>̈œ˜>Ê/œÝˆVœœ}ÞÊ*Àœ}À>“ 1°-°Ê i«>À̓i˜ÌʜvÊi>Ì Ê>˜`ÊՓ>˜Ê-iÀۈVià i˜ÌiÀÊœÀÊ/ iÊ Û>Õ>̈œ˜Ê"vÊ,ˆÃŽÃÊ /œÊՓ>˜Ê,i«Àœ`ÕV̈œ˜

NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of

August 2005 NIH Publication No. 05 - 4473 Table of Contents

Preface...... v

Abstract...... vii

Introduction...... viii

NTP Brief on Methylphenidate ...... 1

References...... 6

Appendix I. NTP-CERHR Amphetamines and Methylphenidate Expert Panel Preface...... I-1 Expert Panel...... I-2

Appendix II. Expert Panel Report on Methylphenidate ...... II-i Table of Contents...... II-iii Abbreviations...... II-v List of Tables...... II-viii List of Figures...... II-x Preface...... II-xi Chemistry, Usage and Human Exposure...... II-1 General Toxicology and Biologic Effects...... II-8 Developmental Toxicity Data...... II-46 Reproductive Toxicity Data...... II-122 Summaries and Conclusions...... II-131 References...... II-135

Appendix III. Public Comments on Expert Panel Report on Methylphenidate No public comments received...... III-1

iii [This page intentionally left blank]

iv Preface

The National Toxicology Program (NTP) chemical is hazardous to humans. The panel established the NTP Center for the Evaluation also identifies areas of uncertainty and where of Risks to Human Reproduction (CERHR) additional data are needed. The CERHR expert in 1998. The CERHR is a publicly accessible panels use explicit guidelines to evaluate the resource for information about adverse repro- scientific literature and prepare the expert panel ductive and/or developmental health effects reports. Expert panel reports are made public associated with exposure to environmental and comments are solicited. and/or occupational chemicals. The CERHR is located at the National Institute of Environmen- Next, the CERHR prepares the NTP-CERHR tal Health Sciences (NIEHS) of the National monograph. The NTP-CERHR monograph in­ Institutes of Health and Dr. Michael Shelby is cludes the NTP brief on the chemical evaluated, the director.1 the expert panel report, and public comments on that report. The goal of the NTP brief is The CERHR broadly solicits nominations of to provide the public, as well as government chemicals for evaluation from the public and health, regulatory, and research agencies, with private sectors. The CERHR follows a formal the NTP’s interpretation of the potential for process for review and evaluation of nominated the chemical to adversely affect human repro- chemicals that includes multiple opportunities ductive health or children’s health. The NTP- for public comment. Chemicals are selected for CERHR monograph is made publicly available evaluation based upon several factors including electronically on the CERHR web site and in the following: hard copy or CD-ROM from the CERHR. • potential for human exposure from use and occurrence in the environment 1 Information about the CERHR is available on the • extent of public concern web at or by contact- • production volume ing the director: • extent of data from reproductive and NIEHS, P.O. Box 12233, MD EC-32, developmental toxicity studies Research Triangle Park, NC 27709 919-541-3455 [phone] The CERHR convenes a scientific expert panel 919-316-4511 [fax] that meets in a public forum to review, discuss, [email protected] [email] and evaluate the scientific literature on the Information about the NTP is available on the web selected chemical. Public comment is invited at or by contact- prior to and during the meeting. The expert panel ing the NTP Liaison and Scientific Review Office produces a report on the chemical’s reproductive at the NIEHS: and developmental toxicities and provides its [email protected] [email] opinion of the degree to which exposure to the 919-541-0530 [phone]

 [This page intentionally left blank]

vi Abstract

The National Toxicology Program (NTP) Cen- This conclusion is based on studies showing ter for the Evaluation of Risks to Human Re- that children treated with therapeutic doses of production (CERHR) conducted an evaluation methylphenidate have no evidence of move- of the potential for methylphenidate to cause ment disorders or tics due to the medication. adverse effects on reproduction and develop- Second, there is minimal concern for meth- ment in humans. Methylphenidate was selected ylphenidate-induced growth restriction. This for evaluation because of 1) widespread usage conclusion is based on growth restriction being in children, 2) availability of developmental observed in animal studies only at high doses studies in children and experimental animals, of methylphenidate using a non-therapeutic and 3) public concern about the effect of this route of exposure. The effect on growth was stimulant on child development. Methylpheni- reversible. Finally, there are insufficient data date is a central nervous system stimulant ap- to draw conclusions on 1) an association be- proved by the U.S. Food and Drug Administra- tween methylphenidate therapy in pregnant tion for the treatment of attention deficit hyper- women and pregnancy loss and 2) possible activity disorder (ADHD) in persons 6 years of reproductive effects of methylphenidate in age and older and for narcolepsy. The results humans. NTP-CERHR monographs are trans- of this evaluation on methylphenidate are pub- mitted to federal and state agencies, interest- lished in an NTP-CERHR monograph which ed parties, and the public and are available in includes: 1) the NTP Brief, 2) the Expert Panel electronic PDF format on the CERHR web site Report on the Reproductive and Developmen- and in printed text tal Toxicity of Methylphenidate, and 3) public or CD-ROM from the CERHR: comments received on the Expert Panel Report. National Institute of . As stated in the NTP Brief, the NTP reached Environmental Health Sciences the following conclusions regarding the pos- P.O. Box 12233, MD EC-32 sible effects of exposure to methylphenidate on Research Triangle Park, NC 27709 human development and reproduction. First, Phone: 919-541-3455 there is negligible concern for methylpheni- Fax: 919-316-4511 date-induced tics and movement disorders.

vii Introduction

In January 2004, the CERHR Core Committee, toxicities of these drugs. The CERHR Amphet- an advisory group composed of representatives amines and Methylphenidate Expert Panel com- from NTP member agencies, recommended pleted its evaluation at a public meeting held on amphetamines and methylphenidate for expert January 10–12, 2005 in Alexandria, VA. panel review. Methylphenidate (CAS RN 113- 45-1) is a central nervous system stimulant This monograph includes the NTP brief on used to treat attention deficit hyperactivity dis- methylphenidate, a list of the expert panel mem- order and narcolepsy in children and adults bers (Appendix I), the expert panel report on and is used off-label to treat depression and methylphenidate (Appendix II), and all public patients with post-stroke cognitive impairment. comments received on the expert panel report d,l‑Methylphenidate hydrochloride (CAS RN (Appendix III). The NTP-CERHR monograph 298-59-9) is marketed under the names of Rit- is intended to serve as a single, collective source alin®, Metadate®, Methylin®, and Concerta®. of information on the potential reproductive d‑Methylphenidate is marketed under the name and developmental effects of methylphenidate. of Focalin. Those interested in reading this monograph may include individuals, members of public in- CERHR selected this chemical for expert panel terest groups, and staff of health and regulatory evaluation because of: agencies. • the increasing use in children, • public concern for long-term effects on The NTP brief included within this monograph child development and behavior, presents the NTP’s interpretation of the poten- • the availability of human exposure data, tial for methylphenidate exposure to cause ad- and, verse reproductive or developmental effects in • findings from developmental studies in people. The NTP brief is intended to provide humans and experimental animals. clear, balanced, scientifically sound informa- tion. It is based on information provided in the As part of the evaluation of methylphenidate and expert panel report, public comments on that amphetamines, the CERHR convened a panel report, and additional scientific information of scientific experts (Appendix I) to review, published following the public meeting of the discuss, and evaluate the scientific evidence on expert panel. the potential reproductive and developmental

