Update on Methylphenidate and Dexmethylphenidate Formulations for Children with Attention-Deficit/ Hyperactivity Disorder

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Clinical Review

Update on methylphenidate and dexmethylphenidate formulations for children with attention-deficit/ hyperactivity disorder

Jim Pheils (PharmD student), University of Maryland School of Purpose. Current literature on the safety and efficacy of intermediate- and Pharmacy, Baltimore, MD, USA long-acting formulations of methylphenidate and dexmethylphenidate for Megan J. Ehret, PharmD, MS, attention-deficit/hyperactivity disorder (ADHD) is evaluated. BCPP, University of Maryland School of Pharmacy, Baltimore, MD, USA Downloaded from https://academic.oup.com/ajhp/article/78/10/840/6145834 by guest on 29 September 2021 Summary. Methylphenidate has been an established treatment for ADHD, but due to its relatively short half-life, numerous intermediate- and long- acting products have been developed. While these extended-release products provide efficacy similar to that of immediate-acting products, the pharmacokinetics and adverse effects can vary. Intermediate-acting methylphenidate products have effects that can last as long as 8 hours, but clinically patients have still required twice-daily dosing. Long-acting products have helped to address these challenges, with recently developed products including controlled-release and bimodal-delivery systems and a patch formulation. Many of these products can be opened and sprinkled on applesauce for ease of administration.

Conclusion. Knowledge of the various formulations of methylphenidate and dexmethylphenidate is crucial for appropriate medication selection for control of ADHD symptoms. Knowledge of differences between release mechanisms and the pharmacokinetic properties are essential for appropriate use of these products.

Keywords: ADHD, children, dexmethylphenidate, formulations, methylphenidate

Am J Health-Syst Pharm. 2021;78:840-849

ttention-deficit/hyperactivity dis- methylphenidate, amphetamine salts, Aorder (ADHD) is characterized by dexmethylphenidate, dextroamphet age-inappropriate symptoms of hyper- amine, and lisdexamfetamine.2 activity, impulsivity, or inattention (or In the last 5 years there has been a a combination thereof) that impair remarkable increase in new methyl- academic achievement and develop- phenidate formulations. While there ment.1 Symptoms typically become evi- are 2 new immediate-release (IR) for- dent in early childhood and may persist mulations available, a grape-flavored throughout adult life. An ADHD diag- oral solution and chewable tablet, the nosis requires that symptoms occur in at product development has focused on least 2 different settings, typically home long-acting formulations with sev- and school, and develop before the age eral novel delivery systems (ie, orally of 12 years.2 The primary tool for diag- dissolving tablets, multilayered bead Address correspondence to Dr. Ehret nosis is clinical interviews along with technology, extended-release chew- ([email protected]). ADHD-specific assessment scales (eg, able tablets, and a delayed-release Conners rating scales, Vanderbilt ADHD delivery system that is taken in the © American Society of Health-System Diagnostic Rating Scale), with most in- evening). Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals. formation obtained from parents and A 2018 meta-analysis comparing the [email protected]. schoolteachers.2 First-line pharmaco- efficacy and tolerability of medications DOI 10.1093/ajhp/zxab069 logic treatment for ADHD is stimulants: prescribed for ADHD in children and

840 aM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 10 | May 15, 2021 METHYLPHENIDATE AND DEXMETHYLPHENIDATE FORMULATIONS Clinical Review adolescents supported methylphenidate that heart rate and blood pressure as the preferred medication for short- KEY POINTS changes with methylphenidate use term treatment of ADHD.3 The study, • Numerous formulations are typically mild and clinically insig- which evaluated outcomes data on over of methylphenidate and nificant (eg, increases of 1-2 beats per 10,068 children and adolescents along dexmethylphenidate provide minute and 1-4 mm Hg in systolic and with 8,131 adults from 133 double-blind various options when selecting diastolic blood pressures),9 but other randomized controlled trials, concluded an appropriate medication studies have shown more substan- that all Food and Drug Administration for control of symptoms of tial increases in blood pressure and (FDA)–approved medications used for attention-deficit/hyperactivity heart rate in a subset (5%-15%) of in- ADHD in children were more efficacious disorder (ADHD). dividuals; a clinician’s knowledge of

