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CONTINUING EDUCATION Attention Deficit/Hyperactivity Disorder: Case-Based Therapeutic Update by Ashley Khan, PharmD June 2, 2014 (expires June 2, 2017) Activity Type: Knowledge-based To earn continuing education credit: ACPE Program 207-000-14-006-H01-P 207-000-14-006-H01-T Upon successful completion of this article, the pharmacist should be able to: 1. Describe the pathophysiology of attention deficit/hyperactivity disorder (ADHD) and the clinical signs and symptoms. 2. Identify notable differences in ADHD between children and adults, and address differing perceptions of the disorder in girls and boys. 3. Select appropriate treatment options for patients from standard and new regimens, and discuss patient counseling conversations that could address knowledge gaps about dietary and alternative treatments for ADHD. 4. Identify the risks for potential abuse and the signs of such abuse in pediatric and adult populations. In this context, interpret the latest research about true abuse risks that could guide patient counseling. 5. Detail the drug interactions possible in outpatient populations, especially those that have clinically relevant consequences in patients with mental health disorders. Upon successful completion of this article, the pharmacy technician should be able to: 1. D escribe the pathophysiology of attention deficit/hyperactivity disorder (ADHD) and the clinical signs and symptoms. 2. Identify notable differences in ADHD between children and adults, and address differing perceptions of the disorder in girls and boys. 3. D iscuss how OTC and dietary supplement purchases are influenced by seeking dietary and alternative treatments for ADHD. 4. Identify the risks for potential abuse and the signs of such abuse in pediatric and adult populations and bring to the attention of a pharmacist. 5. Identify common drug interactions possible in patients taking prescription drugs to treat ADHD. NCPA® is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCPA has assigned 1.5 contact hours (0.15 CEU) of continuing education credit to this article. Eligibility to receive continuing education credit for this article expires three years from the month published. FREE ONLINE CE. To take advantage of free continuing pharmacy education (CPE) for this program, pharmacists and pharmacy technicians must achieve a passing score of 70% on the online continuing education quiz for the program. If a passing score is not achieved, one free reexamination is permitted. To take this test, go to www.pharmacistelink.com and click on the CE tab. Click on the CE Center, which will take you to the online activities that are available. If you have not registered with Pharmacist eLink, you must do so before being able to access the CE Center. You will receive immediate online test results and credits will be posted to CPE Monitor within six weeks. To obtain your CPE Monitor e-Profile ID, please go to www.cpemonitor.com to register. www.americaspharmacist.net45 As a highly diagnosed DSM-5 mental health disorder, attention deficit/hyperactivity disorder afflicts both children and adults as a chronic, treatable condition. However, within-class treatment options and dosages vary considerably because of patient tolerability, safety concerns, and efficacy differences. Additionally, new treatment options and recurring evaluations of medication abuse, safety, and treatment durations continue to change how clinicians view ADHD treatment options. A review of current literature and therapy approaches is warranted periodically to update practitioners about best practices. OVERVIEW The Centers for Disease Control and Prevention estimates that approximately 11 percent of children between the ages of 4 and 17 suffer from ADHD. The American Academy of Pediatrics cites it as the most common psychiatric disorder in children and adolescents. Approximately 4 percent of adults also carry the diagnosis, and the prevalence is rising in all age groups. As researchers gain a better understanding of this neurobehavioral disorder, diagnostic criteria and treatment recommendations continue to evolve, and new medications are being introduced within established treatment classes. Stimulants remain a mainstay of treatment for ADHD, and concerns about their abuse continue to be a source of debate among the public and researchers alike. Questions also linger about the effectiveness of alternative therapies and dietary modifications. As patients and families rely more on the Internet and less on physicians for health information, pharmacists have an opportunity to provide education and reliable resources and promote safe and optimal use of medications for the long-term treatment of this chronic disorder. PATHOGENESIS AND RISK FACTORS Although the precise mechanisms underlying ADHD remain unclear, an imbalance in catecholamine activity in several regions of the brain is believed to play a critical role. Reduced activity of the neurotransmitters norepinephrine and dopamine in several brain regions appear to impair mental and emotional functioning in patients with ADHD. Neuroimaging studies note structural differences in particular brain regions of patients with ADHD. Relative to those of people without ADHD, variations exist in the size, thickness, and symmetry of areas within the prefrontal cortex, cerebellum, and caudate nucleus. The imaging also indicates that children with ADHD have less activity in and less development of the basal ganglia, prefrontal cortex, and cerebellum. The prefrontal cortex plays a significant role in executive functioning; it mediates decision making, organization, attention, and social behavior. The basal ganglia, which includes the caudate nucleus, interacts with 46 the prefrontal cortex and responds primarily to dopamine. As part of the limbic system, it influences emotions and reward learning. The cerebellum contributes to cognitive functions such as attentiveness, although it is primarily known for its role in motor control. Among the causative factors of ADHD, genetics may account for up to 75 percent of all cases. The disorder has a strong hereditary component; children with parents or siblings with ADHD are more likely to develop it. To date, most studies on genetic risk have focused on the role of the particular genes that influence the action of dopamine in the brain. Another 10-15 percent of cases may be attributed to a wide variety of early environmental insults. Prenatal and perinatal exposure to drugs, alcohol, or nicotine through maternal abuses has been tied to the development of ADHD. Low birth weight for any reason may possibly be linked to the disorder as well. Other insults during the early postnatal period, such as head trauma, brain hypoxia, and lead poisoning, also increase the risk of developing ADHD. CLINICAL FEATURES AND DIAGNOSIS ADHD develops in childhood, regardless of age at diagnosis, and the disease is characterized in children or adults by symptoms of inattention and/or hyperactivity and impulsivity that persist for at least six months. The symptoms must be significant enough to negatively affect functioning or development in both social and academic or occupational settings. The disorder can be further classified into three subtypes according to the specific symptoms exhibited: predominantly hyperactive/impulsive, predominantly inattentive, or combined. Diagnosis of ADHD and the subtype in all patients is based on an assessment of nine specific symptoms of hyperactivity-impulsivity and nine symptoms of inattention. Symptoms of hyperactivity and impulsivity, particularly in children, include fidgeting or squirming; leaving one’s seat or running and climbing about inappropriately; being unable to remain quiet; talking excessively; blurting out responses and interrupting others; and having difficulty waiting one’s turn. Inattention, though less obvious than hyperactive disturbances, is an equal contributor to diagnosis. Inattention presents as failure to focus on tasks or details; poor listening and organization skills; failure to complete activities; avoidance of tasks that require prolonged mental effort; forgetfulness; and problems with misplacing items and getting distracted by external stimuli. Table 1 lists these diagnostic criteria according to the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), released in 2013. To reflect new research and help clinicians better diagnose ADHD in patients of all ages, the DSM-5 includes America’s PHARMACIST | June 2014 Table 1. DSM-5 Diagnostic Criteria for Attention Deficit/Hyperactivity Disorder (A)A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development, as characterized by (1) and/or (2). For patients under age 17 years, six or more symptoms of (1) and/or six or more symptoms of (2) must have persisted for at least six months. For patients age 17 years and older, at least five symptoms from a single category are required. (1)Inattention: a.Often fails to give close attention to details or makes careless mistakes in schoolwork, at work or during other activities b.Often has difficulty sustaining attention in tasks or play activities c.Often does not seem to listen when spoken to directly d.Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace e.Often has difficulty organizing tasks and activities f.Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort g.Often loses things necessary for tasks or activities h.Is often easily distracted by extraneous stimuli i.Is often forgetful in daily activities (2)Hyperactivity-Impulsivity: a.Often fidgets with or taps hands or feet or squirms in seat b.Often leaves seat in situations when remaining seated is expected c.Often runs about or climbs in situations where it is inappropriate d.Often unable to play or engage in leisure activities quietly e.Is often “on the go,” acting as if “driven by a motor” f.Often talks excessively g.Often blurts out an answer before a question has been completed h.Often has difficulty waiting his or her turn i.Often interrupts or intrudes on others (B)Several inattentive or hyperactive-impulsive symptoms were present prior to age 12 years. (C)Several inattentive or hyperactive-impulsive symptoms are present in 2 or more settings. (D)There is clear evidence that symptoms interfere with, or reduce the quality of, social, academic, or occupational functioning. (E)The symptoms do not occur exclusively during the course of schizophrenia or another psychotic disorder and are not better explained by another mental disorder. Presentation Subtypes Combined: Both Criterion A1 and Criterion A2 are met for the past 6 months Predominantly inattentive Criterion A1 is met but Criterion A2 is not met for the past 6 months Predominantly hyperactive-impulsive Criterion A2 is met but Criterion A1 is not met for the past 6 months Adapted from DSM-5 substantial updates for two criteria. One key diagnostic change pertains to the time of symptom onset. Through the release of DSM-IV, diagnosis focused on symptom presentation before age 7 years. Now, the DSM-5 extends the time period for symptom identification to before age 12. The updated DSM-5 also makes a distinction between the number of symptoms needed for diagnosis for children and older patients. Six of nine symptoms from at least one of the two groups (inattention or hyperactivity-impulsivity) must be present for children to be diagnosed with ADHD. However, in older adolescents (age 17 and older) and adults, only five symptoms in a given group are required. The DSM-5 provides a better framework for clinicians to assess patients of any age who may have ADHD; it acknowledges ADHD as a chronic condition that requires long-term care. Roughly two-thirds of patients diagnosed as children endure residual symptoms into adulthood. As more research supports this persistence of symptoms, more attention is being directed at recognizing adults with ADHD. The medical community now acknowledges that these individuals do not necessarily “grow out” of this disorder and require continued treatment. Moreover, although a new diagnosis in adults is less common, it can also occur as a result of earlier diagnostic delays and can still be treated at any age. www.americaspharmacist.net47 Table 2. Summary of FDA-Approved Medications for the Treatment of ADHD Stimulants Methylphenidate-based Drugs Amphetamine-based Drugs Brand Names MPH: Ritalin, Methylin; Ritalin-SR, Metadate ER; Ritalin LA, Metadate CD; Concerta; Quillivant XR; Daytrana; DMPH: Focalin, Focalin XR Mixed amphetamine salts: Adderall, Adderall XR; DAMPH: Dextrostat, Procentra, Dexedrine Spansule; LDX: Vyvanse Generic Availability Yes for all except Quillivant XR and Daytrana Yes for all except Vyvanse Formulations IR products: tablet, chewable tablet, oral solution; ER products: tablet, capsule, oral suspension, transdermal patch IR products: tablet, oral solution; ER products: capsule FDA Approvals for ADHD Children ages 6-17 years and adults, except transdermal MPH, which is only approved for children ages 6-17 years Mixed amphetamine salts and IR DAMPH tablets: children ages 3-17 years and adults; IR DAMPH solution: children ages 6-17 years; ER DAMPH and LDX: children ages 6-17 years and adults Recommended Initial Daily Dose MPH: 10 mg - 20 mg; OROS tablet: 18 mg; DMPH: 5 mg Mixed amphetamine salts: Ages 3 to 5: 2.5 mg; Ages 6-17: 5 mg - 10 mg; Adults: 20 mg; DAMPH: Ages 3 to 5: 2.5 mg; Ages 6-17: 5 mg - 10 mg; Adults: 10 mg; LDX: 30 mg Maximum Daily Dose MPH: Labeled: 60 mg; Off-label: 100 mg if over 50 kg; OROS tablet: Labeled: 54 mg; Off label: 72 mg if adolescents/adults; DMPH: IR products—Labeled: 20 mg; Offlabel: 50 mg; ER products—Labeled: 30 mg (children), 40 mg (adults); Off-label: 50 mg Mixed amphetamine salts: IR products—40 mg, rarely up to 60 mg; ER products—Labeled: 30 mg; Off-label: 60 mg if over 50 kg; DAMPH: 40 mg, rarely up to 60 mg; LDX: 70 mg Dose Adjustments Weekly as needed Administration Considerations All: Take in the morning and/or early afternoon; ER Products: Wax matrix tablets and OROS tablets must be taken whole, but all other oral ER products can be opened and contents sprinkled over applesauce; Patch: store in pouch. Once tray opened, use within 2 months; once an individual patch has been removed from pouch and protective liner, use immediately. Do not refrigerate or freeze. Common Adverse Reactions Decreased appetite, weight loss, headache, insomnia, mood lability, GI upset, and tics; Rare: serious cardiac events, sudden death Storage Store at room temperature, and protect from light. Safety Information Avoid use in patients with tics or cardiac conditions All: Take in the morning and/or early afternoon; ER Products: Capsules can be opened and contents sprinkled over applesauce. LDX: Tablets can be dissolved in water MPH: methylphenidate; DMPH: dexmethylphenidate; DAMPH: dextroamphetamine; LDX: lisdexamfetamine; IR: immediate-release; ER: extended-release; yo: years old 48 America’s PHARMACIST | June 2014 Selective Norepinephrine Reuptake Inhibitors Alpha-2 Adrenergic Agonists Atomoxetine Clonidine Guanfacine Strattera Kapvay Intuniv No No No IR capsule ER tablet ER tablet Children ages 6 years and older and adults Children ages 6-17 years, as monotherapy or adjunct to stimulants Patients up to 70 kg: 0.5 mg/kg Patients > 70 kg: 40 mg 0.1 mg 1 mg 1.4 mg/kg 0.4 mg 4 mg Can increase dose after the first 3-4 days of therapy; then increase every 2-4 weeks as needed Weekly as needed; must taper dose when discontinuing Swallow capsules whole Initially, take at bedtime. Tablets cannot be crushed, chewed, or broken. Decreased appetite, headache, insomnia, GI upset, and dry mouth Dry mouth, somnolence, dizziness, headache, constipation, and hypotension Increased risk of suicidal ideation in pediatric patients ER and IR formulations are not interchangeable on a mg:mg basis; retitrate if switching between the two www.americaspharmacist.net49 Some special consideration should be given to how adults present with ADHD. As patients grow older, they typically suffer from less hyperactivity but experience more inattention and impulsivity. However, when adults do exhibit signs of hyperactivity, those symptoms are often less overt than in their younger counterparts. These features, coupled with disorganization, are especially detrimental to home and work life for adults. Statistically, these symptoms are manifested in higher rates of car accidents, job turnover, and divorce, as well as lower income. In a 2008 multinational study, ADHD was associated with 143.8 million lost days of productivity, defined by a combination of missed days and reduced quality and quantity of performance on the job. Clinicians face additional challenges when assessing adults, because an accurate childhood history is required for the diagnosis. Clinicians must also consider medical and psychiatric comorbidities, such as traumatic brain injury, seizures, dementia, learning disabilities, and substance abuse disorders. If these or other psychiatric morbidities remain uncontrolled, they may mimic or worsen the symptoms of ADHD. Any urgent psychiatric conditions or active substance abuse should be addressed first before directing full attention to the management of ADHD. ADHD is often accompanied by comorbid psychiatric conditions, many of which have overlapping symptoms. Approximately 80 percent of adults with ADHD have at least one coexisting condition, many of which are psychiatric in nature. An estimated 30-50 percent of patients have suffered from depression; 40-60 percent anxiety; and 50 percent, substance abuse. Other common psychiatric comorbidities seen in adult ADHD patients include bipolar disorder and antisocial personality disorder. In children, anxiety disorders, sleep disorders, autism, learning disabilities, and oppositional-defiant disorder may coexist with ADHD. As many as 14 percent of children with ADHD are also diagnosed with oppositional-defiant disorder, in which aggression and antisocial behavior become prominent. Symptom presentation can also differ along gender lines. Boys are more likely than girls to be diagnosed with ADHD of either type. Boys are more likely to have the combined type, whereas girls are usually diagnosed with the predominantly inattentive type. The CDC estimates