viii NTP Brief on Methylphenidate N TP B rief What is Methylphenidate? How Are People Exposed to Methylphenidate is a pharmaceutical drug pre- Methylphenidate? scribed to children and adults for treatment of People are exposed to methylphenidate as attention deficit hyperactivity disorder (ADHD) a prescribed drug or through its illegal use. and narcolepsy in persons 6 years of age and Little is known about the occurrence of meth- older. Its mode of action in treating ADHD is ylphenidate in the environment. No informa- not known. tion was located on occupational exposures associated with its manufacture, packaging, or Figure 1. Chemical structure of distribution. Recommended doses of methyl- phenidate are 10 to 60 mg/day. Differences in methylphenidate (C14 H19 NO2) recommended doses are based on the disorder O OCH3 being treated and on the patient’s response to treatment. Although the product label recom- H mends against the use of medication in children N younger than 6 years of age, an estimated 4000 prescriptions were written for children 2 years old and younger in 1998. Approximately 40% of all prescriptions for ADHD are written for d,l-Methylphenidate hydrochloride, the medic­ 3–9 year olds, reflecting a difference between inal form of this drug, is marketed under the approved labeling and clinical practice. Meth- names of Ritalin® by Novartis Pharmaceuti- ylphenidate may also be used to treat ADHD cals Corporation, Metadate® by Celltech Phar- or narcolepsy in pregnant women, but there maceuticals, Inc., Methylin® by Mallinckrodt, is no information on the numbers of pregnant Inc., and Concerta® by Alza Corporation. women prescribed the drug. Additionally, there d‑Methylphenidate is marketed under the name are no data on blood levels in pregnant or nurs- of Focalin by Novartis Pharmaceuticals Cor- ing women using the drug and no information poration. Recommended oral doses are 10–60 on methylphenidate levels in breast milk. mg/day for children older than 6 years of age and for adults. While there are no known sources of illicitly manufactured methylphenidate, it is known that In 2000, the U.S. Drug Enforcement Agency. illegal use of the drug occurs through theft, shar- (DEA) reported sharp increases in methyl­ ing of prescribed drug, or use of prescriptions phenidate use in the early 1990s. However, obtained inappropriately or illegally. There are between 1996 and 2000 reported use leveled no data on human exposure levels resulting from off at about 11 million prescriptions per year, unapproved use or abuse of methylphenidate. primarily for treating children with ADHD. Based on estimates from the DEA and the Can Methylphenidate Affect Human United Nations, U.S. production of methyl- Development or Reproduction?* phenidate increased from about 4000 pounds Possibly. Although a number of studies inves- to over 45,000 pounds per year between 1990 tigating effects of methylphenidate on human and 2002. Use of methylphenidate in the United * Answers to this and subsequent questions may States accounted for approximately 85% of the be: Yes, Probably, Possibly, Probably Not, No global supply in 1999. or Unknown

 development were available for review by the regarding possible developmental effects. First, expert panel, the panel judged the data largely evidence from human studies shows that methyl­ insufficient to support clear conclusions, pri- phenidate does not cause tics or other move- marily because of inadequate study designs. For ment disorders. Second, evidence from animal some studies it was difficult to determine if meth- studies shows that exposure to methylphenidate ylphenidate caused the observed effects because can result in growth restriction in rats treated for appropriate controls were not included. In other various periods from a few days of age to sexual

TP B rief N TP cases factors such as parental tobacco use, alco- maturity. Normal growth occurred when treat- hol use, exposures to other drugs, and mental ment was stopped. Similar effects have been health could have influenced the study results. reported in humans. There were no studies in Further, results from developmental toxicity humans on the possible effects of methylpheni- studies in experimental animals were, in gen- date on reproduction. The expert panel judged eral, judged to be insufficient for a clear deter- the reproductive toxicity data from experimen- mination of developmental effects. However, the tal animal studies insufficient to support a con- expert panel reached two limited conclusions clusion. (Figures 2a and 2b)

Figure 2a. The weight of evidence that methylphenidate causes adverse developmental or reproductive effects in laboratory animals

Clear evidence of adverse effects Some evidence of adverse effects Developmental toxicity 1 Limited evidence of adverse effects Reproductive toxicity Insufficient evidence for a conclusion Limited evidence of no adverse effects Some evidence of no adverse effects Clear evidence of no adverse effects

1 Based on growth restriction in animal studies.

Figure 2b. The weight of evidence that methylphenidate causes adverse developmental or reproductive effects in humans

Clear evidence of adverse effects Some evidence of adverse effects Limited evidence of adverse effects Reproductive toxicity Insufficient evidence for a conclusion Developmental toxicity 1 Limited evidence of no adverse effects Some evidence of no adverse effects Clear evidence of no adverse effects

1 Based on human studies showing no tics or movement disorders resulting from medication.

 Supporting Evidence twice daily on postnatal days 5–24. On postna-

The expert panel report (Appendix II) provides tal day 25, body weight and length and femur N TP B rief details and citations regarding studies on the length were significantly reduced in the meth- possible reproductive and developmental tox- ylphenidate treatment group as compared to icities of methylphenidate. That report also pro- untreated animals. However, there were no dif- vides detailed reasons why, in some cases, the ferences between the control and treated groups expert panel was unable to accept the available by as early as postnatal day 35. The expert panel data as sufficient to reach conclusions. For sev- judged these data sufficient to conclude that eral studies, the expert panel noted that it was postnatal subcutaneous administration of ≥ 35 difficult to distinguish between drug-induced mg/kg body weight/day methylphenidate to adverse effects and effects resulting from the rats causes reversible growth restriction. These health condition being treated with the drug. studies, although scientifically valid, used a non-therapeutic route of exposure. Additional The expert panel evaluated 27 studies on the information on metabolism and distribution growth of children and adolescents on meth- of the drug are needed to determine how the ylphenidate therapy. Although results varied results obtained following subcutaneous injec- among reports, methylphenidate treatment was tion apply to humans who take the drug orally. often associated with decreased gains in height and weight. However, it was not possible to Over 20 studies in children assessed the asso- conclude that methylphenidate treatment alone ciation between methylphenidate therapy and caused the reduced growth. The panel noted that the appearance of tics (involuntary body move- other factors not accounted for in these studies ments) or the worsening of pre-existing tics or may have contributed to the reduced growth, other movement disorders. While some early factors such as seasonal differences in expected studies reported such effects, the effects were growth, measurement of skeletal maturity, not seen in studies that included control sub- height of parents, and other concurrent medical jects (children not treated with methylpheni- conditions. Because of these confounding fac- date) and evaluation by medical personnel who tors, the expert panel judged these data insuf- were not aware of which subjects were taking ficient to clearly determine if methylphenidate methylphenidate and which were not. affects growth in children and adolescents. The expert panel evaluated several studies on The expert panel evaluated 10 studies on the the relationship of methylphenidate therapy in developmental toxicity of methylphenidate in children to the risk of substance abuse later in laboratory animals. Two laboratories reported life. Although some data suggested a reduced subcutaneous administration of methylpheni- risk for illicit substance abuse, the panel judged date at doses of 35 mg/kg body weight/day or these data insufficient to conclude whether meth- higher produced reversible growth restriction. ylphenidate therapy in children alters their risk Repeated dosing with methylphenidate (≥ 35 of tobacco use, problematic alcohol consump- mg/kg body weight twice daily) was found to tion, and illicit substance abuse later in life. inhibit gains in body weight and skeletal growth in neonatal (5–7 day old) and weanling (18–21 A study published after the expert panel meet- day old) rats, but the effects did not persist 12 ing (El-Zein, et al. 2005) reported that chro- months after treatment ended. In another study, mosomal damage was significantly elevated growth was evaluated in rat pups after treatment in blood cells of 11 ADHD children after tak- with methylphenidate at 35 mg/kg body weight ing therapeutic doses of methylphenidate for

 3 months. The frequencies of chromosome methylphenidate treatment must be weighed aberrations, sister chromatid exchanges, and against the risks of untreated disease. The micronuclei were elevated in each of the chil- health care provider and patient are best quali- dren studied compared to frequencies observed fied to assess such risks. in blood samples taken prior to methylpheni- date treatment. The authors concluded “These Children and Adolescents findings warrant further investigations of the Unknown. The expert panel noted that long-