than placebo for short-term treatment this interpatient variability might en- Downloaded from https://academic.oup.com/ajhp/article/78/10/840/6145834 by guest on 29 September 2021 • Understanding of the release of ADHD, but methylphenidate was the courage monitoring of vital signs during mechanisms and pharma- only medication demonstrated to have early treatment.9 Stimulants are not cokinetic properties of each better acceptability and equivalent tol- known to increase the risk of sudden formulation is essential for ap- erability.3 Tolerability and adverse ef- cardiac death among children beyond propriate use of the products. fects are comparable with the various that reported in children not receiving methylphenidate formulations; most • Flexibility based on patient stimulant therapy, although misuse adverse effects are dose and time de- symptoms, cost, and adverse may cause sudden cardiac death and pendent, with the most common being effects is needed to individual- serious cardiovascular events.5 Before appetite suppression and delays in sleep ize treatment plans for patients initiation of methylphenidate it is re- onset.4 Additional short-term, common with ADHD. commended to obtain a history of spe- adverse effects include abdominal pain cific cardiac symptoms, family history and headaches.5 Most stimulant adverse of sudden death or Wolff-Parkinson- effects decrease after the first few weeks White syndrome, hypertrophic car- of methylphenidate use but are often diomyopathy, or long QT syndrome, cited as the main reason for discontinu- ADHD guidelines using the terms me- as sudden death can occur in patients ation of treatment.6 Proper medication thylphenidate, stimulant, extended re- with preexisting structural cardiac ab- administration and education can de- lease, intermediate release, immediate normalities or other serious cardiac crease adverse effects. To avoid effects release, children, attention/hyperactivity problems.5 If any of these risk factors on sleep, stimulants should not be given disorder, and dexmethylphenidate. are present, the prescriber should seek later in the day. Meal management, with Published reports on double-blind additional evaluations from cardiac morning and evening meals consisting clinical trials were included in this re- specialists to address potential safety of larger meals when methylphenidate view. Open-label studies of a given me- risks with the use of any stimulant levels are at the lowest and appetite sup- thylphenidate or dexmethylphenidate medication for ADHD.10 pression is minimal, is preferred.7 preparation were included if no pub- IR methylphenidate’s average onset The most recent Americanlished double-blind studies were iden- of action is between 30 and 45 minutes, Academy of Pediatrics guidelines rec- tified. Medication Guides and package with a mean duration of clinical ef- ommend use of any medication ap- inserts for currently available methyl- fect between 3 and 4 hours and a time proved by FDA for treatment of ADHD phenidate products were identified to peak concentration of 1 to 2 hours. in patients over 6 years of age, while using the FDA Medication Guides data- Methylphenidate products are a racemic the National Institute for Health and base (www.accessdata.fda.gov/scripts/ mixture of 50% d-methylphenidate Care Excellence (NICE) guidelines rec- cder/daf/index.cfm?event=medguide. and 50% l-methylphenidate, with ommend methylphenidate as the first page). In addition, referenced citations d-methylphenidate as the thera- choice in children and adolescents.5 from publications identified in the peutically active isomer.4 The ma- The aim of this article is to provide an search were reviewed. jority of methylphenidate is excreted update on the safety and efficacy of in urine as an inactive metabolite commercially available methylphen- Methylphenidate (ritalinic acid), and metabolism fa- idate and dexmethylphenidate prod- IR formulations. Initiating ADHD vors clearance of l-methylphenidate, ucts and provide insights for clinicians pharmacotherapy with an IR formula- resulting in markedly higher serum to optimize individual regimens. tion allows for assessment of adverse levels of d-methylphenidate soon after effects and treatment effectiveness in administration.4 Literature search the context of a shorter duration of clin- Traditionally, IR formulations had A literature search of PubMed/ ical effect, which could be important the advantage of being crushable for MEDLINE was done to identify review in terms of monitoring considerations. mixing with food to aid in admin- articles, meta-analyses, and current For example, some research indicates istration, but several longer-acting

AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 10 | May 15, 2021 841 Clinical Review METHYLPHENIDATE AND DEXMETHYLPHENIDATE FORMULATIONS formulations that can also be mixed supplied only in 20-mg tablets that the necessity of afternoon doses and with food have been developed. Several cannot be split, which would increase potentially improving adherence new IR products that aid in administra- the surface area of the tablet and to therapy—is increased. Concerta tion have recently become available: change the release rate. The tablets (Janssen-Cilag) was approved by FDA Methylin (methylphenidate oral solu- need to be swallowed whole and not in August 2000 and quickly became tion, Mallinckrodt), a grape-flavored li- chewed or crushed. The time to peak one of the commonly prescribed treat- quid that comes in either 5- or 10-mg per concentration of methylphenidate with ments for ADHD.17 Once-daily 12-hour teaspoon formulations; and Methylin wax-based matrix delivery is between drug delivery is accomplished using chewable tablets (Mallinckrodt), which 4 and 5 hours, which can present a osmotic pressure to deliver the medi- are also grape-flavored.11,12 problem for school-age children who cation at a controlled rate.17 Concerta

