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A Randomized, Placebo-Controlled Trial of Three Fixed
Dosages of Prolonged-Release OROS Methylphenidate
in Adults with Attention-Deficit/Hyperactivity Disorder

Rossella Medori, J. Antoni Ramos-Quiroga, Miguel Casas, J.J.S. Kooij, Asko Niemelä, Götz-Erik Trott,Emma Lee, and Jan K. Buitelaar Background: There is increasing recognition of attention-deficit/hyperactivity disorder (ADHD) in adults and the need to evaluate efficacy
and safety of methylphenidate treatment in these patients.
Methods: In this double-blind trial, 401 adults with ADHD (218 men; 18 – 63 years) were randomly assigned to receive prolonged-release
osmotic release oral system (OROS) methylphenidate (18 mg, 36 mg, or 72 mg/day) or placebo for 5 weeks. Primary outcome was change in
total score on Conners’ Adult ADHD Rating Scale (CAARS: investigator-rated) at end point compared with baseline. Adverse events, vital
signs, and laboratory parameters were assessed.
Results: Treatment with 18-mg, 36-mg, and 72-mg/day prolonged-release methylphenidate, compared with placebo, was associated with
significantly larger improvement in CAARS total symptom score from baseline to end point than placebo: mean change Ϫ10.6 (p ϭ .01),
Ϫ11.5 (p ϭ .01), and Ϫ13.7 (p Ͻ .001) versus Ϫ7.6, respectively. Responders (Ն30% decrease) were 50.5%, 48.5%, and 59.6% versus 27.4%(p Ͻ .001). Other efficacy measures also showed improvements. Incidence of adverse events was 75%, 76%, and 82% in 18-mg, 36-mg, and72-mg/day groups, respectively, and 66% in placebo; most frequent included decreased appetite (25% methylphenidate; 7% placebo) andheadache (21% methylphenidate; 18% placebo). In methylphenidate-treated patients, 4.3% discontinued due to adverse event; one seriousadverse event was possibly related to study drug. Blood pressure and pulse increased at week 1 and then remained stable through week 5.
Conclusions: Prolonged-release methylphenidate is an effective treatment of ADHD in adults, with a safety profile consistent with
methylphenidate use in pediatrics.
Key Words: ADHD, adult, methylphenidate, prolonged release,
The prolonged-release (PR) osmotic release oral system (OROS) formulation of methylphenidate is designed to delivermethylphenidate in a controlled manner for approximately 12 Attention-deficit/hyperactivity disorder (ADHD) is one of hours, thereby allowing coverage of symptoms over a full day.
the most common psychiatric disorders in children charac- This long-acting formulation, designed for once-a-day admin- terized by developmentally inappropriate inattention, hy- istration, was shown to be an effective and safe treatment of peractivity, and impulsiveness. The disorder persists into adulthood ADHD in children and adolescents Several controlled in between 15% and 65% of the patients, depending on definition of studies with immediate-release (IR) formulations suggest persistence The prevalence of ADHD among adults is estimated methylphenidate to be an appropriate treatment of ADHD in to be 4.4% in the United States and 3.4% (range 1.2%–7.3%) in 10 countries in the Americas, Europe, and Middle East Methyl- Two controlled studies evaluated PR methylphenidate in phenidate is one of the most frequently prescribed and studied adults with ADHD using a flexible dose approach in which stimulant medications for treatment of ADHD in children In medication was titrated to optimal response In both children and adolescents, the use of stimulants including methyl- studies, PR methylphenidate was found to be an effective phenidate has been associated with cardiovascular effects treatment of adults with ADHD, with a safety profile consistent With the increasing recognition of ADHD in adults there is with use of IR methylphenidate in children and adults In a need to evaluate the efficacy and safety of methylphenidate in the addition to the studies with PR methylphenidate, a multilayer treatment of ADHD in this population.