TP B rief N TP possible health effects of methylphenidate in term studies on the effects of therapy with humans, especially in view of the well-docu- methylphenidate and exposure through breast mented relationship between elevated frequen- milk are lacking. Several studies reported an cies of chromosome aberrations and increased association between methylphenidate therapy cancer risk.” The NTP recognizes that this study and reduced growth in children, an effect that raises concern about possible hazards of meth- was reversible when therapy stopped. However, ylphenidate treatment. Additional studies are the expert panel judged these data insufficient needed to confirm or refute these findings, as to reach a conclusion on whether or not meth- well as to determine any implications for long- ylphenidate therapy affects growth because term adverse health effects. other factors that might affect growth were not fully accounted for in these studies. Data Should Exposures to Methylphenidate were available but considered insufficient to Cause Concern? reach conclusions regarding how methylphe- nidate treatment of children and adolescents Adults might alter their subsequent risks for tobacco Unknown. No studies on the reproductive use, problematic alcohol consumption, or illicit effects of methylphenidate in humans were substance abuse. available. Studies of reproductive toxicity in experimental animals were judged insuf- The expert panel evaluated the potential for ficient to support a conclusion. According to methylphenidate treatment to increase the inci- the U.S. Food and Drug Administration, the dence of onset or worsening of movement dis- most common side effect of methylphenidate orders or tics. The expert panel judged these treatment is reduced appetite. Less commonly data sufficient to reach a conclusion, i.e., meth- reported side effects are insomnia, headache, ylphenidate treatment of children at standard stomachache, drowsiness, and dizziness. Data therapeutic doses does not increase the inci- were available but considered insufficient to dence of tics or other movement disorders. For reach conclusions regarding how methylpheni- this one specific case, methylphenidate expo- date treatment might alter subsequent risks of sure should Probably Not cause concern. tobacco use, problematic alcohol consumption, or illicit substance abuse. The recent publication by El-Zein et al. (2005) reporting evidence that treatment of children Pregnant Women with methylphenidate results in chromosomal Unknown. The expert panel judged the data damage in blood cells suggests the possibility insufficient to draw conclusions as to whether of long-term adverse health effects including or not the use of methylphenidate by pregnant cancer. If these findings are confirmed, it will women is associated with pregnancy loss or be necessary to re-evaluate the safety of treat- other effects on the developing fetus. As noted ing children and adults with methylphenidate. by the expert panel, any risks associated with

 Based on what is known of exposures to meth- doses of methylphenidate and was reversible,

ylphenidate and studies of reproductive and and (2) a non-therapeutic route of exposure was N TP B rief developmental effects in humans and labora- used in the animal studies. Although some stud- tory animals, the NTP offers the following ies show that methylphenidate-treated children conclusions (see Figure 3). weigh less and/or are shorter than controls, in most cases, results did not reach statistical The NTP concurs with the CERHR Amphet- significance. Furthermore, some of these stud- amine and Methylphenidate Expert Panel ies did not control for other factors that might that there is negligible concern for methylphe- influence growth. nidate-induced tics and movement disorders. The NTP concurs with the CERHR Amphet- This conclusion is based on evidence from amines and Methylphenidate Expert Panel thorough, well-designed studies showing that that there are insufficient data to draw children treated with therapeutic doses of meth- conclusions of an association between methyl­ ylphenidate have no evidence of movement phenidate therapy in pregnant women and disorders or tics due to the medication. Earlier pregnancy loss. studies that suggested an association generally had smaller numbers of subjects and shorter The NTP concurs with the CERHR Amphet- observation periods than later studies. amines and Methylphenidate Expert Panel that there is insufficient evidence to draw The NTP concurs with the CERHR Amphet- conclusions regarding possible reproductive amine and Methylphenidate Expert Panel effects of methylphenidate in humans. that there is minimal concern for methylphe- nidate-induced growth restriction. As noted by the expert panel, any risks associ- ated with methylphenidate treatment must be The panel reached the conclusion of minimal weighed against the risks of untreated disease. concern because (1) growth restriction was The health care provider and patient are best observed in the animal studies only at high qualified to assess such risks.

Figure 3. NTP conclusions regarding the possibilites that human development or reproduction might be adversely affected by exposure to methylphenidate

Serious concern for adverse effects

Concern for adverse effects

Some concern for adverse effects

Developmental Effects1 Minimal concern for adverse effects

Developmental Effects2 Negligible for adverse effects Reproductive and Developmental Effects3 Insufficient hazard and/or exposure data

1 For growth restriction in children and adolescents 2 For methylphenidate-induced tics and movement disorders 3 For fetus and infant

 These conclusions are based on References the information available at the time this brief was prepared. As El-Zein, RA, Abdel-Rahman, SZ, Hay, MJ, Lopez, new information on toxicity and MS, Bondy, ML, Morris, DL, and Legator, MS exposure accumulates, it may (2005) Cytogenetic effects in children treated form the basis for either lowering with methylphenidate. Cancer Letters. In press, or raising the levels of concern ex- available online Feb 16, 2005. NTP Brief NTP pressed in the conclusions.

 Appendix I. NTP-CERHR Amphetamines and Methylphenidate Expert Panel

Preface A 13-member panel of scientists covering dis- duction or development. Panel conclusions were ciplines such as toxicology, epidemiology, and based on the scientific evidence available at the medicine was recommended by the CERHR time of the public meeting. The NTP-CERHR Core Committee and approved by the Associate released the final expert panel reports on meth- Director of the National Toxicology Program. ylphenidate and amphetamines for public com-

Prior to the expert panel meeting, the panelists ment on March 21, 2005 and the deadline for A ppendix I critically reviewed articles from the scientific public comments was May 5, 2005 (Federal literature, as well as a variety of other relevant Register Vol. 70 (49) pp. 12707-12708). The documents. Based on this material, they identi- expert panel report on methylphenidate is pro- fied key studies and issues for discussion. At vided in Appendix II and the public comments a public meeting held January 10–12, 2005, received on the report are in Appendix III. Input the expert panel discussed these studies, the from the public and interested groups through- adequacy of available data, and identified data out the panel’s deliberations was invaluable in needed to improve future assessments. The ex- helping to assure completeness and accuracy of pert panel reached conclusions on whether ex- the reports. The expert panel report on meth- posures to amphetamines and methylphenidate ylphenidate is also available on the CERHR might result in adverse effects on human repro- website .

I- NTP-CERHR Amphetamines and Methylphenidate Expert Panel Mari S. Golub, Ph.D., Chair Erica L. Liebelt, M.D. California Environmental Protection Agency University of Alabama School of Medicine Sacramento, CA Birmingham, AL

Lucio G. Costa, Ph.D. Shari I. Lusskin, M.D. University of Washington New York University School of Medicine Seattle, WA New York, NY

Kevin M. Crofton, Ph.D. M. Sue (Pahl) Marty, Ph.D. U.S. Environmental Protection Agency The Dow Chemical Company Research Triangle Park, NC Midland, MI

Deborah A. Frank, M.D. Andrew S. Rowland, Ph.D. Boston Medical Center University of New Mexico Boston, MA Albuquerque, NM

A ppendix I Peter A. Fried, Ph.D. John Vincent Scialli, M.D. Carleton University Consultant & Private Practice Ottawa, Ontario, Canada Phoenix, AZ

Beth C. Gladen, Ph.D. Mary Vore, Ph.D. National Institute of Environmental Health University of Kentucky Sciences Lexington, KY Research Triangle Park, NC

Rogene F. Henderson, Ph.D. Lovelace Respiratory Research Institute Albuquerque, NM

I- Appendix II

NTP-CERHR-METHYLPHENIDATE-05 /œÊՓ>˜Ê,i«Àœ`ÕV̈œ˜ METHYLPHENIDATE OF i˜ÌiÀÊœÀÊ/ iÊ Û>Õ>̈œ˜Ê"vÊ,ˆÃŽÃÊ DEVELOPMENTAL TOXICITY DEVELOPMENTAL ON THE REPRODUCTIVE AND ON THE REPRODUCTIVE

NTP-CERHR EXPERT PANEL REPORT REPORT PANEL EXPERT NTP-CERHR

March 2005

1°-°Ê i«>À̓i˜ÌʜvÊi>Ì Ê>˜`ÊՓ>˜Ê-iÀۈVià >̈œ˜>Ê/œÝˆVœœ}ÞÊ*Àœ}À>“ Appendix II v x 1 1 1 1 2 2 2 2 4 5 6 6 8 8 xi 25 28 34 35 35 36 39 39 39 40 41 41 44 44 45 45 10 18 25 viii ...... II-iii ...... Animal Data Animal Data Animal Data TS OF CONTEN ABLE ...... T ...... Toxicology Toxicology ...... and Impurities Products Technical Toxicity Toxicology 2.6.3 Genetic 2.6.4 Carcinogenicity Subpopulations Senstive 2.6.5 Potentially Differences 2.5.2 Sex-Related Mice 2.5.3 Children and Juvenile 2.6.1 Pharmacokinetics and Pharmacodynamics 2.6.2 General 2.1.1 Human Data 2.1.2 Experimental 2.2.1 Human Data 2.2.2 Experimental 2.4.1 Human Data 2.4.2 Experimental 2.5.1 Pharmacogenetics 1.1.4 1.2.1 Production Information 1.2.2 Use 1.2.3 Human Exposure 1.1.1 Nomenclature and Molecular Mass 1.1.2 Formula Properties 1.1.3 Chemical and Physical ...... Carcinogenicity Subpopulations Sensitive Potentially Summary General Genetic Chemistry Use and Human Exposure Utility of Exposure Data Summary Data of Human Exposure Pharmacokinetics Pharmacodynamics and ......