that the maleto-female ratio is 4:1 for the predominately hyperactive-impulsive type and 2:1 for the predominantly inattentive type of ADHD. However, it is unclear whether this disparity is a function of biology, diagnostic oversight, or both factors. To elucidate the relationship between gender and ADHD, researchers are beginning to evaluate how hormonal 50 and genetic differences influence ADHD symptoms and compensatory responses, self-perception, and societal attitudes. A 2004 U.S. survey of children with ADHD, as well as parents and teachers, suggests that girls with ADHD respond differently to societal demands as they attempt to manage their disorder. In part, because of the expectations of women in the American culture, girls with ADHD ultimately suffer from lower self-esteem in their efforts to cope. Society’s frequent mislabeling and misperceptions of behavior in girls often precipitates their emotional deterioration. This impairment in females is further compounded by the higher rates of diagnosis during adolescence, a time when puberty and social pressures pose exceptional challenges. Girls with ADHD are more likely to experience depression, be rejected by their peers, and perform worse in school. As girls transition from adolescence into adulthood, those same difficulties persist unless the disorder is accurately diagnosed and effectively treated. Diagnostic accuracy may now improve with use of the Neuropsychiatric EEG-Based Assessment Aid (NEBA) System. Approved by the Food and Drug Administration in July 2013, its purpose is to help health care providers confirm a diagnosis of ADHD or support the decision for additional testing in children ages 6-17 years. This noninvasive test calculates the ratio of theta to beta wave frequencies in the brain, which has been shown to be higher in ADHD patients than in others. Diagnostic confirmation by the NEBA System can help ensure that treatment is appropriately prescribed. TREATMENT APPROACH A multimodal approach remains the mainstay of treatment for all patients. Multimodal therapy encompasses a wide variety of treatments, such as psychoeducation, schoolbased interventions, family counseling, and pharmacotherapy. Treatment can be individualized to best suit the needs of the child and family or of the adult patient. However, cognitive and behavior therapies are often less accessible to patients (http://www.helpguide.org/mental/ adhd _ add _ therapy _ supplement.htm). In some cases, families cannot afford these therapies, or regions may have limited availability and resources for programs. In other instances, the time commitment needed for the success of behavioral therapies pose challenges. Consequently, medications become a central player in the management of ADHD. Just over two-thirds of children diagnosed with ADHD take medications to treat the disorder. Adolescents are more likely than younger children to take medications, and boys are almost three times more likely than girls to receive prescription therapy. The majority of adults with ADHD also report taking medications to manage the condition. America’s PHARMACIST | June 2014 The 2011 practice guidelines from the American Academy of Pediatrics (AAP) offer updated treatment recommendations for children ages 4-18 years. Like the DSM-5, the AAP practice guidelines acknowledge that ADHD is a chronic condition; this consideration is reflected in some of the recommendations. Although these guidelines are limited to pediatric patients, clinicians generally agree that applying the same principles to adults is appropriate. The AAP makes a few distinctions in the specific therapy recommendations for children depending on their age. For children the ages of 4-5 years (considered preschool age), behavior therapy is the initial treatment. After approximately three months, if the behavioral interventions are unsuccessful and symptoms remain moderate or severe, then clinicians may prescribe methylphenidate. If behavior therapy is unavailable, the decision to start a medication at an early age is based on the risks and benefits to the child. For children ages 6-11 years (elementary school age), the guidelines indicate that clinicians can prescribe FDA-approved drugs for ADHD or initiate behavior therapy; a combination of both is preferred. Finally, for patients aged 12-17 years, clinicians are encouraged to prescribe FDA-approved drugs for ADHD, after obtaining consent from the both the parent and the adolescent. Clinicians may also prescribe behavior therapy, which when coupled with medication is preferred in this age group, too. of short- versus long-acting products because the drug formulations vary considerably. Coexisting conditions and potential adverse effects may also steer drug selection. For example, stimulants may exacerbate symptoms of comorbid anxiety and tic disorders; such patients may respond better to guanfacine or clonidine. Finally, the patient’s preference and the cost of the medication should also be considered. Typically, generic medications and short-acting agents are less expensive. FIRST-LINE THERAPY: STIMULANTS Although the precise role of catecholamines in ADHD is not fully understood, stimulants combat the symptoms of the disorder through their effects on these neurotransmitter levels. Both amphetamines and methylphenidate prompt the release of dopamine and norepinephrine in the central nervous system and also prevent their reuptake at the synapses. The resulting rise in concentrations of these catecholamines in the brain improves the function of vital brain regions connected with classic ADHD symptoms. Stimulants have a long-demonstrated history of effectiveness at reducing hyperactivity and impulsivity and improving attention, social behaviors, and concentration. Since their development more than 50 years ago, these drugs and subsequent variations have been used to treat the symptoms of what was ultimately classified as ADHD in the 1980s. Decades of effectiveness, coupled with the benefit of immediate symptomatic improvement upon drug administration, have helped this class maintain its leadership status in ADHD treatment. FDA-APPROVED DRUGS FOR ADHD In most cases, the clinician’s first-line drug therapy is a schedule II stimulant; options include methylphenidateand amphetamine-based products. As a class, stimulants are an effective treatment for ADHD; more than 80 percent of patients experience improved symptom control with one of these agents. Three nonstimulants—atomoxetine, guanfacine, and clonidine—are also available in formulations with an FDA-approved indication for ADHD. These second-line agents are generally reserved for use when stimulants are ineffective or cause unacceptable side effects, or when special situations favor their selection first. For example, a second-line agent is generally more appropriate in patients with cardiac arrhythmias, which precludes the use of stimulants. Table 2 provides a summary of the current FDA-approved drugs for treating ADHD. All FDA-approved stimulants for the treatment of ADHD are variations of methylphenidate or amphetamine. A multitude of immediate-release (IR) and extended-release (ER) formulations are on the market. Although all but one are orally administered, the products are distinguished by their drug delivery systems and associated dosage schedules. The risk evaluation and mitigation strategies (REMS) for stimulant agents requires a medication guide to accompany all new and refill prescriptions. This medication guide describes the risks for heart-related problems, mental (psychiatric) problems, and circulation problems in fingers and toes. Medication guides can be downloaded from http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm if one does not accompany the manufacturer’s bottle. When choosing an initial medication among the many available agents, clinicians must take into account several factors on a case-by-case basis. The desired duration of symptom coverage, the feasibility of multiple daily dosing, and the ability of the patient to swallow the prescribed dosage form need to be evaluated. These practical considerations can influence decisions about the appropriateness Methylphenidate: Today’s Drug of Choice Methylphenidate IR products are available as tablets, chewable tablets, and as an oral solution. IR brand names Ritalin and Methylin are well known; generic products are available for the tablets and oral solution. All of the methylphenidate IR formulations are FDA-approved for use in patients 6 years of age and older. There is some evidence www.americaspharmacist.net51 for its effectiveness in preschool age children, but use of methylphenidate in this population remains off-label. It is worth noting that when drug therapy is warranted in preschool age children, the AAP practice guidelines prefer the use of IR methylphenidate. For children, usual daily doses of IR products range from 10 mg to 30 mg, depending on the patient’s age and weight. Typically, 5 mg twice daily is the recommended starting dosage, although 10 mg twice daily can be considered at the time of initiation in children older than 8 years or heavier than 25 kg. Adults