extended-release formulation of methylphenidate was shown tobe an effective treatment of ADHD in adults using a flexible dose From Janssen-Cilag EMEA (RM), Neuss, Germany; Department of Psychiatry approach Another 5-week study assessed three fixed doses (JAR-Q, MC), Hospital Universitari Vall d’Hebron and Department of Psy- (20 mg, 30 mg, and 40 mg/day) of extended-release dexmethyl- chiatry and Legal Medicine (JAR-Q, MC), Universitat Autònoma de Bar- phenidate in adults with ADHD and showed active treatment was celona, Barcelona, Spain; Psycho-Medical Programs (JJSK), Program Adult ADHD, Den Haag, The Netherlands; Department of Psychiatry We report a large, 5-week, double-blind, placebo-controlled (AN), Oulu University Hospital, Oulu, Finland; (G-ET) Aschaffenburg, Ger- trial designed to evaluate the short-term efficacy and safety of many; Janssen Belgium (EL), Beerse, Belgium; and Department of Psychi- three fixed dosages (18 mg, 36 mg, and 72 mg/day) of PR atry (JKB), University Medical Center, St Radboud, and Karakter Child and methylphenidate in adult patients with ADHD. Selection of Adolescent Psychiatry University Center (JKB), Nijmegen, The Nether- dosages reflected the range of dosages of PR methylphenidate (CONCERTA) approved for use for treating ADHD in children Address reprint requests to Rossella Medori, M.D., Janssen-Cilag EMEA, Rei- ffeisenstrasse 8, 41470 Neuss, Germany; .
and adolescents in various countries, so as to assess the efficacy Received July 30, 2007; revised November 2, 2007; accepted November 3, and safety of fixed dosages of PR methylphenidate used with children in the treatment of ADHD in adults.
Methods and Materials
containers to the study center. Procedures were performed afterpatients took their morning medication and at various times Patients
during the day, depending on when they visited the site. At the The trial included adult men and women with a diagnosis of end of weeks 1 and 3, efficacy measures were administered, vital ADHD according to the criteria of the Diagnostic and Statistical signs measured, and adverse events monitored. At the end of Manual of Mental Diseases, Fourth Edition (DSM-IV) and week 5, or at early withdrawal, efficacy and safety procedures confirmed by the Conners’ Adult ADHD Diagnostic Interview for performed at baseline were repeated. Eligible patients continued DSM-IV (CAADID) Other requirements for inclusion were in a 7-week open-label extension that assessed the safety of age 18 to 65 years; chronic course of ADHD symptomatology methylphenidate in a flexible dose regimen of 18 mg to 90 from childhood to adulthood with some symptoms present mg/day. This report covers the 5-week double-blind phase.
before age 7 years, as determined by investigators following theCAADID interview; and CAARS total score of Ն24 at screening Assessment
The Structured Clinical Interview for DSM-IV Axis I Disor- The Conners’ Adult ADHD Rating Scales (CAARS) for which ders (SCID-I/P) was used to evaluate the presence of other psychometric data have been reported are considered appropri- comorbidities and exclude other symptoms Attention- ate for measuring symptoms in adults with ADHD and have been deficit/hyperactivity disorder was not diagnosed if symptoms used in clinical trials of adult ADHD This study used were better accounted for by another psychiatric disorder (e.g., both Observer (CAARS:O-SV) and Self (CAARS:S-S) forms. The mood, anxiety, psychotic, personality disorder). Patients were CAARS Observer form comprises 18 investigator-rated items excluded if the investigator judged they (or their child) had a corresponding to the 18 DSM-IV ADHD symptoms and provides history of poor response or intolerance to methylphenidate; they a total score referred to as the CAARS total ADHD Symptom had been diagnosed with any current clinically unstable psychi- Score and two subscales. The CAARS Self form is a 26-item, atric condition (e.g., acute mood disorder, bipolar disorder, acute self-report, four-point rating scale that measures symptoms based obsessive-compulsive disorder), as determined by the investiga- on the DSM-IV criteria for ADHD providing total score, ADHD tor; or they had been diagnosed with substance use disorder index, and four subscales. Investigators who performed ratings (abuse/dependence) according to DSM-IV criteria within the last for CAARS assessments successfully completed a formal training 6 months. Other exclusion criteria included family history of schizophrenia or affective psychosis; serious illnesses (e.g., The primary efficacy measure was the change in CAARS:O-SV hepatic or renal insufficiency or significant cardiac, gastrointes- total score at end point compared with baseline. Secondary end tinal, psychiatric, or metabolic disturbances); hyperthyroidism, points included changes in CAARS:O-SV total and subscale myocardial infarction, or stroke within 6 months of screening; scores at weeks 1, 3, and 5, and changes from start to the end of and history of seizures, glaucoma, or uncontrolled hypertension.
treatment in the following: 1) CAARS:S-S total and subscalescores; 2) Clinical Global Impression Severity of Illness subscale Procedure
(CGI-S) used to rate the severity of a patient’s illness on a 7-point This double-blind, randomized, placebo-controlled, parallel- scale and 3) Sheehan’s Disability Scale (SDS) designed to group, fixed-dose trial was conducted at 51 investigator sites in measure impairment on work, social and home life, or family 13 European countries from April 2005 to June 2006. The responsibilities with a self-administered 10-point visual analog research protocol was approved by the ethics committees at each scale for three items. A trained and certified clinician adminis- site, and all participants gave written informed consent.
tered these tests in each patient’s native language.