The common concern with use of need the benefit from the stimulants in is comprised of a nonabsorbable tablet Downloaded from https://academic.oup.com/ajhp/article/78/10/840/6145834 by guest on 29 September 2021 IR methylphenidate is its short half-life the morning hours. that resembles a traditional tablet but (approximately 2.5 hours) and dur- Ritalin LA and Metadate CD both contains an osmotically active trilayer ation of action (3-4 hours), which ne- use a capsule delivery system filled with core surrounded by a semiperme- cessitates scheduling of 2 to 3 doses delayed-release beads. The delayed- able membrane.17 The semipermeable per day to cover the entire school day. released beads are sugar spheres con- membrane is coated in an IR medi- Administration of the additional doses taining the active ingredient that are cation that makes up 22% of the me- during the school session requires the coated with either a delayed-release thylphenidate contained in the tablet help of a school official or a school coating or an IR coating. The rate of re- and dissolves within the first hour of nurse and entails the logistical problem lease of methylphenidate from the cap- administration. The trilayer core is of making sure the medication is on sules is fairly consistent and is designed made up of 3 layers: methylphenidate, hand when needed. The limitations of to mimic the rate of release after inges- excipients, and a push layer, which is IR formulations have led to the devel- tion of 2 IR tablets 4 hours apart but osmotically active.17 The semiperme- opment of longer-acting dosage forms with less peak-to-trough fluctuations. able membrane has a precision-drilled that allow reduced dosage frequency. The contents of the capsules can be opening on the medication layer end of Intermediate-release oral me- opened and sprinkled on applesauce the tablet, and when the tablet is intro- thylphenidate. The intermediate-re if a child has difficulty swallowing, but duced to an aqueous environment, like lease formulations of methylphenidate, the applesauce should not be heated the gastrointestinal tract, water per- UCB’s Metadate ER13 Novartis’s Ritalin and should be consumed immediately meates the nonabsorbable semiper- LA,14 and UCB’s Metadate CD,15 have and entirely.14 The contents of the cap- meable membrane into the core. The a duration of action between 6 and 8 sules should not be chewed or crushed osmotically active polymer excipient hours. The methylphenidate supplied and should not be taken with alcohol expands with the introduction of water, in these formulations is bioequivalent because either practice would change pushing the methylphenidate out the to that in the IR tablets but is released the release characteristics of methyl- opening in the medication layer.17 Due more slowly. The longer duration of ac- phenidate, resulting in release of a to the medication-concentration gra- tion allows for a reduction of dosing fre- greater amount of the drug in the first dient in the top 2 layers of the trilayer, quency, but most patients still require hour. Ritalin LA contains 50% IR beads the amount of methylphenidate that is twice-daily dosing. The aim of using and 50% delayed-release beads. The released increases over a 6- to 7-hour intermediate-release products is to time to first peak concentration is ap- period, giving a second, gradually provide a more consistent therapeutic proximately 2 hours after administra- increasing peak concentration between level of methylphenidate throughout tion, and a second peak concentration 6 and 10 hours after administration. the day, which should reduce the fre- occurs 3.5 to 4.5 hours later.14 Metadate Concerta minimizes peak-to-trough quency of adverse effects and increase CD contains 30% IR beads and 70% fluctuations normally seen with IR for- the effectiveness of the medication. delayed-release beads; the first peak mulations by providing 3-time dosing of The available intermediate-release concentration occurs at 1.5 hours and methylphenidate. The nonabsorbable, products employ 2 different delivery the second peak 3 hours later.15 biologically inert component of the methods. Metadate ER tablets release Long-acting formulations. tablet stays intact and is elimin- methylphenidate using a wax-based Concerta. The advantages of a long- ated in the stool. The FDA-mandated matrix delivery system. The matrix de- acting medication include providing Medication Guide warns that the tablet livery system works by the formation benefits from early morning to long may be visible on abdominal x-rays. of a water channel through the tablet after the school day or workday is com- Concerta must be swallowed whole and release of the drug through the pleted. With use of a medication whose with a liquid. It is taken in the morning channel.16 The thickness of the matrix effects can last up to 12 hours, the like- with or without food, and no differ- layer in the tablet determines the re- lihood of adequate treatment effects ence in either pharmacokinetics or lease rate.16 Metadate ER is currently with a single daily dose—eliminating pharmacodynamics was noted after

842 aM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 10 | May 15, 2021 METHYLPHENIDATE AND DEXMETHYLPHENIDATE FORMULATIONS Clinical Review a high-fat meal. Taking the medica- ranging in age from 6 to 12 years and with A sleep study analysis was per- tion with food does not change the re- an overall mean age of 8.8 years were formed during 2 studies of Aptensio lease rate of the medication. Relexxii enrolled. Permanent Product Measure XR for treatment of ADHD.24 One of the (Vertical Pharmaceuticals) contains of Performance scores were obtained studies involved 26 patients ranging in a 72-mg dose that is also delivered via before dosing, at 45 minutes, and at 2, age from 6 to 12 years and included an the osmotically controlled delivery 4, 8, 10, and 12 hours post dosing. At all open-label dose optimization phase method.18 At this time there is only postdose time points, scores for both and a double-blind crossover phase in one FDA-approved generic version of problems attempted and problems which the optimized dose was evalu- the Concerta formulation (marketed solved were significantly higher with ated against placebo use.24 The other by Actavis Generics) that uses the os- Quilllivant XR vs placebo use.22 Quillivant study enrolled 230 patients from 6 to