can tolerate starting dosages of 5 mg to 10 mg two to three times per day. In all patients, the FDA does not recommend exceeding daily doses greater than 60 mg of methylphenidate, although 100 mg per day has be used in patients weighing more than 50 kg. All of the IR products have a 3-5 hour duration of action, which necessitates multiple administrations during the day. Methylphenidate is preferably given 30-45 minutes before meals, usually breakfast and lunch, and no later than 6 p.m. if a third daily dose is necessary. This offsets the effect of food in delaying the time to reach maximum blood concentrations and the potential for insomnia with late evening administration. However, clinicians do sometimes encourage patients to take these products with meals to minimize the loss of appetite, which often occurs secondary to stimulant use. ER versions of methylphenidate expand the daily dosage flexibility beyond IR capabilities. The variety of such methylphenidate ER products is considerable. Tablets, capsules, oral solutions, and patches are marketed to meet the various needs and preferences of patients. Wax matrix tablets (Ritalin-SR and Metadate ER) are designed to provide slow and continuous release of methylphenidate into the bloodstream. This results in a more gradual onset, as well as a longer duration of action, up to eight hours. These ER products can be administered once or twice daily without regard to meals, depending on the duration of coverage desired by the patient. Generally, children and adults who tolerate a regimen of the IR methylphenidate product can be switched to the closest eight-hour dosage equivalent available in the wax matrix tablets, if this type of coverage is preferred. The smallest strength of Ritalin-SR and its generic equivalents is 20 mg; for Metadate ER, it is 10 mg. Unlike the IR counterparts, these tablets cannot be crushed, chewed, or broken. Capsules filled with a mixture of immediate- and long-acting beads (Ritalin LA and Metadate CD) provide rapid and durable symptom control in one formulation. The Ritalin LA mixture is evenly divided between IR beads and enteric-coated, delayed-release beads. Formulations with 52 this SODAS technology provide a drug release that mimics twice daily dosing of conventional IR methylphenidate. Alternatively, Metadate CD is composed of 30 percent IR beads and 70 percent ER beads; in this design, a portion of the dose is released immediately, and the rest then is released gradually into the bloodstream. Both products have an approximate duration of action of 6-9 hours, so the capsules can be taken once daily every morning. Although the whole capsule and the beads within cannot be crushed or chewed, it is acceptable, especially when dosing for young children, to sprinkle the contents of the capsule over applesauce for immediate ingestion. The typical starting dosage of both products is 20 mg daily for children and adults. Concerta provides a combination of IR and ER methylphenidate activity in tablet form by employing OROS technology. Concerta tablets have an IR overcoat but then rely on osmotic pressure to release most of the drug from the tablet over a 12-hour time period. Because of its extended coverage, Concerta is administered once every morning; its starting dose in all patients is 18 mg. The FDA notes a maximum daily dose of 54 mg in children and 72 mg in adults; higher doses have been prescribed off-label. Although the tablet must be swallowed whole to maintain its distinct coating and pressure drug releases, meals have no significant effect on the drug’s absorption. Because the tablet’s outer shell and elements of the inner core are insoluble, patients may notice something that resembles a tablet in their stools. Advise patients that the drug has been delivered properly, and this elimination of the shell is normal. The package insert also states that the tablet may be visible on digitally enhanced abdominal x-rays. The above, established methylphenidate formulations are all available in generic equivalents. Be sure to note that these generics are not necessarily bioequivalent with each other but only with their corresponding brand formulation. Two new ER methylphenidate products are available as brand names only. Daytrana is a transdermal patch approved in 2006 for the treatment of ADHD in children ages 6-17 years, although it is prescribed off-label to adults. Transdermal administration of the drug slows its rate of absorption compared with oral IR products, so Daytrana should be applied two hours before symptom control is needed. Daytrana is worn for nine hours every day, which provides a duration of action approaching 12 hours. However, the patch can be left on the body for up to 16 hours if longer symptom control is desired. The initial dose is 10 mg for patients who are just starting methylphenidate or converting from an oral formulation. Patches are available in 10-, 15-, 20-, and 30-mg (maximum) strengths, and are supplied in sealed pouches; patches should be used immediately after removal from the America’s PHARMACIST | June 2014 individual pouches. Additionally, Daytrana should be applied to clean, dry skin on the hip area, alternating sites each day. Counsel caregivers or mature patients that the waistline should be avoided because clothing may cause the patch to rub off and to avoid application to oily, irritated or damaged skin. Bathing and swimming may also reduce the patch’s adherence to the skin; exposure to heat may increase drug absorption from the patch. Quillivant XR, the newest methylphenidate treatment option, is the first ER oral suspension. It became available in 2013 and is approved for patients 6 years of age and older. The 5 mg/mL, banana-flavored suspension offers long-awaited flexibility in dosing options for children who cannot swallow whole tablets. Quillivant XR is administered once daily in the morning without regard to meals, and it has a duration of action of approximately 12 hours. The starting dose is 20 mg for all patients, and like most other oral methylphenidate products, 60 mg is the maximum daily dose. The drug is manufactured as a powder for suspension that the pharmacist must reconstitute before dispensing. After reconstitution, it has a shelf life of up to four months at controlled room temperature. Patients should shake the product vigorously for 10 seconds before each administration to ensure accurate dosing. Methylphenidate can be provided in isomeric formulations, also. Dexmethylphenidate is the more active isomer of methylphenidate, and IR and ER formulations are marketed for patients 6 years of age and older. Focalin, or its generic equivalent, lasts approximately 4-5 hours and is given twice daily. Focalin XR, which was made available as a generic product in late 2013, has a duration of action of 8-12 hours. Focalin XR uses the same delivery system (SODAS) as Ritalin LA, that mimics twice daily dosing in the convenience of one capsule. The initial total daily dose for either product is 5 mg in children and 10 mg in adults. Patients may take the capsules whole or sprinkle the contents over applesauce for immediate use. Like other long-acting medications, Focalin XR should not be crushed or chewed. Amphetamines: Another First-Line Option Mixed and single amphetamine salt products contribute additional treatment options for prescribers. Although all of the IR formulations are FDA-approved in children 3-17 years of age, the AAP practice guidelines do not endorse their use in preschool age children, citing insufficient evidence for both its safety and efficacy. The AAP asserts that approval in children younger than age 6 years was more a result of lenient criteria than empirical research. All of the amphetamine-based stimulants have been used to treat ADHD in adults, although some currently lack FDA indications in this population. There are two oral formulations of mixed amphetamine salts, composed of 75 percent dextroamphetamine and 25 percent l-amphetamine. Originally known as Adderall but now only manufactured as a generic, the IR product lasts 5-8 hours, which offers somewhat longer symptom control than the IR methylphenidate products. Once or twice daily dosing is reasonable according to symptoms; however twice daily administration should be imbalanced, with a larger dose in the morning to minimize the potential for sleep disturbances. Although the maximum recommended daily dose of the IR product is 40 mg in all patients, clinicians should start at 2.5 mg to 5 mg per dose in children and 10 mg in adults. Adderall XR, or its generic equivalent, is an ER formulation approved for patients age 6 years and older. Common starting doses are 10 mg in children and 20 mg in adults; the FDA has approved total daily doses up to 30 mg. Adderall XR lasts 10-12 hours and is given once daily without regard to meals. Like other capsules formulated for ADHD, its contents can be sprinkled on applesauce for immediate use but cannot be crushed or chewed. Dextroamphetamine is an isomer of amphetamine that also comes in a variety of dosage forms: a short-acting tablet, a solution, and a long-acting capsule. The IR