Eligible patients were randomized into one of four treatment Safety evaluations included monitoring of adverse events, groups to receive oral dosages of 18 mg, 36 mg, or 72 mg clinical laboratory tests, vital signs, and physical examination.
methylphenidate or placebo once daily. Patients receiving 18 mgor 36 mg/day methylphenidate or placebo received the treatment Statistical Analysis
dose for 5 weeks. Patients in the 72-mg methylphenidate group A sample size of 94 patients per group was calculated to were titrated from a starting dose of 36 mg/day for 4 days to 54 provide Ն90% power to detect a mean difference of six units mg/day for 3 days, after which 72 mg/day was administered for between an active-dose group and placebo in change from 4 weeks. Randomization was based on a computer-generated baseline for the primary end point, based on a two-sample, randomization and stratification scheme prepared before the two-tailed, t test with alpha ϭ .016 and standard deviation of 11.
study. Randomization was balanced by using permuted blocks of Adjusting for a rate of 6% for patients without baseline or treatments, stratified by study center, and implemented via an postbaseline efficacy assessments, the required number of pa- tients was 100 per treatment group and 400 total.
The trial included a washout period of up to 4 weeks during Efficacy analyses included patients who received at least one which current therapy was tapered to discontinuation. Patients dose of medication and had at least one postbaseline efficacy on a stable dosage of antidepressant therapy for at least 3 months measurement. Primary end point was change in CAARS:O-SV prior to screening were allowed to continue at the same daily total score from baseline to last postrandomization assessment.
dose during the study, with the exception of monoamine oxidase Change from baseline at each visit and end point (last observa- inhibitors, which were tapered to discontinuation with a mini- tion carried forward [LOCF]) was analyzed using analysis of mum washout period of 2 weeks. Baseline procedures included covariance that included treatment, sex, and country as factors administration of efficacy measures, clinical laboratory tests and baseline scores as a covariate. Treatment effects were (hematology, biochemistry), vital signs (supine and standing estimated based on least squares means of the difference.
blood pressure, pulse), and physical examination. Patients were Dunnett’s procedure was used to adjust for multiple comparisons instructed to take their medication in the morning, beginning the of the three PR methylphenidate dosages versus placebo at end day after baseline assessments. Their medication compliance was point. Pairwise comparisons between each of the methylpheni- checked by having them return all used and unused blister date dosing groups were performed using analysis of covariance that included treatment, sex, and country as factors and baseline Responders were predefined as showing Ն30% reduction of A total of 448 patients were screened and 402 patients were CAARS:O-SV total score from baseline at end point and were randomized into placebo or one of the three PR methylphenidate analyzed using the Cochran-Mantel-Haenszel test, controlling for groups. Overall, 365 (91%) of randomized patients completed the country. Sidak correction was used to adjust for multiple com- 5-week double-blind study period: 94.1%, 90.2%, and 86.3% in parisons of the three PR methylphenidate dosages versus pla- the 18-mg, 36-mg, and 72-mg/day PR methylphenidate groups, cebo in the responder analysis. Patients with Ն50% improvement respectively, and 93.8% in the placebo group. Mean (SD) dura- in CAARS:O-SV total score were also analyzed. Clinical Global tion of exposure was 33.9 (6.53) days in the four groups. Mean Impression Severity of Illness subscale was analyzed with anal- (SD; range) daily dosage was .24 mg/kg (.048 mg/kg; .1–.4 ysis of variance on ranked changes from baseline, with treat- mg/kg ), .50 mg/kg (.112 mg/kg; .3–.8 mg/kg ), and .96 mg/kg ment, sex, and country as factors at each assessment time point (.198 mg/kg; .6 –1.7 mg/kg ) in the 18-mg, 36-mg, and 72-mg/day and end point, and CAARS:S-S and SDS comparisons of change PR methylphenidate groups, respectively. The statistical analysis from baseline to end point were analyzed using analysis of of efficacy included 394 patients, and safety assessment included covariance, with treatment, sex, and country as factors and 401 patients who received at least one dose of trial medication.