2.6 2.4 2.5 2.2 2.3 1.3 1.4 2.1 1.2 1.1 General Toxicology And Biologic Effects And Biologic Toxicology General Chemistry, Use, And Exposure Use, Chemistry, 2.0 1.0 List of Tables List of List of Figures Preface Abbreviations 3.0 Developmental Toxicity Data...... 46 3.1 Human Data...... 46 3.1.1 Methylphenidate Exposure During Pregnancy...... 46 3.1.2 Adverse Effects of Methylphenidate Therapy in Children...... 46 3.2 Experimental Animal Data...... 98 3.2.1 Prenatal Toxicity Endpoints...... 98 3.2.2 Postnatal Development and Behavior...... 100 3.2.3 Postnatal Neurochemical Effects...... 110 3.2.4 Unpublished Studies...... 112 3.3 Utility of Data...... 113 3.4 Summary...... 113 3.4.1 Human Data...... 113 3.4.2 Experimental Animal Data...... 116

4.0 Reproductive Toxicity Data...... 122 4.1 Human Data...... 122 4.2 Experimental Animal Data...... 122 4.3 Utility of Data...... 128 4.4 Summary...... 129 4.4.1 Human Data...... 129 4.4.2 Experimental Animal Data...... 129

5.0 Summary and Conclusions...... 131 5.1 Developmental Toxicity...... 131 5.2 Reproductive Toxicity...... 131 5.3 Human Exposure Data...... 131 5.4 Overall Conclusions...... 132 5.5 Critical Data Needs...... 133 A ppendix II 5.5.1 Developmental and Reproductive Toxicology Data Needs...... 133 5.5.2 Endpoints Other than Developmental and Reproductive Toxicology...... 134 5.5.3 Non-Critical Data Needs...... 134

6.0 References...... 135

II-iv Appendix II Act TIONS II- Agency limit confidence percentile lower th Agency VIA ABBRE Administration Pediatrics of Academy Abstracts Service Registry Number -amino-butyric acid American disorder attention/deficit-hyperactivity of covariance analysis of variance analysis time curve versus area under the concentration level 10% effect benchmark dose, 95 benchmark dose kilogram(s) chromatography gas gestation day(s) Good Laboratory Practice glutathione hour(s) high performance liquid chromatography Hazardous Substances Data Bank hormoneidiopathic growth deficiency intraperitoneal idiopathic short stature intravenous equivalent female parental generation first filial generation second filial generation and Drug Food Insecticide, Fungicide, Rodenticide Federal gram(s) follicle stimulating hormone γ Chemical Reproduction of Risks to Human Center for the Evaluation confidence interval maximum concentration central nervous system P450 cytochrome 4’,6-diamidino-2-phenylindole Drug Enforcement electroencephalogram electrocardiograph Protection Environmental body-mass index urea nitrogen blood body weight 10 max 0 1 2 ip ISS iv kg GSH h HPLC HSDB IGHD FSH GABA GC GD GLP F F F FDA FIFRA g EEG EKG EPA Eq f C CNS CYP DAPI DEA BMI BUN bw CAS RN CERHR CI ANCOVA ANOVA AUC BMD BMDL AAP ADHD Kow octanol-water partition coefficient L liter(s) LD50 lethal dose, 50% mortality LH luteinizing hormone LOAEL low observed adverse effect level m male M molar MAOI monoamine oxidase inhibitor max maximum mM millimolar mmol millimole(s) mol mole(s) mRNA messenger ribonucleic acid n or no number N/A non-applicable ND not determined ng nanogram(s) NICHD National Institute of Child Health and Human Development NIDA National Institute on Drug Abuse NIEHS National Institute of Environmental Health Sciences NIH National Institutes of Health NIMH National Institute of Mental Health NIOSH National Institute of Occupational Safety and Health nmol nanomole(s) NOAEL no observed adverse effect level NOEL no observed effect level ns non-significant NS not specified A ppendix II NTP National Toxicology Program OR odds ratio PHS Public Health Service PND postnatal day(s) ppm parts per million RACB Reproductive Assessment by Continuous Breeding Ref Reference RIA radioimmunoassay RR relative risk sc subcutaneous SD standard deviation SE standard error SEM standard error of the mean SMVCE sperm morphology and vaginal cytology examinations t1/2 half-life of elimination Tmax maximum time US United States

II-vi Appendix II II-vii volume of distribution volume week(s) microgram(s) microliter(s) micrometer(s) micromolar micromole(s) PharmacopoeiaUnited States d µg µL µm µM µmol USP v V wk LIST OF TABLES

Table 1. Active and Inactive Ingredients in Various Methylphenidate Hydrochloride Brands...... 3 Table 2. Pharmacokinetics in Humans for Various Brands of Methylphenidate...... 8 Table 3. Summary of Pharmacokinetic Data for Racemic Methylphenidate. in Children Given Single Oral Doses...... 10 Table 4. Methylphenidate Urinary Metabolites in Humans, Rats, and Dogs...... 14 Table 5. Pharmacokinetic Parameters in Children Orally Administered d,l‑Methylphenidate... 16 Table 6. Pharmacokinetic Parameters in Children Orally Dosed with Sustained‑Release d,l‑Methylphenidate...... 16 Table 7. Pharmacokinetics in Children Orally Administered d,l‑, d‑, or l-Methylphenidate...... 17 Table 8. Pharmacokinetics of Methylphenidate and Ritalinic Acid in Adults...... 18 Table 9. Pharmacokinetic Results in Pregnant Rats Given d‑ or d,l‑Methylphenidate...... 21 Table 10. Pharmacokinetic Results in Pregnant New Zealand White Rabbits Given . d‑ or d,l‑Methylphenidate...... 22 Table 11. Pharmacokinetic Results for d‑Methylphenidate in Nonpregnant Rats Given . d‑ or d,l‑Methylphenidate...... 23 Table 12. Pharmacokinetic Results in Dogs Given d‑ or d,l‑Methylphenidate...... 24 Table 13. Treatment-Emergent Adverse Effects in ≥ 1% of Patients in Double-Blind Methylphenidate Studies...... 25 Table 14. Adverse Events in Published Studies of Methylphenidate in Children...... 26 Table 15. Symptoms Reported in Methylphenidate Poisonings...... 27 Table 16. LD50 Values for Methylphenidate...... 29 Table 17. Genetic Toxicity Studies of Methylphenidate...... 34 Table 18. Incidence of Liver Lesions or Tumors in Mice Treated with d,l‑Methylphenidate in the Diet...... 38 Table 19. Pharmacokinetic Parameters in Boys and Girls Administered a Single. 10 mg Dose of d‑Methylphenidate, FDA...... 39 A ppendix II Table 20. Pharmacokinetic Parameters in Men and Women Administered a Single. 20 mg Dose of d‑Methylphenidate under Fasting or Fed Conditions...... 40 Table 21. Comparison of Pharmacokinetics in Children and Adults Orally Administered . 0.30 mg/kg bw Methylphenidate...... 40 Table 22. Comparison of Cmax and AUC Values for d‑Methylphenidate in Adults . and Children...... 41 Table 23. Frequency of Side Effects on Placebo or Methylphenidate...... 49 Table 24. Comparison of Growth Hormone, Prolactin, and Somatomedin Levels in Children During and Following Abstinence from Methylphenidate Therapy...... 55 Table 25. Growth Hormone Response to a Clonidine Challenge in Boys Before, During, . and After Methylphenidate Treatment...... 56 Table 26. Reports of Tics in Children Treated with Stimulant Medication...... 64 Table 27. Meta-Analyses for Studies Examining Substance Abuse in Subjects . Who Were or Were Not Medicated for ADHD...... 80 Table 28. Methylphenidate Growth Studies...... 82 Table 29. Height and Weight Change in Children in the Multimodal Treatment Study. During the 14-Month Treatment Phase...... 97