tablet Dextrostat, now only available as a generic product, lasts 4-6 hours; it is given two to three times a day. ProCentra, or its generic equivalent, is a 5 mg/5 ml, bubble gum-flavored oral solution of dextroamphetamine that has the same duration of action and dosing as the IR tablet. Starting doses for these IR dextroamphetamine formulations are 2.5 mg to 5 mg per dose in children, and 10 mg per dose in adults. A long-acting product, Dexedrine Spansule, or its generic equivalent, is a capsule composed of a mixture of IR and ER beads that provide coverage for 6-8 hours. Similar to Metadate CD, this formulation is designed to release some of the drug immediately and the rest of the dose gradually. Although twice daily dosing is acceptable, once daily dosing is more common. Doses are initiated at 5 mg in children and 10 mg in adults. The same administration guidelines for other long-acting capsules for ADHD apply to this product, too. A new amphetamine derivative approved in 2007, lisdexamfetamine (Vyvanse) offers another novel delivery mechanism. This agent functions as a prodrug, requiring conversion to dextroamphetamine in the gastrointestinal tract for activation. Lisdexamfetamine has a duration of 10-12 hours in children, although it may last up to 14 hours in adults. The gelatin capsules should be taken once daily, either whole or with the powder contents dissolved in a glass of water for immediate use. The initial dose for patients of all ages is 30 mg; the maximum is 70 mg per day according to the manufacturer. The need for activation www.americaspharmacist.net53 in the gut also reduces its abuse potential, which may be useful in some patients. SECOND-LINE THERAPY: NONSTIMULANTS Selective Norepinephrine Reuptake Inhibitors: Atomoxetine Atomoxetine, sold under the brand name Strattera, is a non-stimulant FDA-approved for the treatment of ADHD in children 6 years of age and older as well as adults. This drug works as a selective norepinephrine reuptake inhibitor and lasts at least 10-12 hours. The total prescribed dose can be administered either once daily or divided into two doses. If the patient weighs 70 kg or less, the starting dose is approximately 0.5 mg/kg/day (maximum dose 1.4 mg/kg/ day); those weighing more than 70 kg can begin with 40 mg (maximum daily dose 100 mg). Unlike stimulants, atomoxetine has a gradual onset of effect. It may take 1-2 weeks for symptoms to start improving, and roughly 4-6 weeks are necessary to see the full benefit at a given dose. The delay results from the time required for synaptic changes in the brain to occur, which atomoxetine mediates. Although the response rate (approximately 60 percent) is lower than that of methylphenidate, atomoxetine may be more appropriate in those with significant anxiety or substance abuse. It causes less nervousness, irritability, and insomnia than stimulants and also lacks addictive properties. Atomoxetine should not be taken with, or within two weeks of, a monoamine oxidase inhibitor (MAOI) and, like the stimulants, must be dispensed with a medication guide that describes risks for suicidal thoughts and actions in children and adolescents and the risk for severe liver damage (for online enrichment, the med guide can be downloaded at http://www. fda.gov/downloads/Drugs/DrugSafety/ucm089138.pdf). Alpha-2 Adrenergic Agonists: ER Clonidine and ER Guanfacine The alpha-2 adrenergic agonists guanfacine and clonidine also play a role in the treatment of ADHD. Alpha-2 adrenergic agonists were originally marketed as antihypertensive medications but were found to be useful in ADHD because of their modulation of norepinephrine in the CNS. These agents appear most useful in decreasing irritability, mood swings, overarousal, and tics. ER formulations of both drugs have FDA approval for use in children 6-17 years old as a monotherapy and also as an adjunct to stimulants. Kapvay, an ER clonidine tablet, has a duration of action of at least 10-12 hours and is given twice daily. However, patients should begin at a dosage of 0.1 mg at bedtime; then clinicians can titrate doses by 0.1 mg per week up to 0.4 mg per day total in divided doses. Intuniv, an ER guanfacine tablet, lasts at least 8-12 hours. It should be given once daily at a typical starting dose of 1 mg; the FDA-approved maximum dose is 4 mg per day. It should not be adminis54 tered with high-fat meals, as this increases drug exposure. These alpha-2 adrenergic agonist tablets should not be crushed, chewed, or broken because of their ER properties. Because abrupt withdrawal of alpha-adrenergic activity can precipitate transient elevations in blood pressure, the dose of either agent must be tapered if therapy is to be discontinued. Pharmacists should help patients who are instructed by the prescriber to discontinue treatment by planning a slow taper. ER clonidine doses should be decreased by no more than 0.1 mg every 3-7 days, and ER guanfacine doses should be decreased by no more than 1 mg every 3-7 days. Off-Label Drugs for ADHD A few medications have been used off-label to treat ADHD, most often in adult populations. Research to substantiate the use of these drugs is slim. Practice guidelines for the pediatric population do not endorse the use of any off-label agents. Modafinil (Provigil), a drug primarily used for the treatment of narcolepsy, has shown some effectiveness in ADHD at doses of 200 mg to 300 mg per day. The precise mechanism in this setting is unclear, but it does increase mental alertness and vigilance through several CNS pathways. Small-scale studies with adults and children have shown that modafinil improves symptoms of ADHD, although it is not superior to methylphenidate. Several antidepressants have also been used off-label for ADHD. Bupropion, an atypical antidepressant, may be especially helpful for those adults with comorbid substance abuse and mood disorders. Bupropion is presumed to work by preventing the reuptake of dopamine and norepinephrine. Like atomoxetine, the onset of clinical effect is gradual; improvements may be evident as early as two weeks after initiation. Total daily doses of 200 mg to 450 mg have been used. It should not be used in patients with a history of seizures, as it lowers the seizure threshold. Secondary to its metabolism by cytochrome P450 enzymes, relevant drug interactions should also be considered. Similarly, tricyclic antidepressants (TCAs), which block the reuptake of norepinephrine, have been used off-label in adults. Secondary-amine TCAs like desipramine and nortriptyline may be the best choices because they have a greater effect on norepinephrine than serotonin. The initial dosage of desipramine, which has been studied the most, is usually 25 mg daily; the drug is titrated to a target of 150 mg to 200 mg daily. Despite the modest reductions in hyperactivity and improvements in mood, TCAs are still inferior to stimulants. Moreover, they have little or no effect on concentration and cognition, and use is limited because of the high rate of drug interactions and adverse effects. Patients commonly experience dry mouth, drowsiness, and constipation with these older antidepressants; there is also a risk of QT interAmerica’s PHARMACIST | June 2014 val prolongation. TCAs must also be tapered for discontinuation because of the likelihood of precipitating withdrawal, secondary to their effects on serotonin. ADJUSTING THE REGIMEN Dose Titration The AAP practice guidelines emphasize that clinicians should titrate doses according to symptoms to optimize pharmacotherapy. Like any condition, the goal is to achieve the greatest treatment benefit with the fewest adverse effects. It may take 1-3 months to determine the best medication and dose, and monitoring at regular intervals is critical in these initial stages. Patients should follow up with the clinician on a weekly basis at first, although not all of the follow-up has to be done in person. Less frequent checks can be arranged as the regimen is stabilized. Adherence to the drug regimen is crucial to accurately assess and maintain its effectiveness. Dosage adjustments are warranted when patients are not well controlled with initial therapy or if patient adherence issues make success with a particular product unlikely. Adjustments are also warranted if patients experience “rebound,” in which ADHD symptoms or adverse effects occur as the prescribed medication wears off during the day. Medications should be started at the lowest dose that may have a clinical effect and increased from that point. Clinicians should also recognize that patients may have variable metabolisms and also respond differently to a given medication. One special consideration in starting drugs for ADHD in preschool age children pertains to pharmacokinetics. As a result of naturally slower metabolism of stimulants in 4-5 year olds, lower doses should be initiated in this population, and doses should also be titrated in smaller increments. Polymorphisms in the dopamine transporter gene DAT1 are also linked to variable responses to stimulants. More pharmacogenetics research will likely find other relationships between ADHD drugs and clinical responses