baseline score as covariate, with comparisons of the three PR Baseline demographic and clinical characteristics were methylphenidate dosages versus placebo adjusted using Dun- similar across placebo and the three PR methylphenidate nett’s procedure. All statistical analyses were performed using groups . Overall, median age was 34 years, 54% were SAS (Version 8.02; SAS Institute, Cary, North Carolina).
men, and 98% were Caucasian. Median age at diagnosis of Table 1. Baseline Demographic and Clinical Characteristics of Randomized Patients
Childhood ADHD subtypeb, n (%) ADHD, attention-deficit/hyperactivity disorder; CAADID, Conners’ Adult ADHD Diagnostic Interview for DSM-IV; CAARS:O-SV, Conners’ Adult ADHD Rating Scale: Investigator rated; CAARS:S-S, Conners’ Adult ADHD Self Report Short Version; CGI-S, Clinical Global Impression–Severity, investigator rated; CI,confidence interval; PR, prolonged-release; SDS, Sheehan’s Disability Scale, self-report.
aOther is defined as Black or African heritage, Hispanic, and Other.
bCAADID responses.
cPatients were excluded if diagnosed within the last 6 months; information was obtained after screening for three patients.
dPatients were excluded if symptoms better accounted for by another psychiatric disorder than ADHD.
ePossible range of scores on each measure: CAARS:O-SV: 0 –54; CAARS:S-S: 0 –78; CGI-S: 1–7; SDS: 0 –30. SDS excluded since visual analog raw scores are not considered appropriate for group comparisons.
ADHD was 32 years, with the majority (71%) diagnosed with treated with PR methylphenidate. Mean decrease in weight from ADHD combined subtype. Currently active and stable psychiatric baseline at end point was Ϫ.9, Ϫ1.1, and Ϫ1.9 kg in the 18-mg, comorbidities in the study population included mood and anxi- 36-mg, and 72-mg groups, respectively (p-values Ͻ .001), versus ety disorders in 12% of patients and personality disorders in 1% of patients. Mean baseline scores of efficacy measures were Most adverse events were mild or moderate in all treatment groups, with only four patients reporting a serious adverse eventin the 18-mg and 72-mg PR methylphenidate groups. In the Efficacy
18-mg group, a cerebrovascular accident was reported in a Mean (SD) change from baseline to end point in CAARS:O-SV 59-year-old man who temporarily stopped treatment and recov- total score with LOCF was Ϫ10.6 (10.34), Ϫ11.5 (9.97), and ered in 16 days, and anxiety disorder was reported in a 43-year- Ϫ13.7 (11.11) in 18-mg, 36-mg, and 72-mg PR methylphenidate old woman who continued treatment and recovered in 4 days. In groups, respectively, versus Ϫ7.6 (9.93) in placebo the 72-mg group, a 34-year-old woman recovered from a mi- The decrease (improvement) in CAARS:O-SV total score from graine attack after 2 days without stopping treatment, and a baseline to end point was significantly larger in the three PR 21-year-old man was reported with the onset of a depressive methylphenidate groups versus placebo (p-values Ͻ .015). Sta- disorder after a breakdown of his relationship; he continued tistical significance was not reached between any of the three PR study treatment, received additional counseling, and recovered methylphenidate treatment groups. Interactions and main effects in 4 weeks. The investigators considered depression possibly of country and gender were not significant (p-values Ͼ .06). The related and the other three events as not related or doubtfully effect sizes1 for the 18-mg, 36-mg, and 72-mg PR methylpheni- date groups were .38, .43, and .62, respectively.
Thirteen (4.3%) patients treated with PR methylphenidate There were significantly more responders (Ն30% reduction in permanently discontinued trial medication due to one or more CAARS:O-SV total score) in the PR methylphenidate groups adverse events, with 1, 4, and 8 patients in the 18-mg, 36-mg, and compared with placebo: 50.5%, 48.5%, and 59.6% in 18-mg, 72-mg groups, respectively. Most frequently reported adverse 36-mg, and 72-mg groups, respectively, versus 27.4% of placebo- events leading to discontinuation were anxiety (four patients), treated patients; p Ͻ .001. Patients with Ն50% improvement in irritability and nervousness (both reported by three patients), and CAARS:O-SV total score was 22.2%, 24.8%, and 31.3% in 18-mg, tremor, insomnia, and restlessness (all reported by two patients).