motic release delivery system. Two XR could be an ideal product for children 18 years of age with an ADHD diagnosis Downloaded from https://academic.oup.com/ajhp/article/78/10/840/6145834 by guest on 29 September 2021 other generic formulations (respect- with ADHD who have difficulty with ad- and was an open-label, fixed-dose ively marketed by Mallinckrodt and ministration of solid dosage forms. evaluation of Aptensio XR safety and UCB) were voluntarily removed from QuilliChew ER tablets con- efficacy, with the assigned dose given the market after the companies failed tain 30% uncoated IR methylphen- throughout the study with no titration.24 to demonstrate that their products pro- idate microparticles and 70% coated The patients’ parents completed ei- vided the same therapeutic effect, and microparticles for extended release.20 ther the Children’s or Adolescent Sleep FDA changed the formulations’ Orange QuilliChew ER is a cherry-flavored Habits Questionnaire. The investigators Book therapeutic equivalence code tablet that can be chewed or swallowed concluded that extended-release me- to BX (denoting that data are insuffi- whole with no difference in pharma- thylphenidate therapy may be associ- cient to determine therapeutic equiva- cokinetic characteristics.4 Following a ated with short-term subjective reports lence) from AB (indicating therapeutic 40-mg QuilliChew ER dose, the time of delayed sleep onset but was associ- equivalence).19 to peak concentration is a median of ated with improvements in sleep habits QuilliChew ER and Quillivant XR. 5 hours, with a duration of action of over time.24 Adverse sleep effects may Pfizer’s QuilliChew ER20 and Quillivant 12 hours.20 A high-fat meal does not be transient in nature, and improve- XR21 both contain methylphenidate change the time to peak concentration ments in ADHD symptoms with stimu- microparticles that are coated (for ex- but increases the maximal concentra- lant use may have a beneficial impact tended release) or uncoated (for im- tion by about 20%.20 on sleep.24 mediate release). The delivery system is Aptensio XR. Aptensio XR (Rhodes Cotempla X-ODT. Cotempla X-ODT created by the formation of drug-polymer Pharmaceuticals)23 is a 12-hour extended- Neos Therapeutics)25 was approved by complexes. Quillivant XR powder for release capsule that contains multi- FDA in 2017 and is an oral dissolving reconsitution consists of uncoated IR layered beads. Each bead is com- tablet that disintegrates in saliva and microparticles (20% of drug content) and posed of an IR outer layer containing should not be chewed or crushed. No a proprietary coating of varying thick- 40% of the methylphenidate dose, and liquid is needed for administration. ness for the extended release portion the remaining 60% is contained in a Cotempla X-ODT is comprised of 25% (80% of drug), which confers multiple pH-dependent extended release layer.24 IR microparticles and 75% extended- release profiles.22 A peak concentration This layered approach provides a bi- release methylphenidate ionically bound is achieved at 5 hours, with an onset of phasic pattern of methylphenidate con- to the sulfonate of polystyrensulfonate action 45 minutes after administration. centration, with a rapid rise to the first particles.25 After administration of Comparison of 60 mg of Quillivant XR to peak at 2 hours and then a gradual de- 51.8 mg, the plasma methylphenidate 60 mg of IR methylphenidate showed 95% cline in concentration over the next 4 to concentration peaked at 5 hours after relative bioavailability.22 The Quillivant 6 hours. The extended-release layer pro- dosing, with a duration of action of XR powder is reconstituted with water vides a second peak concentration at 8 around 12 hours.25 Taking the medica- before dispensing by a pharmacist. The hours post dose, with gradual decline in tion with a high-fat meal shortened the reconstituted suspension has a con- serum levels thereafter and a total dur- median time to peak concentration to centration of 5 mg of methylphenidate ation of action of 12 hours.23 Aptensio 4.5 hours and decreased the peak me- product per milliliter and is stable for up XR capsules can be swallowed whole or thylphenidate concentration.25 Patients to 4 months at room temperature. The opened and sprinkled on applesauce. are advised that they can take the medi- suspension should be shaken for at least The beads should not be chewed or cation with or without food but should 10 seconds before dose administration crushed. Aptensio XR can be taken with be consistent from one administration to ensure a uniform dose. A random- or without food but should be taken to the next. The tablets are supplied in ized, double-blind, placebo-controlled the same way each morning. Taking the a blister pack and should remain in the crossover study was completed to as- medication with a high-fat meal results unopened condition until needed for sess the efficacy, safety, and tolerability in a higher first peak concentration and administration. Patients should use dry of Quillivant XR.22 Forty-five students lower second peak.23 hands when handling the product, and

AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 10 | May 15, 2021 843 Clinical Review METHYLPHENIDATE AND DEXMETHYLPHENIDATE FORMULATIONS the tablet should not be pushed through Delexis delays the release of medica- Transdermal formulation. Day the blister pack foil for removal. tion overnight and has extended-release trana (Noven Pharmaceuticals)28 is an Extended-release formulations. properties that control the release of the adhesive-based matrix transdermal Adhansia XR. Adhansia XR (Purdue medication throughout the following system that needs to be applied to in- Pharmaceuticals)26 is one of the newest day. The capsules contain beads that tact skin.28 The methylphenidate is methylphenidate products, with FDA have 2 functional film coatings sur- dispersed in acrylic adhesive that is approval granted in 2019. Adhansia is a rounding a drug core containing methyl- dispersed in a silicone adhesive.28 capsule containing multilayered beads. phenidate hydrochloride.27 The outer Methylphenidate is incorporated The beads have an IR layer, which con- coating delays the initial release of the into the adhesive so that the dosage tains approximately 20% of the me- medication, and the inner core regulates strength is uniform across the patch.