in the future. Titration recommendations are specific to each drug, but some general statements can be made for each class. With stimulants, immediate symptomatic improvements occur within 30 minutes to an hour of drug administration, but these effects will still increase gradually over the course of a few days. To see the maximal improvement, doses should be increased no faster than every 3-7 days and titrated until symptoms improve by approximately 50 percent, or until adverse effects become unacceptable. Atomoxetine dosages can be increased in both adults and children after the first 3-4 days of therapy and then usually at 2-4 week increments because of the gradual onset of its clinical effect with each new dose. Titration of the alpha-2 adrenergic agonists can be done on a weekly basis up to the maximum dose. In most cases, monotherapy is sufficient, but combination drug therapy is an option if optimal disease control cannot be achieved with tolerable doses of a single agent. A stimulant coupled with an alpha-2 adrenergic agonist or off-label drug is most common. Using two medications of the same therapeutic class is not clinically appropriate. For example, there is no benefit to combining methylphenidate with dextroamphetamine. Changing Medications If core diagnostic ADHD symptoms do not improve at all after appropriate titration to the maximum dose of the initial agent, it may be prudent to switch to another drug. In these cases of treatment failure, clinicians can switch within or between stimulant subclasses or change to a different, non-stimulant, drug class altogether. At least half of patients who do not respond to one type of stimulant will have favorable outcomes with another. Patients may also opt to try new drugs or different formulations to better suit their schedules, address cost concerns, or meet other personal needs. Maintaining symptom control during a medication change depends on the appropriate dosing of the new agent. Dosing guidelines for transitions among the different formulations of a given stimulant are readily available in the prescribing information. When switching from methylphenidate to dexmethylphenidate, clinicians should initially prescribe half of the patient’s total daily dose of methylphenidate to achieve a similar effect. Unfortunately, reliable data are limited for dose conversions between products with methylphenidate and those with amphetamines, especially the ER agents. For these conversions, it may be safest to simply start with the initial recommended dose of the new agent and titrate to the desired effect. While a patient transitions from any drug to atomoxetine, an overlap is warranted for a few weeks, at doses with tolerable adverse effect profiles. The agent being replaced provides coverage for a patient’s symptoms while atomoxetine reaches its therapeutic concentrations. Conversely, if a patient is being switched from atomoxetine to another drug, no overlap is necessary; atomoxetine can be stopped immediately. No withdrawal symptoms have been noted with abrupt discontinuation. When switching from an alpha-2 adrenergic agonist to another medication, it must still be tapered on a weekly basis and not abruptly discontinued to avoid short-term elevations in blood pressure. Clinicians should also recognize that dosages of the ER clonidine and ER guanfacine products do not convert on a mg per mg basis to those of their corresponding IR formulations. Instead, patients using IR clonidine or IR guanfacine off-label for ADHD who are switching to the FDA-approved ER agents should be started on the recom- www.americaspharmacist.net55 mended initial dose and have the dose titrated to achieve the desired effect. Interruption and Discontinuation of Drug Therapy The issue of whether a medication can or should be held for certain periods of time arises frequently. Parents of children with ADHD are especially curious to know if these agents are necessary on weekends or during the summer, when school-level focus is less relevant, and they need guidance about using ADHD medications noncontinuously. Drug holidays are only feasible for patients taking stimulants. Stimulants as prescribed for ADHD lack many of the characteristics that facilitate physical dependence, such as developing tolerance, inducing cravings, and prompting the desire for compulsive or uncontrolled use. Thus, these agents can be stopped abruptly without the risk of severe withdrawal or drug-seeking behavior. When used in clinically appropriate ways, this class of drugs poses little risk of physical dependence in adults or children, even with long-term use. On the contrary, the long half-lives of atomoxetine and alpha-2 adrenergic agonists make any interruption in therapy impractical and can undercut their effectiveness. Implementing a drug holiday with ER clonidine or guanfacine would also precipitate adverse effects. Every patient’s situation is different, and appropriate patient selection for a drug holiday is crucial to disease control. Adherence relies on daily therapy routines, and dosing consistency is essential for adequate symptom management. If symptoms are fairly mild or primarily associated with inattention, then breaks from stimulants on weekends or other less demanding times could be considered. However, clinicians usually do not recommend drug holidays unless the patient is experiencing considerable adverse effects. Without stimulants, any ADHD symptoms will return, so patients with moderate to severe symptoms may not benefit as much from drug holidays. The lack of noradrenergic stimulation can also make patients initially feel fatigued and moody, among other effects. Moreover, adolescents and adults with ADHD are typically involved in tasks that require attention and concentration outside of academic and occupational settings, so drugs holidays become less feasible. For example, safe driving and participation in extracurricular activities often necessitate the therapeutic effects obtained from stimulants consistently. The decision to terminate drug therapy altogether for ADHD is also individualized. For many patients, the symptoms of ADHD improve naturally over time. This may evolve by several mechanisms: the development of coping skills, cultivation of compensatory strategies, or even natural 56 biological repair of the affected CNS pathways. The AAP practice guidelines acknowledge that, if a patient has been stable on an effective regimen for several years, a trial without medication can be attempted to see if treatment is still necessary. For those whose ADHD symptoms return or worsen, the medication regimen should be resumed. If appropriate, this process can be undertaken periodically to reassess whether the patient can successfully discontinue therapy. Although these trials are warranted to avoid unnecessarily medicating patients, the AAP does not specify any maximum duration of drug therapy for ADHD. Alternative Therapies Although not endorsed by the AAP practice guidelines, certain supplements and dietary modifications are believed by the public and some researchers to mitigate the symptoms of ADHD. One of the most studied supplements is omega-3 fatty acid. A recent meta-analysis of 10 trials showed that nonprescription options with high doses of eicosapentaenoic acid (EPA) cause modest improvements in ADHD symptoms. Such benefits are presumed to result from the effects of omega-3 fatty acids on cell membranes, which indirectly increase transmission of catecholamines in the CNS. However, these studies show that omega-3 fatty acids with EPA are still inferior to the current pharmacologic agents available for ADHD and should not replace standard treatment. Proponents suggest that omega-3 fatty acid supplementation could be considered as an adjunct to traditional prescription medications. Other supplements and herbal products, such as zinc, St. John’s wort, and melatonin, have not shown any substantial benefit. Parents of children with ADHD sometimes try increasing dietary protein intake to mitigate symptoms of the disease. High-protein diets are believed to boost levels of neurotransmitters associated with alertness. The Feingold diet, which involves eliminating artificial flavorings, food colorings, sweeteners, and preservatives, is similarly popular with parents who believe that these additives worsen the symptoms of ADHD in their children through various biochemical mechanisms. With the Feingold diet, salicylates found in aspirin and in certain fruits and vegetables, are eliminated, because some studies have suggested that these compounds increase hyperactivity and irritability. Similar arguments have been made for sugar, so many parents try to minimize its intake in their children with ADHD. However, most research strongly suggests that symptoms of ADHD are not influenced by diet. General information on the more popular alternative treatments and dietary modifications is provided on public websites of national organizations such as Children and Adults with Attention-Deficit/ Hyperactivity Disorder (CHADD) (www.chadd.org) and ADDitude. (www.additudemag.com). America’s PHARMACIST | June 2014 DRUG TREATMENT