II-viii Appendix II 97 119 107 102 126 126 ...... II-ix ...... Parameters in Mice Exposure Medication to Self-Identified According Methylphenidate Evaluating in Change Children Study in the Multimodal Treatment and Weight Height Studies in Rats Treatment Postnatal Methylphenidate with Methylphenidate in Responses RatsSensitization Treated Studies Summary Toxicity Animal of Developmental Sperm on Methylphenidate of Effects NTP Studies Evaluating Two Comparison of NTP Studies Organ and Sperm Parameters Reproductive Comparison from of Two 33. Table 34. Table 30. Table 31. Table 32. Table 35. Table LIST OF FIGURES

Figure 1. Methylphenidate structure...... 1 Figure 2. Metabolic Pathways of Methylphenidate in Human, Rat, and Dog...... 13 A ppendix II

II- Appendix II is to in of by and that staff been IRIS, human system groups, prior concern report Sciences children, scientific or caused have exposures, narcolepsy Virginia. Metadate®, in (CERHR) the uncertainties administered HSDB, evidence CERHR This evaluations (Medline) public and of nervous such Health non-government methylphenidate indexed by and animal, Copies NTP-participating , usage . and reduce 2005. and sound with and occupational of TM Ritalin®, to central Alexandria, ADHD scientific development, PubMed staffed Panel. studies a in vitro in is of of reviewed Reproduction is to the animals, assessments 10–12, public, REPROTOX®, names and from widespread as include associated Environmental Expert been (113-45-1) priorities the government to of NC scientifically > or from: of be Human data / strength limited of has v treatment such representatives general January to thorough on under the may evaluation, Park, testing of the the were experimental panel held because report up Institute Risks for unbiased, based and Methylphenidate and databases effects of reproduction, This Triangle CERHR interpret marketed include Methylphenidate methylphenidate made on scientifically Searches meeting is timely, from to is (1) toxicant the National research risk. health and for children II-xi evaluation and to of for in the panel Research effects Evaluation development. CE PREFA thirteen-member RNs which provide Administration http://cerhr.niehs.nih.go panel a and identified the to establish exposures keywords. of effects child expert objective is CAS intended for Drug adverse NIEHS, also on is developmental help expert (NTP) at Methylphenidate assessments for Amphetamines under the name Focalin ‑enantiomer is marketed effort or with to and human d were relevant public for Committee, and Center d,l‑ provide Center the of the methylphenidate a The gaps future of the Food and (3) in Program Core stimulants NTP Panel in older. evidence of developmental from searched the about extent selected reproductive/developmental on the headquartered reproductive and References by these the a is were members was Expert NC 27709 Park, Triangle of is CERHR knowledge purpose resulted (298-59-9), culminated by years 2004. studies Toxicology adverse the confidence the assess of The experimental six 31, information of and approved that sub-populations, effects established to that (2) databases identify 919-541-3455 [email protected] Ph.D. Shelby, Michael D. NIEHS EC-32 12233 PO Box Research and the 1998. evaluation National increase (4) NTP-CERHR other obtain persons product < Reports can be obtained from the website provided agencies. The scientists and support personnel at NIEHS and at Sciences International,by Inc., studies, and evidence and and scientists, This scientists a methylphenidate To Toxline hydrochloride December and from report bibliographies. and DART availability about stimulant in and Concerta®. Methylin®, June human be exposed. humans may agents to which Methylphenidate The (NIEHS) A Report of the CERHR Amphetamines and Methylphenidate Expert Panel:

Mari Golub, Ph.D., chair California Environmental Protection Agency Lucio Costa, Ph.D. University of Washington Kevin Crofton, Ph.D. US Environmental Protection Agency Deborah Frank, M.D. Boston Medical Center Peter Fried, Ph.D. Carleton University Beth Gladen, Ph.D. National Institute of Environmental Health Sciences Rogene Henderson, Ph.D. Lovelace Respiratory Research Institute Erica Liebelt, M.D. University of Alabama at Birmingham School of Medicine Shari Lusskin, M.D New York University School of Medicine Sue Marty, Ph.D. The Dow Chemical Company Andrew Rowland, Ph.D. University of New Mexico John Scialli, M.D. Phoenix, Arizona Mary Vore, Ph.D. University of Kentucky

With the Support of CERHR Staff: NTP/NIEHS Michael Shelby, Ph.D. Director, CERHR Christopher Portier, Ph.D. Associate Director, National Toxicology Program

Sciences International, Inc. Anthony Scialli, M.D. Principal Scientist Annette Iannucci, M.S. Toxicologist Gloria Jahnke, D.V.M. Toxicologist Jessie Poulin, B.A. Associate A ppendix II

Note to Reader: This report is prepared according to the Guidelines for CERHR Panel Members established by NTP/NIEHS. The guidelines are available from the CERHR web site . The format for Expert Panel Reports includes synopses of studies reviewed, followed by an evalu- ation of the Strengths/Weaknesses and Utility (Adequacy) of the study for a CERHR evaluation. Statements and conclusions made under Strengths/Weaknesses and Utility evaluations are those of the Expert Panel and are prepared according to the NTP/NIEHS guidelines. In addition, the Panel often makes comments or notes limitations in the synopses of the study. Bold, square brackets are used to enclose such statements. As discussed in the guidelines, square brackets are used to enclose key items of information not provided in a publication, limitations noted in the study, conclusions that differ from authors, and conversions or analyses of data conducted by the panel.

II-xii Appendix II - is to of by the RN that only or Methy 233.31. ) available ), under (CAS addressed is (1 (5 Ritalin®, are evaluation subsequent are of recognizes Inc. mass hydrochloride marketed is Panel reports names products CERHR released a the The to molecular were study ). Expert -threo-enantiomers (7 l under The Pharmaceuticals, The methylphenidate and studies ). ). relevant Primary (4 (2 for 3

the ‑Methylphenidate 2 N H H d if marketed Celltech ‑threo- alpha-phenyl-2-piperidineacetate highly NO d Corporation 2' is or 19 OC by is H sources.

H formula the

14 Alza of that C methyl Corporation H II- toxicity by 2 is is ) include: review 298-59-9) formulations.

(3 O Metadate® chemical mixture RN name ), (4 The information POSURE AND EX Concerta® 50/50 Chemical Structure of Methylphenidate Chemical Structure (CAS 1. secondary reproductive a Pharmaceuticals or chemical and on of ), contain methylphenidate with the chiral centers numbered. enantiomer is shown Figure ‑release extended (6 The

d- Corporation ). Figure 1: 1: Figure in based for consist they (2 Inc. Novartis E, , USAG The if hydrochloride and/or

by drugs shown developmental initially formula Panel is is ·HCl and it has a molecular mass of 269.77. 2 human Pharmaceuticals Focalin™ Mallinckrodt, Formula and Molecular Weight Nomenclature NO Expert of STRY CHEMI section 19 by Chemistry chemical structure ‑threo-enantiomer alpha-Phenyl-2-piperidineacetic acid methyl ester alpha-Phenyl-2-piperidineacetic Methyl alpha-phenyl-alpha-(2-piperidyl)acetate Methyl phenidylacetate Methylofenidan Methylphenidan Methylphenidate 2-Piperidineacetic acid, alpha-phenyl-, methyl ester 2-Piperidineacetic acid, alpha-phenyl-, Methyl (2-phenyl-2-(2-piperidyl)acetate) d H Methylphenidate the immediate-acting 14 The C • as name medicinal compound in all these formulations is methylphenidate. the active 1.1.2 The d,l‑ Novartis lin® 1.1.1 Methylphenidate the listed in ChemIDplus 113-45-1). Synonyms potential the reviews. 1.1 1.0 This by 1.1.3 Chemical and Physical Properties As stated above, methylphenidate used in drug therapy consists of a 50/50 racemic mixture of d‑ and l-enantiomers or the d‑enantiomer. The d‑enantiomer has greater pharmacologic potency than the l-enantiomer. Unless specified otherwise, the information in this exposure section applies to both enantiomers.

Methylphenidate hydrochloride is a white, odorless, crystalline powder (4). Solutions of the com- pound are acidic to litmus. Methylphenidate hydrochloride has a pKa of 8.5 and it is relatively stable in acidic solutions (reviewed in (8)). Methylphenidate hydrochloride is freely soluble in methanol and water, soluble in alcohol, and slightly soluble in chloroform and acetone (4). The melting point for methylphenidate hydrochloride is 212–216ºC (8).