thylphenidate dose, and a controlled the release of the medication throughout The total dose of methylphenidate de- Downloaded from https://academic.oup.com/ajhp/article/78/10/840/6145834 by guest on 29 September 2021 release layer containing the remaining the day.27 During the first 10 hours after livered is dependent on the size of the dose. Adhansia XR has been shown to dosing, the delayed-release coating is patch and the wear time. The trans- result in improvement in clinical re- designed to release less than 5% of the dermal patch is made up of 3 layers, the sponse for as long as 16 hours post ad- total drug content into the plasma.27 The outer layer is a polyester/ethylene vinyl ministration.26 The first concentration median time to peak concentration is 14 acetate laminate film backing that faces peak occurs 1.5 hours and the second hours, followed by a gradual decline over the outside, a proprietary adhesive peak 12 hours after administration. In the next 10 to 14 hours. The target for formulation which contains the me- a comparison of the effects of 100 mg drug delivery is the colon, which has less thylphenidate, and a fluoropolymer- of Adhansia XR vs 3 doses of IR me- absorptive properties than other areas of coated polyester protective liner which thylphenidate 20 mg given at 4-hour the gastrointestinal tract; this method of is attached to the adhesive surface be- intervals, Adhansia produced a 22% delivery results in a prolonged absorp- fore administration and must be re- higher first peak, a 50% greater mean tive window. Relative bioavailability moved before the patch is placed.28 extended exposure, and a 288% greater compared to an identical daily dose of Calculatation of the total amount of minimum concentration at steady state IR methylphenidate given 3 times a day delivered methylphenidate is based on on postdosing day 3.26 Adhansia XR can is 73.9%.27 a 9-hour wear time. The onset of action be taken with or without food. Taking Jornay PM should be taken at the for the transdermal patch is approxi- the drug with a high-fat meal does not same time each evening and should mately 2 hours after application. The change the concentration peak or ex- be taken consistently either with or recommendation is that the patch not tent of absorption but increases the time without food. Taking the medication be worn for more than 9 hours each to peak concentration by 1 hour.26 The with a high-fat meal at night decreases day. The patch can be removed at any capsules can be opened and sprinkled the mean concentration peak and ex- time to provide more individualized on applesauce or yogurt, but the beads tends the time to peak concentration therapy and control over response dur- should not be chewed or crushed. The by approximately 2.5 hours. A morning ation. After the patch is removed the recommended starting dose for a child meal has no effect on the pharmaco- methylphenidate in the skin continues is 25 mg, with weekly titrations of 10 to kinetics of the medication. The capsule to be absorbed for an additional 2 to 3 15 mg as needed. A disproportionate in- can be swallowed whole or sprinkled hours, but the plasma concentrations crease in adverse events was associated on applesauce, but the beads should decline steadily. with doses greater than 70 mg daily in not be crushed or chewed. If patients A Daytrana patch should not be children and greater than 85 mg daily in forget to take the medication at the cut or used if damaged in any manner. adults. Because of the long duration of scheduled time, they may take it as The patch needs to be applied to a clinical response and steady state, the soon as they remember that same dry, clean area of the hip. The appli- most common adverse effects are de- evening. If they forgot to take their dose cation site should not have any breaks creased appetite and trouble sleeping. the prior evening, they should not take in the skin or areas that are prone to Jornay PM. Jornay PM (Ironshore it in the morning but wait until their be rubbed by clothing. In the event Pharmaceuticals)27 is the first delayed- next scheduled time. the patch becomes damaged during release/extended-release formulation of Adverse events reported with use use or becomes detached or partially methylphenidate and was approved by of Jornay PM are comparable to those detached, it should be removed and FDA in 2018. Jornay PM was designed of other methylphenidate formula- discarded. If a new patch is applied, for evening administration between tions, with the exception of sleep dis- it should be placed on a different lo- 6:30 and 9:30 pm (with 8 pm as the most turbances; instead of interfering with cation on the hip. The application site common time in clinical trials) in order sleep onset, Jornay PM can cause early- should be changed daily; it is suggested to target an onset of action the next morning awakening. This usually can to alternate application sites from left morning. Jornay PM uses a proprietary be corrected by adjusting the timing of to right. Studies show a variation in ab- drug delivery platform called Delexis. the evening dose. sorption at different sites of the body;

844 aM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 10 | May 15, 2021 METHYLPHENIDATE AND DEXMETHYLPHENIDATE FORMULATIONS Clinical Review therefore, for consistency the general The transdermal patch formula- unclear, with some studies suggesting location (hips) should be constant. tion has additional risks that should be that l-methylphenidate may actually The patient or caregiver should considered. The largest patch contains interfere with the action of the active avoid touching the adhesive side of the a total of 82.5 mg of methylphenidate; enantiomer.31 patch while applying or removing the if a child were to remove the patch and The recommended starting dose patch, in order to avoid absorption of chew or swallow portions of it, that of Focalin for a patient not currently methylphenidate. The patch contains dose could result in accidental poi- taking methylphenidate or taking a dif- unused methylphenidate in the adhe- soning. After the patch is applied, no ferent stimulant for ADHD is 5 mg per sive even after 9 hours of wear time, and heat (eg, from an electric blanket, direct day (2.5 mg twice daily).29 If a patient proper disposal procedure should be sunlight, or a blow dryer) should be ap- is switching from methylphenidate