CAUTIONS Adverse Effects For stimulants, the most common adverse effects include decreased appetite, weight loss, headache, insomnia, mood lability, and gastrointestinal upset. This is secondary to their stimulation of the sympathetic nervous system. Tics occur in some patients, especially those taking methylphenidate-based products; it may be necessary to switch to a nonstimulant in these cases. Rarely, psychosis and hallucinations may occur; the drug should be discontinued, and the patient should also be evaluated for other psychiatric disorders. Long-term use of higher doses of stimulants in children can slightly slow growth rates, ultimately reducing height by 1 cm to 2 cm. Although this effect appears to diminish by the third year of therapy, no rebound growth occurs with drug discontinuation. Growth reductions presumably result from changes in dopamine activity in the hypothalamus, which mediates such endocrine functions. Cardiovascular adverse effects can also be serious and life threatening. Strokes and heart attacks have been reported in adults taking stimulants. Sudden death has occurred in patients who have a history of heart defects or other heart problems, although this is extremely rare in children. Less severe cardiovascular effects include slight elevations in blood pressure and heart rate. In any case, a complete medical history is critical, but at this time an electrocardiogram is not necessary. Another rare but serious adverse reaction caused by methylphenidate products is priapism. The FDA released a warning in December 2013 and encouraged health care professionals to educate caregivers and patients on signs, symptoms, and the need for immediate medical care. The risks of priapism, sudden cardiac events, and serious psychiatric effects are detailed in the medication guide that must be provided to patients when stimulants are dispensed. Stimulants are listed as Pregnancy Category C drugs, in which risk cannot be ruled out; however, data clarifying actual fetal risks are limited. Common adverse reactions of atomoxetine are similar to those of stimulants because it also activates the sympathetic nervous system. Patients may experience decreased appetite, headache, insomnia, gastrointestinal upset, and also dry mouth. Gastrointestinal upset, specifically nausea, vomiting, and abdominal pain, as well as initial somnolence, are especially common if the dose is increased too quickly. Although rare, priapism may also occur in patients taking this medication. Atomoxetine also carries an FDA black box warning regarding use in pediatric patients because of a potential increased risk of suicidal ideation. Patients should be monitored closely for clinical worsening, unusual behavior, or suicidal thoughts when therapy is initiated. The FDA requires that a medication guide be dispensed with atomoxetine. It carries a Pregnancy Category C rating, as well. Adverse effects associated with ER clonidine and guanfacine include dry mouth, somnolence, dizziness, headache, constipation, and hypotension. Most of these effects are dose-related. Withdrawal symptoms include nervousness and anxiety, and rebound hypertension, and these can occur when alpha-2 adrenergic agonists are stopped abruptly. Although clonidine is a Pregnancy Category C agent, guanfacine is defined as Pregnancy Category B, in which there is no risk to the fetus. Relevant Drug Interactions Certainly pharmacists should screen for any drug interactions, but this may be more important for adults with ADHD as they are more likely to be taking other medications. Administration of stimulants during or within 14 days of any MAOIs is contraindicated, as this can precipitate a hypertensive crisis. To a lesser severity, methylphenidate can reduce the effect of antihypertensive drugs because of their sympathetic activation in the vasculature. Stimulants can also increase the effects of some anticonvulsants such as phenobarbital and phenytoin through inhibition of their metabolism; concomitant use with tricyclic antidepressants may increase the risk for cardiovascular effects. Monitoring therapy is usually sufficient with these interactions, although dose adjustments may be necessary in some cases. Additionally, vitamin C and acidic foods and drinks reduce absorption of amphetamines and consequently, its clinical effects; the drug should not be administered with such supplements, foods or beverages. Like stimulants, atomoxetine is also contraindicated with MAOIs, but due to the risk of serotonin syndrome, which can be fatal. Patients should be cautioned that atomoxetine can also enhance tachycardia associated with beta-2 agonists, such as albuterol. Although not substantial enough to warrant a change in therapy, monitoring therapy is adequate. Because atomoxetine is partly metabolized by CYP2D6, inhibitors and inducers of this isoenzyme may alter atomoxetine concentrations. ER clonidine and ER guanfacine tend to increase the hypotensive effect of any drug designed to lower blood pressure or that has this adverse effect. Patients’ blood pressure should be monitored in these cases. Patients taking beta-blockers concomitantly carry the risk of worsening rebound hypertension upon discontinuation of the alpha-2 adrenergic agonist because alpha stimulation in the vasculature is unopposed. Patients should be monitored especially closely when treatment is terminated. There www.americaspharmacist.net57 are two other interactions with guanfacine worth noting. Strong CYP3A4 inhibitors or inducers alter guanfacine’s concentrations significantly; alternative therapy may need to be considered, or the dose of guanfacine may need to be adjusted, with close patient monitoring. St. John’s Wort has also been shown to reduce concentrations of guanfacine, and if the patient chooses to take both, the guanfacine dose may need to be as much as doubled to achieve therapeutic effects. For all of these drugs, alcohol should be avoided. CNS depression from both substances is augmented when used in combination. Alcohol can even enhance the effect of stimulants by increasing their concentrations in the blood. Stimulant Abuse Schedule II stimulants, as a class, are controlled substances with a high potential for abuse because of their effects on dopamine pathways. Besides recreational pleasure, anyone can abuse stimulants in attempts to lose weight or temporarily enhance mental performance at school or work. Individuals may take large doses or consume the drugs around the clock to precipitate the desired effects. For example, college students may take several tablets of methylphenidate to stay awake all night and study “better” for an exam scheduled the next day. Substantially larger doses than those typically prescribed for ADHD are required to elicit the euphoric effects that encourage abuse. The effects of stimulants are also generally more pronounced in individuals without ADHD, so patients taking their prescribed dose are even less likely to experience a “high” with usual treatment. Whereas other commonly abused stimulants are frequently snorted or injected for rapid absorption, these routes of administration are more difficult to achieve with the newer, complex delivery systems of prescription stimulants for ADHD. This further reduces the likelihood of abuse of prescription stimulants among patients. Among all adolescents, abuse of stimulants has been declining since 2011, according to the National Institutes of Health. Nevertheless, the issue remains a concern in the general public as more stimulants are prescribed for patients of all ages. Interestingly, research continues on whether stimulants actually have an effect on the likelihood of developing substance abuse disorders in ADHD patients. In 2013 alone, numerous studies conducted in pediatric ADHD patients came to opposing conclusions. Some studies found that stimulants actually reduce the risk of substance abuse among ADHD patients. These researchers believe that stimulants mitigate the behaviors and associated consequences that can lead to drug abuse. 