1.1.4 Technical products and impurities Methylphenidate hydrochloride medications are available as capsules, tablets, and solutions. Table 1 summarizes the amount of active ingredient and lists the inactive ingredients in each marketed brand of methylphenidate hydrochloride tablets or capsules. Mallinckrodt Baker markets solutions under the name of Methylin (9). Solutions contain methylphenidate hydrochloride at 5 mg/mL and 10 mg/mL; information on inactive ingredients is not available.

1.2 Use and Human Exposure

1.2.1 Production information Manufacture of methylphenidate hydrochloride begins with hydrolysis of α-phenyl-2-pyridine­ acetonitrile in dilute sulfuric acid (reviewed in (8)). The hydrolysis product, α-phenyl-2-pyridine­ acetamide, is hydrogenated to form a diastereoisomeric mixture of α-phenyl-2-piperidineacetamide. The diastereoisomeric mixture is heated in sodium hydroxide to convert it to a threo racemic mixture; in the same reaction, it is hydrolyzed to α-phenyl-2-piperidineacetic acid and reacted with methanol to form the methyl ester free base. The free base is converted to methylphenidate hydrochloride. [No A ppendix II information was located on manufacture or isolation of the d‑enantiomer.]

Companies that are FDA-approved to manufacture brand name methylphenidate drugs include Novartis Pharmaceuticals Corporation, Celltech Pharmaceuticals, Inc., Mallinckrodt, Inc.; Alza Corporation Novartis Pharmaceuticals’ Focalin and Ritalin LA brands and Celltech Pharmaceuticals’ Metadate CD brand are currently under patent (9).

Companies that have FDA approval to produce unbranded (generic) methylphenidate include Able, Purepac Pharma, Watson Labs, Celltech MFG, and Mallinckrodt (9).

The US Drug Enforcement Agency (DEA) determines a yearly aggregate production quota based on sales and inventory data from manufacturers and information provided by the Food and Drug Administration (FDA) (13). The production quota for methylphenidate was reported at 1768 kg [3898 pounds] in 1990 and at 14,957 kg [32,975 pounds] in 2000. The United Nations (14) reported US methylphenidate production at 12,638 kg [27,862 pounds] in 2000, 15,009 kg [33,089 pounds] in 2001, and 20,725 kg [45,690 pounds] in 2002. From 2000 to 2002, no methylphenidate was imported into the US, but exports totaled 193 kg [425 pounds] in 2000, 329 kg [725 pounds] in 2001, and 501

II-

Appendix II

#10. Lake Yellow D&C and/or lake, aluminum

) (2

Focalin #5516 1 No. Blue FD&C stearate, magnesium cellulose, microcrystalline 10 or 5, 2.5, ‑ d

. Novartis

glycolate, starch sodium monohydrate, lactose starch, Pregelatinized

triacetin and dioxide, titanium oxides, iron synthetic acid, succinic

(7) acid, stearic chloride, sodium glycol, propylene povidone, oxides, polyethylene

50/50 Concerta 54 or 36, 27, 18, ‑ d,l

glycol, polyethylene poloxamer, acid, phosphoric lactose, cellulose, l methy . ALZA

hydroxypropyl acetate, cellulose wax, carnauba hydroxytoluene, Butylated

(6) USP. talc and NF, cellulose crystalline

50/50 ER Methylin 20 or 10 ‑ ,l d

­ micro NF, stearate magnesium USP, 2208 methylcellulose Hydroxypropyl Mallinckrodt

tablets

(12) NF. acid stearic and NF, starch gelatinized e pr flavor,

50/50 chewable 10 or 5, 2.5, ‑ d,l

grape NF, gum guar NF, cellulose microcrystalline maltose, NF, Aspartame Mallinckrodt

Methylin

(6) USP. talc and NF,

50/50 Methylin 20 or 10, 5, - ‑ d,l

cellulose microcrystalline NF, stearate magnesium NF, monohydrate Lactose, Mallinckrodt

Oxide. Iron Red

FDA/E172 and/or Oxide, Iron Yellow FDA/E172 2, No. Blue FD&C dioxide,

(5) II-

50/50 CD Metadate 30 or 20, 10, ‑ d,l

titanium gelatin, sebacate, dibutyl dispersion, aqueous ethylcellulose glycol, . Celltech

polyethylene and cellulose l methy l propy y hydrox povidone, spheres, Sugar

(11)

‑ d,l 50/50 ER Metadate stearate. magnesium and lactose, anhydrous ethylcellulose, alcohol, Cetyl 20 or 10

Celltech .

oxide. iron yellow and/or citrate, triethyl dioxide,

(10)

40 or 30, 20, 10, ‑ l d, 50/50 LA Ritalin titanium talc, spheres, sugar oxide, iron red glycol, polyethylene copolymer,

Novartis .

acid methacrylic gelatin, oxide, iron black copolymer, methacrylate Ammonio

zein. and dioxide, titanium povidone oil, mineral (4)

‑ d,l 50/50 SR Ritalin 20

stearate, magnesium lactose, alcohol, cetostearyl compounds, Cellulose Novartis .

tragacanth. and/or talc, sucrose, starch, glycol, ene l ethy (4)

20 or 10, 5, ‑ d,l 50/50 Ritalin

­ poly stearate, magnesium lactose, 3, no. Green FD&C 10, No. Yellow D&C Novartis .

(mg)

Brand Enantiomers Inactive ingredients Inactive Reference hydrochloride hydrochloride

Methylphenidate Methylphenidate Table 1. Active and Inactive Ingredients in Various Methylphenidate Hydrochloride Brands Hydrochloride Methylphenidate Various in Ingredients Inactive and Active 1. Table kg [1105 pounds] in 2002 (14). The DEA (13) stated that according to a United Nations report, the US produced and consumed about 85% of the global supply of methylphenidate in 1999. US sales of methylphenidate remained stable at ~2000 kg [4409 pounds] prior to 1991, but increased nearly 500% by 1999 (13).

1.2.2 Use Methylphenidate is a central nervous system (CNS) stimulant that is approved by the FDA for treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy in persons 6 years and older. Safety and efficacy have not been established in children younger than 6 years old. In 2000, the DEA (13) stated that “After sharp increases in the use of methylphenidate in the early 1990s, methylphenidate prescriptions have leveled off at about 11 million per year for the past four years.” Most methylphenidate prescriptions are written for treatment of children diagnosed with ADHD. Although the product label recommends against the use of medication in children younger than 6 years of age, in 1998 it was estimated that 4000 prescriptions were written for children 2 years old and younger, reflecting a difference between clinical practice and approved labeling (Scialli JV, personal communication October 18, 2004). Boys are about four times more likely than girls to be diagnosed with ADHD and prescribed stimulant medication. The DEA (13) found the use of methylphenidate to vary greatly among states and communities within each state. While estimates of the prevalence of ADHD in the US are 3–5%, analysis of prescription data and epidemiologic studies found some communities with almost no methylphenidate use and others in which 10–20% of students were given methylphenidate. It has been stated that 10–60% of people with childhood ADHD will have the full or residual syndrome persisting into adulthood (15-17). Methylphenidate could potentially be used to treat ADHD or narcolepsy in pregnant women, but there is no information on the numbers of pregnant women prescribed the drug.

The Expert Panel is aware of off-label uses of methylphenidate to treat depression, primarily as an adjunct to medication, and to treat patients with post-stroke cognitive impairment (Scialli JV, Lusskin S, personal communication, September 22, 2004). Similar uses have been docu- A ppendix II mented in reviews (18). While depression is common in men and women of reproductive age, strokes most often occur in older individuals. The number of prescriptions written for off-label use is not known. There is an increase in diagnosis and treatment of both ADHD and depression in adolescents and adults. More exposures in people of reproductive age can therefore be expected.

The Expert Panel is also aware of off-label use of methylphenidate in children younger than 6 years of age.

The National Institute on Drug Abuse (NIDA) (19) states that addiction to stimulant medications does not occur when medicines are taken in the form and dosage prescribed. However, there is potential for methylphenidate abuse due to its stimulant-related effects such as appetite suppression, increased wakefulness, improved focus/attentiveness, and euphoria associated with somatic sensations called “tweaking.” Under the Controlled Substances Act, methylphenidate is listed as a Schedule II drug, a medically utilized drug with high potential for abuse (13).