followed to reduce the risk of accidental plied to the patch, as heat increases the to dexmethylphenidate, the recom- Downloaded from https://academic.oup.com/ajhp/article/78/10/840/6145834 by guest on 29 September 2021 exposure or overdose. Hands should be rate and amount of drug release into the mended starting dose is half the dose washed after contact with the adhesive, systemic circulation. Improper disposal of the racemic methylphenidate, with and any visible adhesive residue on the could result in accidental exposure, as a maximum recommended dose of application site after patch removal up to 60% of the methylphenidate re- 20 mg per day (10 mg twice daily). should be removed to minimize con- mains in the patch after use. Focalin is an IR formulation that has a tinued systemic absorption. time to peak concentration of 1 to 1.5 Methylphenidate is a racemic Dexmethylphenidate hours and a duration of action between formulation and with oral delivery, Dexmethylphenidate hydrochloride 3 and 6 hours, which requires twice- first-pass metabolism clears the is the d-threo-enantiomer of racemic daily dosing at intervals of at least 4 l-methylphenidate first, resulting in methylphenidate hydrochloride, which hours to cover the complete school day. much higher systemic circulation of is a 50:50 ratio of l-threo-enantiomer Focalin can be taken with or without the d-methylphenidate enantiomer. and d-threo-enantiomer. Focalin food, but eating a high-fat meal was The transdermal patch delivers the (dexmethylphenidate hydrochloride, shown to increase the time to peak con- medication into the systemic cir- extended-release; Novartis Phar centration from 1.5 hours to 2.9 hours.29 culation at an approximately 50:50 maceuticals) is the IR formulation of A double-blind, placebo-controlled ratio of d- and l- methylphenidate. dexmethylphenidate. Methylphenidate study was conducted to evaluate the ef- The l-methylphenidate enantiomer exists as l-threo, d-threo, l-erythro, ficacy and safety of twice-daily dosing is largely inactive and its therapeutic and d-erythro isomers.29 Dexmeth of dexmethylphenidate as a treatment significance likely minimal. Because ylphenidate is the more pharmaco- for ADHD and to compare the duration the bioequivalence is not the same as logically active enantiomer of the of action in a natural environment to for oral dosage formulations, it is re- d-threo and l-threo enantiomers, while that with twice-daily methylphenidate commended to start with the 10-mg erythro isomers have no activity.30 In dosing.32 The study involved 132 chil- dose regardless of the previous oral rat models, d-threo-methylphenidate dren between the ages of 6 and 17 years dosage used. was at least 10 times more active with ADHD. The primary measure of The safety and tolerance profile than l-threo-methylphenidate in efficacy was the change from base- of Daytrana is comparable to those of inhibiting dopamine uptake into line to the last study visit in teacher- other methylphenidate formulations, the striatum and hypothalamus.30 completed Swanson, Nolan, and with the additional frequently reported Studies have shown large differences Pelham Rating Scale (Teacher SNAP) adverse effect of localized contact between l-methylphenidate and scores. The researchers reported sig- dermatitis, which is mostly manifested d-methylphenidate in metabolism nificantly improved Teacher SNAP as slight and transient redness at the and disposition.31 The main pathway scores for both the methylphenidate site of application. Alternating the site of metabolism of methylphenidate is and dexmethylphenidate groups com- of application should minimize this rapid deesterification to the inactive pared to the placebo group.32 Both me- risk. The dermatitis appears to be a metabolite, ritalinic acid. The process thylphenidate and dexmethylphenidate reaction to the adhesive as opposed has been shown to be highly stereo- were found to be well tolerated, with to methylphenidate. Hydrocortisone specific, with an up to 6-fold higher no patients in the dexmethylphenidate cream can be applied to the affected difference favoringl -methylphenidate group and only 2 patients in the methyl- areas. Additionally, chemical leuko- over d-methylphenidate, resulting phenidate group discontinuing study derma may occur within 2 months to in much greater serum concentra- participation.32 The average titrated dose 4 years after initiation of treatment. tions of d-methylphenidate in circu- of dexmethylphenidate was 18.25 mg Some patients have also reported dis- lation than are seen with traditional per day in divided doses (given at 8 AM comfort when removing the patch, methylphenidate therapy.31 The con- and noon), and the average titrated which can be minimized by alternating tribution of l-methylphenidate to dose of methylphenidate was 32.14 mg the application site. the pharmacological profile remains per day, also given in 2 divided doses.32

AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 10 | May 15, 2021 845 Clinical Review METHYLPHENIDATE AND DEXMETHYLPHENIDATE FORMULATIONS Continued on next page Comments Downloaded from https://academic.oup.com/ajhp/article/78/10/840/6145834 by guest on 29 September 2021 before administration before nonabsorbable tablet nonabsorbable tablet basis; cherry flavored methylphenidate dose without chewing methylphenidate dose

Vigorously shake for ~10 seconds Vigorously May be split or crushed solution Grape-flavored tablets Grape-flavored Must be swallowed whole; Must be swallowed whole; Do not substitute on mg-per-mg Dose not equivalent to oral Allow tablet to disintegrate on tongue Dose not equivalent to oral

Must be swallowed whole Capsule may be opened and sprinkled Capsule may be opened and sprinkled Available Available Dosage Forms 10 mg/5 mL 40 mg 60 mg (capsule) (tablet) 85 mg (capsule) 60 mg

