionogi) mg once daily at bedtime or divided bid 22 Atomoxetine Strattera (Lilly) 10, 18, 25, 40, 24 h 0.5 mg/kg/d once daily or 40 mg once daily/80 mg , 80, 100 mg caps divided bid/1.2 mg/kg/d once daily or divided bid once daily or divided bid 15. Contains 20% immediate-release and 80% extended-release drug particles. 16. Must be reconstituted before administration and is stable for up to 4 months. It is available in bottles containing 60, 120, 150, or 180 ml. Each bottle is packaged with an adapter and dosing syringe. 17. Taking the drug with ascorbic acid or fruit juice decreases its absorption, while alkalinizing agents such as sodium bicarbonate increase its absorption. Acidification of the urine increases amphetamine excretion. 18. FDA-approved only for use in children 3-16 years old (short-acting) or 6-16 years old (long-acting). 19. Initial dose for children 3-5 years old is 2.5 mg once daily. 20. According to the manufacturer. 21. Dosage can be increased in 1 mg/week increments to a maximum dose of 7 mg/day. 22. Up to 0.4 mg/day is FDA-approved but may be more likely to cause hypotension. 23. Cost of 40 mg capsules. The duration of action of lisdexamfetamine is longer than that of other amphetamine preparations, but its efficacy appears to be similar. 14,15 ADVERSE EFFECTS The most common adverse effects leading to discontinuation of treatment with stimulants have been motor or vocal tics, anorexia, insomnia, and tachycardia. Some children, especially teenagers, say that stimulants make them feel less spontaneous and less comfortable in their social interactions. Tactile and visual hallucinations can occur. Stimulants can slow growth; the effect on final adult height is unclear. They should be used with caution in patients with a history of mania, psychosis, drug dependence, or alcoholism. Stimulants rarely can cause priapism; boys and men should be instructed to seek immediate medical attention if it occurs. 16 Despite some earlier concerns, several large studies have found no evidence that stimulants used to treat ADHD increase the risk of serious cardiovascular events in children or adults In the absence of a history or clinical evidence of heart disease, there is no need to require an electrocardiogram or a consultation with a cardiologist before starting treatment with a stimulant. 20 NON-STIMULANTS EXTENDED-RELEASE ALPHA 2 -AGONISTS Two alpha 2 -adrenergic agonists have been approved by the FDA for treatment of ADHD in children 6-17 years old. Neither is a stimulant or a controlled substance. Originally approved for treatment of hypertension, both have been used for years for treatment of ADHD, either alone or concurrently with stimulants, particularly in children with tics. Guanfacine The extended-release formulation of guanfacine (Intuniv, and generics), which has been approved by the FDA both as monotherapy and as an adjunct to a stimulant for treatment of ADHD, leads to higher serum 39

5 The Medical Letter Vol. 57 (1464) March 16, 2015 concentrations of the drug in children than it does in adults. It has been shown to be modestly more effective than placebo in producing improvement in ADHD rating scales, but somnolence has been a problem, and bradycardia, hypotension, and syncope have occurred. 21 Clonidine The extended-release formulation of clonidine (Kapvay, and generics) is FDA-approved as monotherapy and as an adjunct to a stimulant for treatment of ADHD. Children with ADHD treated with Kapvay have shown statistically significant improvements in ADHD rating scales, and children treated with both a stimulant and clonidine have shown significantly greater improvement than those treated with a stimulant alone. 22 Clonidine may be more sedating than guanfacine. ATOMOXETINE A selective norepinephrine reuptake inhibitor, atomoxetine (Strattera) is approved by the FDA for treatment of ADHD in both children and adults. 23 It is neither a controlled substance nor a stimulant. Efficacy Atomoxetine was less effective than methylphenidate in reducing ADHD symptoms in a large randomized, double-blind clinical trial. 24 It has been used for patients who have not responded to or cannot tolerate stimulants, particularly children with low weight and short stature, and those for whom use of a controlled substance is unacceptable. Adverse Effects Somnolence, nausea, and vomiting have occurred in children starting atomoxetine, particularly when the dose is increased from initial to maximum levels within a few days. Atomoxetine rarely can cause priapism; this effect appears to be more common with atomoxetine than with methylphenidate. As with stimulants, boys and men taking the drug should be instructed to seek medical attention immediately if priapism occurs. 1. HM Feldman and MI Reiff. Clinical practice. Attention deficithyperactivity disorder in children and adolescents. N Engl J Med 2014; 370: ND Volkow and JM Swanson. Clinical practice: adult attention deficit-hyperactivity disorder. N Engl J Med 2014; 2013; 369: S Dalsgaard et al. Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015 February 24 (epub). 4. Z Chang et al. Serious transport accidents in adults with attention-deficit/hyperactivity disorder and the effect of medication: a population-based study. JAMA Psychiatry 2014; 71: P Lichtenstein et al. Medication for attention deficit-hyperactivity disorder and criminality. N Engl J Med 2012; 367: L Greenhill et al. Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry 2006; 45: T Epstein et al. Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults. Cochrane Database Syst Rev 2014 Sept 18; 9:CD WE Pelham et al. Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings. Pediatrics 2001; 107:E FDA. Methylphenidate hydrochloride extended release tablets (generic Concerta) made by Mallinckrodt and Kudco. Available at: Accessed March 5, D Coghill et al. Long-acting methylphenidate formulations in the treatment of attention-defecit/hyperactivity disorder: a systematic review of head-to-head studies. BMC Psychiatry 2013; 13: Transdermal methylphenidate (Daytrana) for ADHD. Med Lett Drugs Ther 2006; 48: Quillivant XR an extended-release oral suspension of methylphenidate. Med Lett Drugs Ther 2013; 55: Lisdexamfetamine dimesylate (Vyvanse) for ADHD. Med Lett Drugs Ther 2007; 49: LA Adler et al. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2008; 69: D Elbe et al. Focus on lisdexamfetamine: a review of its use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 2010; 19: LS Eiland et al. Priapism associated with the use of stimulant medications and atomoxetine for attention-deficit/hyperactivity disorder in children. Ann Pharmacother 2014; 48: WO Cooper et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med 2011; 365: LA Habel et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA 2011; 306: H Schelleman et al. Cardiovascular events and death in children exposed and unexposed to ADHD agents. Pediatrics 2011; 127: SA Shahani et al. Attention deficit hyperactivity disorder screening electrocardiograms: a community-based perspective. Pediatr Cardiol 2014; 35: Guanfacine extended-release (Intuniv) for ADHD. Med Lett Drugs Ther 2010; 52: Another extended-release alpha 2 -agonist for ADHD. Med Lett Drugs Ther 2011; 53: Atomoxetine (Strattera) for ADHD. Med Lett Drugs Ther 2003; 45: JH Newcorn et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry 2008; 165:

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