36-mg, and 72-mg groups, respectively, versus 13.7% of placebo- Patients recovered from all of the adverse events, except for one treated patients, p Ͻ .01. The largest improvement in CAARS: report of aggression and delusion of reference in the 36-mg O-SV total and subscale scores occurred after week 1 for all group, tinnitus in the 72-mg group, and hypertension in the groups, with additional improvement through week 5 placebo group. The investigators considered hypertension On CAARS:S-S (total score, ADHD index, four subscales), and delusion of reference as very likely related and the other CGI-S, and SDS efficacy measures, significant improvements two events as doubtfully or possibly related to the trial occurred in mean change from baseline to end point in the three medication, and delusion of reference was reported resolved PR methylphenidate groups compared with placebo Adverse Events
Cardiovascular-Related Effects
Adverse events are summarized by preferred term (Medical As shown in PR methylphenidate was associated with Dictionary for Regulatory Activities2) in for the 401 statistically significant increases in blood pressure, but these patients who received at least one dose of trial medication. More were limited to week 1 (systolic and diastolic) in the 72-mg group patients in the PR methylphenidate groups (75%– 82%) compared and week 3 (diastolic) in the 36-mg group. In all groups, change with placebo (66%) reported a treatment-emergent adverse from baseline in blood pressure occurred at week 1, with only event, and more events were considered at least possibly related slight further increases or decreases from week 1 through week to trial medication in the PR methylphenidate groups (52%– 69%) 5. Clinically relevant criteria for systolic (Ն140 mm Hg) and/or than in placebo group (43%). The highest percentage of adverse diastolic (Ն90 mm Hg) blood pressure were met by a percentage events was reported in the 72-mg group. The most frequently of patients at baseline (Յ38%) and at least one time point during reported adverse events (Ͼ10% treated with PR methylpheni- treatment (Յ43%) in PR methylphenidate and placebo groups.
date) were decreased appetite, headache, insomnia, nausea, and Pulse showed statistically significant increases at the three time dry mouth, with decreased appetite and dry mouth exhibiting points in the three PR methylphenidate groups and at week 3 dose-relatedness. Psychiatric-related adverse events (e.g., irrita- for placebo. In all groups, increase from baseline in pulse bility, anxiety, nervousness) occurred more frequently in meth- occurred at week 1, with only slight further increases or de- ylphenidate-treated patients, particularly at the highest dose.
Tachycardia (5.6%) and palpitations (3.9%) were reported in the There were no clinically notable changes in laboratory values three PR methylphenidate groups but not in placebo. Decreased weight was reported as an adverse event in 22 (7.2%) patients Discussion
1Defined as the treatment difference between the PR methylphenidate In this large 5-week, double-blind, randomized, placebo- group and placebo in least square means divided by the square root controlled trial, three fixed doses of PR methylphenidate, 18 mg, of the mean square error, based on a mixed model with random 36 mg, and 72 mg/day, were an effective treatment of ADHD in intercept and an unstructured covariance matrix.
adults, as indicated by changes in primary and secondary MedDRA the Medical Dictionary for Regulatory Activities terminology is the international medical terminology developed under the auspices measures versus placebo. Over 5 weeks of treatment, PR meth- of the International Conference on Harmonization of Technical ylphenidate was statistically superior to placebo at 18 mg, 36 mg, Requirements for Registration of Pharmaceuticals for Human Use and 72 mg/day with effect sizes of .38, .43, and .62, respectively.
Efficacy of the medication was apparent in the first week of Table 2. Efficacy Outcomes by Mean Change From Baseline to Double-Blind End Point
Prolonged-Release (PR) Methylphenidate Treatment All analyses were intention to treat with last observation carried forward values for CAARS: O-SV (administered at baseline and weeks 1, 3, and 5) and actual values for other efficacy measures (administered at baseline and week 5). p value for comparison between each dose group and placebo using two-tailed t test.
ADHD, attention-deficit/hyperactivity disorder; CAARS:O-SV, Conners’ Adult ADHD Rating Scale: Investigator rated; CAARS:S-S, Conners’ Adult ADHD Self Report Short Version; CGI-S, Clinical Global Impression–Severity, investigator rated; CI, confidence interval; PR, prolonged release; SDS, Sheehan’s Disability Scale, self-report.