25 mg/5 mL 5, 10, 20 mg 5 mg/5 mL, 2.5, 5, 10 mg 18, 27, 36, 54 mg 72 mg 20, 30 mg; scored 10, 15, 20, 30, 40, 50, 8.6, 17.3, 25.9 mg 25, 35, 45, 55, 70,

20 mg 10, 20, 30, 40 mg 10, 20, 30, 40, 50,

12 12 12 13 3-4 3-4 3-4 3-8 6-8 6-8 10-12 10-12 10-12 Action, h Duration of

1 3 3 3 1 1 1 1 1 1

1-2 1-2 1-2 Doses/d Time to Peak Concentration, h

5 1-2 1-2 1-2 ~4-5 1st peak: 2 2nd peak: 5.5-6.5 1st peak: 1.5 2nd peak: 4.5 1st peak: 1 2nd peak: 6-10 1st peak: 1 2nd peak: 6-10 5 1st peak: 2 2nd peak: 8 5 1st peak: 1.5-2 2nd peak: 10-12

Delivery Mechanism 80% ER beads CR CR 70% ER 60% CR IR, 75% CR 80% CR

Coated microparticles: 20% IR, Coated microparticles: NA NA NA matrix Wax-based 50% IR, delayed-release 30% IR, 70% ER beads Osmotic system: 22% IR, 78% Osmotic system: 22% IR, 78% 30% IR, Coated microparticles: beads: 40% IR layer, Multilayered Orally disintegrating tablet: 25% beads: 20% IR, Multi-layered

25 20

15 13 26 21 23 11 14 12 17 18 14 Solution Tablets Metadate ER Adhansia XR Aptensio XR Methylin Oral Methylin Chewable methylphenidate HCl QuilliChew ER Quillivant XR Cotempla X-ODT Ritalin LA Metadate CD methylphenidate HCl

Intermediate-acting Relexxii ER methylphenidate HCl Ritalin Concerta Table 1. Methylphenidate and Dexmethylphenidate Preparations Table Product IR methylphenidate HCl Long-acting

846 aM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 10 | May 15, 2021 METHYLPHENIDATE AND DEXMETHYLPHENIDATE FORMULATIONS Clinical Review

The investigators concluded that with twice-daily dosing, dexmethylphenidate may have a longer duration of action than methylphenidate and that its use may result in greater improvement in Teacher SNAP ratings at the 6 PM assessment (methylphenidate use was not associated with a significant difference in 6 PM scores relative to placebo use).32 Comments Focalin XR (Novartis Pharma 33

ceuticals) is an extended-release for- Downloaded from https://academic.oup.com/ajhp/article/78/10/840/6145834 by guest on 29 September 2021 mulation of dexmethylphenidate with

9:30 PM dosage not equivalent to oral me - thylphenidate dose split or crushed a bimodal release profile. Focalin XR

Take in evening between 6:30 and Take after 9 hours; Apply to hip; remove High-fat meal may delay peak; be Capsule may be opened and sprinkled capsules contain 2 different beads, with half the dose as IR beads and the other half as enteric-coated delayed- release beads.33 The time to first peak concentration is similar to Focalin’s, at Available Available 1.5 hours, and the time to second peak Dosage Forms 100 mg (capsule) 35, 40 mg is about 6.5 hours after administra-

20, 40, 60, 80, 10, 15, 20, 30 mg 2.5, 5, 10 mg 5, 10, 15, 20, 25, 30, tion.33 Once-daily dosing of Focalin XR is associated with fewer peak-to-trough

3-6 fluctuations, with a lower second peak 9-12 24-36 10-12

Action, h concentration and a higher interpeak Duration of minimum concentration, compared to Focalin daily administration as 2 doses 33

1 1 1 4 hours apart. 2–3 A 5-week multicenter, double-blind, Doses/d randomized, placebo-controlled study was conducted to evaluate the benefits of 3 doses of Focalin XR.34 The study included 253 pediatric outpatients with ADHD from 6 to 12 years of age and was conducted across 34 centers in the

Time to Peak United States. The primary objective Concentration, h was improved control of ADHD symp-

14 10 1-1.5 1st peak: 1.5 2nd peak: 6.5 toms, as evaluated by teachers using the Conners’ ADHD/DSM-IV scale for teachers (CADS-T), with use of once- daily Focalin XR (10, 20, or 30 mg) or placebo.34 All 3 doses of Focalin XR were significantly better than placebo in terms of teacher-assessed improvements from baseline to the final study visit, and a significant treatment effect Delivery Mechanism was observed over time, showing sus- multipolymeric adhesive beads 34

Two functional film-coated beads Two from Continuous release NA 50% IR, delayed-release tained efficacy. Additionally, ratings on a parental version of the CADS in- dicated similarly significant (P < 0.001) degrees of improvement with all 3 29 27 33 fixed doses compared to the placebo.34 28 The study also concluded that adverse events were mild to moderate, which Focalin (IR) methylphenidate Focalin XR Jornay PM was in line with previous observations Continued from previous page 1. Methylphenidate and Dexmethylphenidate Preparations Table Daytrana Transdermal Transdermal Dexmethylphenidate HCl Product NA, not applicable (IR formulation). IR, immediate release; HCl, hydrochloride; ER, extended release; Abbreviations: with this class of stimulants.34