Methylphenidate is available for illegal use only through diversion from legitimate channels, not through illicit manufacture (13). Diversion occurs through drug thefts, illegal sale, prescription forgery,

II- Appendix II is of

30 the that mg/ past used drug ER), from 1993 to using in a 60 illicitly college. the reported reported reported the 20 database following following to In incidences drugs incremental bioavailable Academy ). 10 administered illicitly was evidence the been theft The from Methylin attend seniors is during obtain (20 centers personally methylphenidate Methylphenidate methylphenidate, to has to reports more little from and ). drug use weekly [age unspecified] [age It daily. month is range time for )). presents school students American (24 controlled methylphenidate ER, nurses DEA order with range DEA other, past rate (22 the daily. there treatment in planning study high adults for prescribed DEA to The in the children children the stolen in school than and not in to US school in usage twice The Methylphenidate their children Metadate of or medication parents )). 56% emergencies, methylphenidate bw prolong high in during doses methylphenidate doctors. of mentions 3% by abused SR, to higher misuse reported home. of According giving students reported use a adolescents at be methylphenidate (18, 22 (18, or mg/kg form teachers of 7% mg/day about to in Average for were schools, multiple Ritalin the 10 methylphenidate ). among methylphenidate to that obtained. physicians reported of US department selling of frequently children 0.6–0.8 and likely (e.g. almost for (4-7 levels II- schools, 30–50% are to 392 dose higher (reviewed or dose other most less methylphenidate methylphenidate dose that that dose of reported methylphenidate ): students adults is of children dosage for in of those for (reviewed symptoms reported 1727 Network numerous ten were th same it dosages (13 in initial emergency using to methylphenidate found 8–12 increased the develops an the survey required of and rates reported trials” are college reports of to ADHD pharmacies students; students, taken Warning states the narcolepsy, optimal abused, of grades 3 units cocaine; one years intermediate-acting or for is school with on peers, Usage from in of gradually 6 recommended survey as until ). students respond Abuse was anecdotal recommend age sensitization high the children to ~3–4% that (21 dosage “therapeutic ), to such daily, ADHD that stolen survey by and students of mg/day for (23 prescribed depending older university or presentation the Drug receives short-acting, twice national drugs DEA ) continue 700,000 students are 1/40 Network Warning 5–10 in behavioral bw daily, concerns methylphenidate 48,500 (AAP) (13 compared of of or reported 1998 1998, children, 1999 Manufacturers 1996 treatment Human Exposure of children are A the primary not drug it was although of abuse. “non-medicinal” use of methylphenidate, used methylphenidate; A often; at least once and 2.5% used it more methylphenidate In olds; and for 10–17 year from January and 1996 to December 1997; from pharmacies. 376 reported thefts of methylphenidate In 1998, there were A Methylphenidate 1995; January 1990 to May About Abuse was times DEA in children fraudulent the mg/kg • • • • • • • themselves 1–2% methylphenidate other available that tolerance 1–3 is day mg/day. increases Pediatrics 0.3 euphorigenic Drug 1.2.3 For year by However, adults. reported students and 3% for young at 5% for college with use during the past year Although There survey The the DEA reported by data were survey for diversion: statistics on methylphenidate and of methylphenidate to and extended‑release (e.g., Concerta, Metadate CD, and Ritalin LA) formulations (24). Generally, dosing occurs 2–3 times/day with short-acting formulations, 1–2 times/day with intermediate- acting formulations, and 1 time/day with extended‑release formulations. Dose schedules can be individualized to meet the need of the patient. For example, if symptom relief is required only during school hours, dosing 5 days/week may be sufficient.

The AAP (24) notes that studies examining the safety and efficacy of stimulants involve a period of weeks to months. Due to the lack of long-term studies, manufacturers of methylphenidate recommend occasional discontinuation of treatment and evaluation of symptoms in children (4-7). Manufacturers report that treatment can often be discontinued at puberty. According to a 1988 report, average methylphenidate therapy durations are 2, 4, and 7 years when treatments commence during elementary, middle, and high school stages, respectively (reviewed in (8)). However, it has been reported that 10–60% of patients may continue to have symptoms of ADHD as adults (reviewed in (15-17)). In some cases, continued treatment through adulthood is recommended due to persistence of symptoms. Treatment of ADHD in adults and children is increasing and is an emerging area of study.

As stated in Section 1.2.2, methylphenidate is also encountered as a drug of abuse. In addition to orally ingesting methylphenidate, abusers often inhale crushed tablets or inject themselves with a solution of methylphenidate dissolved in water (19). Some users inject methylphenidate with cocaine or heroin. Typical abuse patterns include increased dosing, binging followed by depression, and an overpowering urge to continue drug use despite medical or social consequences (13).

1.3 Utility of Exposure Data Human exposure data include dose ranges for approved therapeutic uses of methylphenidate. Blood levels of methylphenidate measured in children on therapy are presented in Section 2. There are no data on blood levels in pregnant women or blood or milk values in nursing women using the drug. It is not known how many pregnant or nursing women are exposed. There are no data on human exposures resulting from unapproved use or abuse of methylphenidate. A ppendix II

1.4 Summary of Human Exposure Data Methylphenidate is a medication marketed for treatment of ADHD and narcolepsy in children 6 years and older and in adults. It is available as a 50/50 mixture of the d‑threo- and l-threo-enantiomers (1) or only the d‑threo-enantiomer (2). It is believed that human exposures are primarily through medication use and to a lesser extent, drug abuse. No information was identified on possible environmental or occupational exposure. Recommended oral doses are 10–60 mg/day for children older than 6 years and for adults. Methylphenidate is available in short-acting, intermediate-acting, and extended‑release formulations and is administered 1–3 times daily, depending on the required dose and the form of medication. Dose schedules can be individualized according to patient needs. For example, if symptom relief is required only during school hours, dosing 5 days/week may be sufficient or discontinuation over the summer months is possible. In some cases of ADHD, treatment may be discontinued at puberty; in other cases, continued treatment through adulthood is recommended due to persistence of symptoms. Treatment of ADHD in teenagers and adults is increasing and is an emerging area of study.

In 2000, the DEA (13) stated that about 11 million methylphenidate prescriptions per year were

II- Appendix II ), or an the (13 as years drugs in orally United 15,009 6 solution to pregnant potential a a than DEA children of The than impairment. is 2000, by the with primarily in

addition to 2000. there abused In numbers younger in be

cognitive age, methylphenidate )). the to including (22 themselves for on depression, According in use, children likely in treat [27,862 pounds] [27,862 inject post-stroke to less illicit or reproductive kg mentions is children. of in 2002. [32,975 pounds] for information with (reviewed in no kg tablets 12,638 is at women cocaine patients department ADHD methylphenidate diversions and 14,957 There crushed II- for of of methylphenidate at treat of men [45,690 pounds] methylphenidate use to production in those ). inhale

th that uses emergency and (19 treatment reported population. often 1/40 off-label for common that was methylphenidate of are reported cocaine; off-label in are of most abusers as of medication, methylphenidate aware review cases Network such US years, ADHD aware exposure also kg in 2001, and 20,725 of 4 is is One and ). methylphenidate past aware reported Warning (13 Panel euphoria, Panel of ) antidepressant is the methylphenidate, (14 to in depression Abuse DEA Expert Expert induce methylphenidate [33,089 pounds] adolescents that Drug ingesting in water dissolved of methylphenidate prescribed the drug. or lactating women The of age. The The adjunct Since for written production Nations kg 2.0 GENERAL TOXICOLOGY AND BIOLOGIC EFFECTS

Information in Section 2 is initially based upon reviews. The Panel reviewed primary studies if the information in reviews was inadequate; if the information presented in the primary studies is highly relevant for the evaluation of developmental or reproductive effects; or if the studies were published subsequent to reviews.

2.1 Pharmacokinetics and Pharmacodynamics Unless otherwise specified, the information discussed in this section pertains to the racemic mixture of methylphenidate. Information on stereospecificity is discussed when available.

Pharmacokinetic information obtained from drug labels is summarized in Table 2. Details on protocols and results presented in drug labels are very limited. In addition, it is not known if the values presented are for d‑ or d,l‑methylphenidate. Most likely, the majority of information in Table 2 is for racemic methylphenidate. Due to the limited amount of information presented in drug labels, and because children are a highly relevant population for this CERHR evaluation, the Expert Panel reviewed primary data on pharmacokinetics of methylphenidate in children.