Table 3. Mean Change From Baseline to Treatment Weeks 1, 3, and 5 in CAARS:O-SV Total and Subscale Scores
Prolonged-Release (PR) Methylphenidate Treatment All analyses were intention to treat with observed values. p value for comparison between each dose group and placebo using two-tailed t test.
CAARS:O-SV, Conners’ Adult ADHD Rating Scale: Investigator rated; CI, confidence interval; PR, prolonged release.
treatment and appeared dose-dependent. Adverse events (e.g., For cardiovascular parameters, PR methylphenidate was as- decreased appetite, headache, insomnia, nausea, dry mouth), sociated with statistically significant increases in blood pressure, including psychiatric-related (e.g., irritability, anxiety) and car- but these were small and occurred primarily at week 1 with only diovascular-related events (e.g., tachycardia and palpitations), slight further increases or decreases from week 1 through week occurred more frequently in PR methylphenidate than placebo 5. Clinical relevant criteria for hypertension (systolic Ն140 mm groups; some adverse events appeared dose-related (e.g., de- Hg and diastolic Ն90 mm Hg blood pressure) were met by a creased appetite, dry mouth); adverse events seldom led to similar percentage of patients in all treatment groups. Pulse discontinuation of medication; and adverse events were rarely showed statistically significant increases at the three time points in all PR methylphenidate groups but was similar to placebo in Table 4. Summary of Adverse Events
Possibly related to trial medicationa All MPH, combined 18-mg, 36-mg, and 72-mg/day PR methylphenidate treatment groups; PR, prolonged release.
aIncludes trial medication relationship of ‘possibly,’ ‘probably,’ and ‘very likely.’bSummarized by preferred term according to Medical Dictionary for Regulatory Activities (MedDRA).
Table 5. Summary of Cardiovascular-Related Measurements
Met Clinically Relevant Criteria, n (%) bpm, beats per minute; PR, prolonged release. Range is the minimum and maximum of actual values.
aMeasured while patient standing.
bStatistically significant change at .05 level versus baseline (two-tailed paired t test).
the 18-mg group and larger in 36-mg and 72-mg groups. As with Using a similar definition of clinical response (Ն30% decrease in blood pressure, increase in pulse occurred primarily at week 1, the main outcome measure), the NNT for the present study are with only slight further increases or decreases from week 1 4.3 (18 mg), 4.7 (36 mg), and 3.1 (72 mg), and 3.4 for the Biederman et al. evaluated PR methylphenidate in adults Attention-deficit/hyperactivity disorder is not as well under- with a flexible dose approach in which medication was titrated to stood in adults as in children, and in turn, there is more concern optimal response (e.g., dose was increased by 36 mg/day only about the validity of the diagnosis in adults. The diagnosis is still for subjects who failed to attain an a priori definition of improve- questioned in Europe where this trial was completed, but there is ment) up to a maximum daily dose of 1.3 mg/kg over a 6-week increasing literature on the recognition and need for treatment of treatment period. Other differences from the present study ADHD in adults reflecting growing evidence that symp- included efficacy measures (Clinical Global Impression-Improve- toms persist beyond childhood and symptoms in adults show the ment [CGI-I] and Adult ADHD Investigator System Report Scale same responsiveness to methylphenidate treatment as seen in [AISRS]) Mean daily dose of methylphenidate at week 6 was children A recent systematic European review of the 80.9 mg (Ϯ31.8 mg). In both studies, treatment with PR methyl- efficacy of prolonged-release stimulants (methylphenidate, dex- phenidate was associated with clinically and statistically signifi- amphetamine) and atomoxetine for treatment of ADHD in cant reductions in DSM-IV symptoms of inattention and hyper- children, adolescents, and adults includes the recommendation activity/impulsivity relative to patients treated with placebo.
for their use in adults, with the observation that psychotherapeu- Given the reported information, we were able to compute a tic interventions also have an important role common metric, the numbers needed to treat (NNT); namely, the The safety profile in the present study was consistent with number of patients that should be treated to improve one Biederman et al. and reflects a large sample of patients who additional patient compared with use of the comparator, where received PR methylphenidate (305 and 67 patients, respectively).
a smaller number is associated with more effective treatment.