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See Table 1 for a complete list of me- Table 2. Switching Between Methylphenidate Products4 thylphenidate and dexmethylphenidate preparations. Approximate IR Approximate ER Medication Dose Equivalent Dosea Equivalent Dosea Clinical applications Concerta17 18 mg 5 mg three times daily NA Over the last few years several new methylphenidate products have 27 mg 10 mg three times daily NA been approved by FDA for treatment 36 mg 10 mg three times daily NA of pediatric ADHD. All these products 54 mg 15 mg three times daily NA involve changes in the pharmaceutical Relexxii18 72 mg 20 mg three times daily NA delivery, duration of action, or onset of Downloaded from https://academic.oup.com/ajhp/article/78/10/840/6145834 by guest on 29 September 2021 action of the existing methylphenidate QuilliChew ER20 20 mg 10 mg twice daily (given 20 mg dailyb compound. Most of the new advances 6 hours apart)b involve use of coated microparticles 30 mg 15 mg twice daily 20 mg daily or multilayered beads to alter or delay 40 mg 20 mg twice daily 40 mg daily medication release. Knowledge of 21 individual variability in clinical re- Quillivant XR 2 mL 5 mg twice daily 10 mg daily sponse and metabolism has advanced, 4 mL 10 mg twice daily 20 mg daily allowing clinicians to formulate more 6 mL 15 mg twice daily 30 mg daily individualized therapeutic plans 8 mL 20 mg twice daily 40 mg daily tailored to each patient to optimize response and decrease adverse events. Aptensio XR23 10 mg 5 mg twice daily 10 mg daily New flavored IR products allow easier Cotempla X-ODT25 8.6 mg 5 mg twice daily 10 mg daily administration, and delayed-release 17.3 mg 10 mg twice daily 20 mg daily capsules that allow the patient to ad- minister the product the night be- 25.9 mg 15 mg twice daily 30 mg daily fore increase treatment options and Adhansia XR26 25 mg 5 mg three times dailyc NA can help improve patient adherence. 100 mg 20 mg three times daily NA Different durations of action allow Jornay PM27 20 mg 4 mg three times daily, NA for individualization of dosing regi- starting in the AM mens for patients based on symptoms experienced. Various formulations 40 mg 8 mg three times daily, NA starting in the AM additionally allow for ease of administration to those who struggle with 60 mg 12 mg three times daily, NA starting in the AM swallowing of medications. Treatment decisions are never 80 mg 16 mg three times daily, NA based solely on formulation alone starting in the AM but are often determined by the Daytrana28 10 mg patch 5 mg twice daily 10 mg daily ever-changing costs of various prod- 15 mg patch 7.5 mg twice daily 15 mg daily ucts, which requires the clinician’s 20 mg patch 10 mg twice daily 20 mg daily knowledge and flexibility based on the understanding of available medi- 30 mg patch 15 mg twice daily 30 mg daily cations. Medications such as Ritalin Abbreviations: ER, extended release; IR, immediate release; NA, not applicable. LA, Aptensio XR, and Focalin release aApproximate substitutions. When time allows, start new formulation based on original recommendations. a larger portion of their IR compo- bLower overall bioavailability (–11%) and peak concentration (–20%) when QuilliChew ER is nent in the morning, which can be administered. cInitial peak concentration significantly (22%) higher with administration of Adhansia XR. beneficial for patients with more early-morning symptoms, while Cotempla-X ODT and Adhansia XR provide a larger medication release providers in the event that a specific Conclusion later in the day, which can be helpful formulation is unavailable. Providers With the ever-expanding product for those whose symptoms may ex- will likely have to adjust medications choices for treatment of ADHD, more tend into later in the day. Table 2 pro- to find the optimal regimen for each individualized treatment plans should vides potential switching options for patient. lead to better adherence and improved

848 aM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 10 | May 15, 2021 METHYLPHENIDATE AND DEXMETHYLPHENIDATE FORMULATIONS Clinical Review long-term outcomes for pediatric pa- management. Published March 2018. 21. Qullivant XR. Medication Guide. Pfizer tients with ADHD. Accessed January 20, 2019. www.nice. Inc; 2015. org.uk/guidance/ng87 22. Robb A, Findling R, Childress A, Berry S, 9. Cortese S, Holtmann M, Belden H, Wigal S. Efficacy, safety, and Disclosures Banaschewski T, et al; European tolerability of a novel methylphen- The authors have declared no potential con- ADHD Guidelines Group. Practitioner idate extened-release oral suspension flicts of interest. review: current best practice in the (MEROS) in ADHD. J Atten Disord. management of adverse events during 2017;21(14):1180-1191. References treatment with ADHD medications 23. Aptensio XR. Medication Guide. Rhodes in children and adolescents. J Child Pharmaceuticals LP; 2019. 1. American Psychiatric Association. Psychol Psychiatry. 2013;54(3):227-246. 24. Owens J, Weiss M, Nordbrock E, et al. Diagnostic and Statistical Manual of 10. Perrin JM, Friedman RA, Knilans TK; Effect of Aptensio XR (methylphenidate Mental Disorders, Fifth Edition (DSM-5).

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