58 However, others concluded that the use of stimulants in ADHD patients had no effect on substance abuse disorders. In either case, it appears that treatment with stimulants does not encourage drug abuse, which may alleviate the concerns of parents and even adult patients. In general, some populations may be at higher risk of stimulant abuse. For example, children or adults with concomitant psychiatric or sociobehavioral issues are more likely to misuse prescription medications or obtain drugs illegally. Problems in school, work, or home settings can instigate these changes as well. When abuse of stimulants by the patient or someone else in the household is a genuine concern, a number of signs may help identify a potential problem. Behavioral changes, problems at school or work, legal trouble, secrecy, isolation, and long periods of not sleeping or eating could be manifestations of stimulant abuse. Additionally, some notable effects observed by colleagues, family, and clinicians can include memory lapses, confusion, aggression, euphoria, weight loss, dilated pupils, and even seizures. Comments that the patient makes and newly developed habits may also serve as indicators of stimulant reliance or abuse. The Substance Abuse and Mental Health Services Administration (SAMHSA) has information about preventing prescription drug abuse, helping patients and caregivers screen for abuse and locating treatment services at www.findtreatment. samhsa.gov, or 1-800-662-4357. SUMMARY ADHD prevalence in the community necessitates ongoing awareness of the disorder and regular evaluation of our diagnostic methods and treatment for optimal patient care. The updated DSM-5 offers revised criteria for diagnosing this chronic condition in both children and adults. The AAP continues to review its own practice guidelines for ADHD and gives a creditable foundation to steer clinicians. As the disorder receives more attention, newer formulations of stimulants with advanced delivery systems, and second-line agents, have entered the market to offer greater flexibility to the patients. Research is now suggesting that there is no association between the use of stimulants for ADHD and substance abuse disorders, although some patients may be at risk for other reasons. Pharmacists can be an excellent source of information for patients and their families and work with providers to optimize drug therapy. ■ Ashley Khan, PharmD, is a clinical pharmacist at Carilion Roanoke Memorial Hospital in Roanoke, Va., focusing on pediatrics, psychiatry, and neurology. She also works as a freelance medical writer/editor and as a public speaking consultant. America’s PHARMACIST | June 2014 CE QUIZ Continuing Education Quiz Select the correct answer. Answer questions 1-5 using the following case. Mrs. Barton comes to the pharmacy and wants to speak with a pharmacist about her 15-year-old son. Since Alex was diagnosed with ADHD in first grade, he has been prescribed stimulants to manage his symptoms. He has been taking Metadate CD 60 mg (ER methylphenidate) daily for the past year. Unfortunately, during the past few months, he’s been doing poorly in school: not paying attention in class, failing to do his homework, interrupting his teachers, and “bouncing off the walls.” His two younger brothers also have ADHD, but both of them are doing well on their medications. 1. Which of the following could be risk factors for the development of ADHD in Alex’s case? a. Genetics b. History of cardiac arrhythmias c. C hronically low magnesium levels d. All of the above 2. Which neurotransmitters play a critical role in the pathophysiology of ADHD, causing symptoms like the ones Alex experiences? a. D opamine and serotonin b. Dopamine and glutamate c. N orepinephrine and dopamine d. Norepinephrine and serotonin 3. According to the new DSM-5, if Alex had presented with symptoms at age 10 instead of in first grade, he would still meet the age requirement for ADHD diagnosis. a. True b. False 4. On the basis of his recent behavior, Alex most likely has which type of ADHD? a. P redominantly inattentive type b. Predominantly hyperactive-impulsive type c. C ombined type d. Alex was misdiagnosed and actually has bipolar disorder. 5. When it was first prescribed for Alex, Metadate CD was a reasonable choice because a. It can be given once daily. b. It is a stimulant, which is a first-line treatment option for ADHD. c. It is affordable because it is available as a generic product. d. All of the above Answer questions 6-8 using the additional case information. Mrs. Barton also tells you that a few weeks ago, Alex transferred to a different school. Because he liked the new school and wasn’t getting into trouble, he quit taking his medication. Alex had been complaining that Metadate CD made him feel jittery and agitated; he’d also been having trouble falling asleep and never felt hungry. Since he stopped taking Metadate CD, these side effects have resolved, but his ADHD symptoms are worsening again. 6. If he were to resume Metadate CD, what would you tell Mrs. Barton to help reduce the risk of some of these adverse reactions? a. A lex should divide his total dose to allow twice daily administration and mix the capsule contents in pudding to reduce his nervousness. b. A lex should take the medication early in the morning to minimize sleep problems. c. A lex should take the medication with acidic foods and drinks to limit its effects on his appetite. d. T hese adverse effects cannot be mitigated. 7. If Alex were switched to an amphetamine-based stimulant to see if he tolerates it better than Metadate CD, what would be the best initial regimen? a. V yvanse (lisdexamfetamine) 30 mg daily b. V yvanse (lisdexamfetamine) 60 mg daily c. IR mixed amphetamine salts 30 mg twice daily d. E R dexmethylphenidate 40 mg twice daily 8. If Mrs. Barton asks about treatment alternatives to prescription medications, what could you suggest? a. Z inc supplements b. B ehavior therapy c. S ugar-free diet d. Acupuncture Answer questions 9-12 using the case information below. Two weeks later, Mrs. Barton returns to the pharmacy with a new prescription for Intuniv (ER guanfacine). 9. The prescription is written for Intuniv 0.1 mg by mouth twice daily. Based on the FDA’s initial dosing recommendations, what concerns do you have? a. T his product cannot be administered orally. b. The strength is incorrect, but the frequency is acceptable. c. The strength and frequency are both incorrect. d. T he dosage is correct. www.americaspharmacist.net59 CE QUIZ 10. Which of the following statements about Intuniv is true? a. The dose can be increased every 2-4 weeks. b. T he drug is a beta-2 adrenergic agonist. c. T he drug can be discontinued abruptly. d. T he duration of action is approximately 8-12 hours. 11. Alex has also recently started taking propranolol for migraine prophylaxis. What should be monitored when this is taken with Intuniv? a. Liver function b. R enal function c. B lood glucose d. B lood pressure 12. If Mrs. Barton asks if Alex can take a drug holiday during the summer, what would you suggest? a. Drug holidays are only feasible with stimulants. b. D rug holidays are never appropriate for any patient. c. Drug holidays are very effective for patients taking Intuniv. d. D rug holidays are usually more effective during the school year. 13. What information would you tell a patient with a new prescription for Daytrana (transdermal ER methylphenidate)? a. The patch should be applied four hours before the patient needs symptom control. b. Bathing or swimming may reduce the patch’s adherence to the skin. c. Exposure to heat may decrease absorption from the patch. d. A ll of the above 14. The American Academy of Pediatrics recommends that pharmacologic treatment for ADHD be limited to three years, and only behavior therapy should be used thereafter. a. True b. False 15. Bupropion is similar to Strattera (atomoxetine) in its gradual onset of clinical effect and utility in ADHD patients with comorbid substance abuse disorders. a. True b. False Answer questions 16-20 using the case below. Tammy is a 32-year-old female who comes to the pharmacy with questions about her Strattera (atomoxetine) prescription. She tells you that she was recently diagnosed with ADHD and wants to know more about the disorder and its treatment. 60 16. On the basis of current research on adults and females with ADHD, which of the following statements might be true in Tammy’s case? a. Females are more frequently diagnosed with the predominantly inattentive type of ADHD. b. A s patients with ADHD age, symptoms of hyperactivity decline, whereas inattention and impulsivity increase. c. Most adults with ADHD have at least one other psychiatric condition. d. A ll of the above are true. 17. What should Tammy know about how Strattera works? a. H er ADHD symptoms should improve immediately. b. S trattera is a selective serotonin reuptake inhibitor. c. It may take 4-6 weeks to achieve maximal benefit at a given dose. d. S trattera tends to cause more nervousness and insomnia than stimulants. 18. Tammy is concerned that Strattera might interact with her other medications. She takes an oral contraceptive and occasionally uses an albuterol inhaler. How do you advise Tammy? a. S trattera may decrease the effectiveness of the oral contraceptive, so she should use a back-up method. b. T aking Strattera with albuterol might increase her heart rate, but she and her doctor can monitor this effect. c. Both A and B are correct. d. T here are no drug interactions. 19. A common adverse effect that Tammy may experience with Strattera is a. W eight gain b. Aphasia c. Dry mouth d. B lurred vision 20. Tammy mentions that she’s worried about things she’s read on the Internet regarding drug abuse with ADHD medications. She’s afraid she’ll become addicted to the Strattera or any other drug she’s later prescribed. What can you tell her? a. S trattera lacks addictive properties and has little to no abuse potential. b. R esearch now suggests that the use of stimulants has no effect on the risk of substance abuse disorders among ADHD patients. c. Doses of stimulants typically prescribed for ADHD do not produce euphoria. d. A ll of the above are true. America’s PHARMACIST | June 2014