In both studies, the most frequently reported adverse events with PR methylphenidate treatment included decreased appetite, proved compliance with a once-daily administration and possi- headache, insomnia, nausea, and dry mouth. Our study sug- ble reduced risk of abuse with the formulation, have been gested that adverse events such as decreased appetite and dry mouth may increase with higher doses. The same trend was The present study evaluated three fixed doses up to 72 observed for the incidence of adverse events belonging to the mg/day, the maximal dose FDA has approved in adolescents.
following body systems: psychiatric disorders, gastrointestinal Although not designed for direct comparisons between dosages, disorders, metabolism and nutrition disorders, and cardiac dis- this study indicates a clinical benefit of treatment with PR orders. In the present study, as in Biederman et al. adverse methylphenidate for ADHD in adults at fixed daily doses of 18 events did not generally lead to discontinuations of PR methyl- mg and 36 mg and that these benefits were more pronounced phenidate, and adverse events were rarely serious. In both with a daily dose of 72 mg. If weight-base dosing is considered studies, treatment was associated with small but statistically appropriate for this medication, then higher doses would need to significant increases in blood pressure and heart rate and with The U.S. Food and Drug Administration (FDA) directed manufacturers of all drug products approved for treatment of This study was supported by Janssen Pharmaceutica N.V., ADHD to develop patient medication guides to alert patients to possible cardiovascular risks and risks of adverse psychiatric (NCT00246220; CR002479): A Study of the Effectiveness and symptoms associated with these medicines In this study, Safety of Prolonged-Release Methylphenidate Hydrochloride in patients were not enrolled if they had serious illnesses (e.g., Adult Patients With Attention Deficit/Hyperactivity Disorder. significant cardiac, vascular, pulmonary disturbances) or were diagnosed with any clinically unstable psychiatric condition We thank the investigators, their study teams, and patients for (e.g., acute mood disorder, bipolar disorder, acute obsessive- participating in the study. Joachim Dejonckheere of SGS Life compulsive disorder). Biederman et al. excluded patients Sciences analyzed the data. We also acknowledge Bradford with significant chronic medical conditions.
Challis, Ph.D., and Susan Glasser, Ph.D., of Johnson & Johnson In the three PR methylphenidate (18-mg, 36-mg, 72-mg) Pharmaceutical Research & Development, L.L.C., for their con- groups, there were reports of tachycardia (4%, 4.9%, 7.8%) and tribution to the preparation of the manuscript. palpitations (2%, 4.9%, 4.9%) suggestive of a dose-response Drs. Rossella Medori and Emma Lee are employees of Janssen, relationship; these events did not require an intervention and and the other authors were investigators in the clinical study. Dr. were not serious. There were small increases in blood pressure Ramos-Quiroga reports having received lecture and consulting (.1, .4, 2.2 mm Hg for standing systolic and Ϫ.7, 1.7, 1.6 mm Hg fees from Janssen-Cilag and Laboratorios Rubió and research for diastolic at week 5) and statistically significant increases in funding from Janssen-Cilag. Dr. Casas reports having received pulse at 5 weeks of treatment (3.9, 5.2, 9.8 beats per minute lecture and consulting fees from Janssen-Cilag and Laboratorios [bpm]). Blood pressure and pulse increases occurred primarily at Rubió and research funding from Janssen-Cilag. Dr. Kooij week 1, with slight further increases or decreases from week 1 reports having been a consultant, member of advisory board, through week 5. In Biederman et al. cardiovascular com- and/or speaker for Janssen Cilag BV and Eli Lilly. Dr. Buitelaar plaints were reported in 9% of the PR methylphenidate group, reports having been a consultant, member of advisory board, although no event was characterized as tachycardia or palpita- and/or speaker for Janssen Cilag BV, Eli Lilly, Bristol-Myer tion or as serious. Biederman et al. reported changes in Squibb, UBC, Shire, Medice. Dr. Niemelä reports having received blood pressure and pulse at week 6 and there were increases in lecture fees from Janssen-Cilagand. Dr. Trott reports no applica- blood pressure (2.2 and 1.6 mmHg for systolic and diastolic) and ble financial interests or potential conflicts of interest. pulse (4.5 bpm). Further research will need to evaluate possible Supplementary material is available online. cardiovascular risks associated with long-term PR methylpheni-date treatment, including changes in blood pressure and pulse 1. Faraone SV, Biederman J, Mick E (2005): The age-dependent decline of attention deficit hyperactivity disorder: A meta-analysis of follow-up In the present study, reports of psychiatric symptoms (e.g., studies. Psychol Med 35:1–7.
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