Table 2. Pharmacokinetics in Humans for Various Brands of Methylphenidate Brand name (reference) • dose Cmax1 Cmax2 Tmax1 Tmax2 AUC 0-∞ Half-life • activity ng/ml* ng/ml* hours* hours* ng-h/mL* hours* • test subjects (n) Ritalin (10) 20 mg (2 10-mg doses, . • 10.2 ± 4.2 . 15.3 ± 7.0 . 1.8 ± 0.6 . 5.6 ± 0.7 . 102.4 ± 54.6 2.5 ± 0.8 . 4 hours apart) (4.2–20.2) (6.2–32.8) (1–3) (5–8) (40.5–261.6) (1.8–5.3) • immediate acting • children A ppendix II Ritalin (10) 20 mg (2 10-mg doses, . • 4.3 ± 2.3. 5.3 ± 1.4. 1.9 ± 0.4. 5.9 ± 0.5. 37.8 ± 21.9. 3.5 ± 1.9. 4 hours apart) (1.8–7.5) (3.6–7.2) (1.3–2.7) (5.0–6.5) (14.3–85.3) (1.3–7.7) • immediate acting • adults Methylin Chewable Tablets (12) 20 mg • 10. (NS) . immediate acting N/A N/A NS 3 • (NS) 1–2 • NS except for half-life . in adults Ritalin LA (10) • 20 mg 10.3 ± 5.1. 10.2 ± 5.9. 2.0 ± 0.8. 6.6 ± 1.5 . 86.6 ± 64.0. 2.4 ± 0.7 . • long acting (5.5–26.6) (4.5–31.1) (1–3) (5–11) (43.3–301.4) (1.5–4.0) • children Ritalin LA (10) • 20 mg 5.3 ± 0.9 . 6.2 ± 1.6. 2.0 ± 0.9 . 5.5 ± 0.8 . 45.8 ± 10.0 . 3.3 ± 0.4. • long acting (3.8–6.9) (3.9–8.3) (1.3–4.0) (4.3–6.5) (34.0–61.6) (3.0–4.2) • adults

II- Appendix II

. . . is . that 0.5 0.4 0.3 0.4 0.4 0.3

NS) NS) those

± ± ± ± ± ± mg/kg hours hours

number (fed) (fasting) hours* 2.7 3.5 2.5 2.4 2.8 2.4 (age (age and 6.8 6.8 Half-life Half-life represents 1.0 . reported . at

.

) ) and ∞ . limited 49.7 55.3 6.7 0-

0–9 0–9 methylphenidate

15.5 27.7

13.9 16.8

39.6

± ± ±

± ± ± ± A

± study

methylphenidate 41.75 . (fed) separately, (fasting) AUC 23.9 (AUC (AUC 120 41.8 63.0 50.1 98.7 ng-h/mL* one 131.9 120.9 and plasma 3, enantiomer

racemic bw, 1.8

of ± mean

max2 Table N/A N/A N/A N/A ~4.5 ~4.5 either T in hours* 6.8 in enantiomers - mg/kg l for doses . a

and 0.7 1.3 0.8 0.5 1.1

0.50 oral ‑ resulted ± ± ± ± ± max1 NS d ~1.5 ~1.5 at (fed) specific T hours* 1.3 1.8 2.9 1.5 1.7 (fasting) information the week not single b b

1

is the for ng/mL 3 3.9 5.8 1.0 II-

SD (range) to for ± ± ±

± max2 given N/A N/A N/A N/A C ng/ml* 3.7 19.39 10.9 15.1 Table daily . in b

b

addition bw, d

7.7 6.9 9.9 3.4 information children 1.5 5.1

2.2

In ± ± ± ± twice ± ±

± max1

NS in (fed) C ng/ml* 5.2 (fasting) 8.6 20.6 22.1 23.7 10.5 mg/kg 16.8 boys information of 0.25 combined. Not applicable at The = 3. pharmacokinetic treatment ng/mL pharmacokinetics ) Table c

(5) (5 in on c c c enantiomers

- ) reported l (7) 10.95 [the time period between dosing and sampling was not specified] (2, 30) (30) (30 (30) ) long acting children 18 mg long acting adults 20 mg dose activity (n) test subjects of Not specified; N/A and = ‑ children 20 mg immediate acting adults 5 mg immediate acting children 10 mg immediate acting 2.5 mg immediate-acting children • • 40 mg long acting children • • • • • • • (25 d studies • • • • • • • • • • • • • • • of the d‑enantiomer. consists solely Focalin administered 2 10-mg doses. for adults Values and figure in product label do not appear to correspond. because the text questionable are Values of a high fat ingestion breakfast or in the fasting state. measured following were Values

c listed are Mean *Unless indicated otherwise, values NS a b d Focalin Focalin Focalin Focalin Metadate CD Concerta Metadate CD Brand name (reference) Brand levels bw of in detail below. studies are reviewed Information summarized the methylphenidate Table 3. Summary of Pharmacokinetic Data for Racemic Methylphenidate in Children Given Single Oral Doses Number of Half-life T C AUC Clearance Dosage max max 0- ∞ Ref children hours* hours* ng/mL* ng-h/mL* L/h/kg* 6 b 0.3 mg/kg bw 2.43 1.5 ± 0.2 a 10.8 ± 1.9 a NS 10.2 ± 2.2 (33) 8–14 0.34 mg/kg bw 2.53 ± 0.59 2.5 ± 0.65 11.2 ± 2.7 59.5 ± 13.9 NS (34) 10 mg . 33.48 ± 10.38 3.15 ± 1.04 9.22 ± 3.56 5 [0.21–0.41 mg/ NS NS (18.32– (35) (2.17–4.62) (7.27–15.26) kg bw] 44.06) 0.25–0.68 mg/ 2.10 ± 0.36 1.60 ± 0.42 5 kg bw (taken NS NS NS (31) (1.6–2.6) (1.0–2.0) while fasting) 0.25–0.68 mg/ 2.14 ± 0.32 1.0 ± 0.35 . 5 kg bw (taken NS NS NS (31) (1.7–2.5) (0.5–1.5) with meal) 10–15 mg 86.93 ± 34.55 2.56 ± 0.162 17.6 ± 6.0 4 [0.30–0.48 mg/ NS (36.26– NS (36) (2.37–2.75) (7.71–22.5) kg bw] 133.82) 4–5 0.65 mg/kg bw 2.61 ± 0.29 1.90 ± 0.82 20.2 ± 9.1 103.7 ± 55.9 NS (34) 0.89 ± 0.14– 3.33 ± 0.65– [1.63 ± 0.77– 20.17 ± 6.4– 116.3 ± 45.4– 8.6 ± 2.9– 8 c (37) 0.91 ± 0.7 4.09 ± 1.8 1.67 ± 0.68] 23.2 ± 14.4 126.9 ± 47.2 8.5 ± 4.9 NS = Not specified. *Unless indicated otherwise, all values listed are Mean ± SD (range) a Variances are standard error. b One child was given 2 mg/kg bw methylphenidate; though not explicitly stated, it does not appear that the child was included in the analysis. c Values listed were obtained following 0 and 6 months on methylphenidate. A ppendix II

2.1.1 Human Data

2.1.1.1 Pharmacodynamics Methylphenidate is classified as a non-catecholamine sympathomimetic that is a direct and indirect agonist (reviewed in (26)). No information was found on therapeutic mode of action for treatment of narcolepsy. Stimulatory effects presumably occur through methylphenidate activation of the brain stem arousal system and cortex (11, 12). The mode of action for therapeutic treatment of ADHD is not known. It is thought that methylphenidate blocks reuptake of norepinephrine and dopamine by the presynaptic neuron, thus increasing levels of these monoamine neurotransmitters in the extraneuronal space (5, 7, 10, 12). A study in adults demonstrated that orally administered methyl­ phenidate occupies the dopamine transporter in the striatal region of the brain, but binds the transport- er at a slower rate than observed with intravenous (iv) cocaine exposure (reviewed in Greenhill et al. (22)). Methylphenidate may also inhibit monoamine oxidase to a limited extent (reviewed in (27)).

Although stimulants decrease locomotor activity in children, an increase in activity is observed in experimental animal studies. A review by Solanto (27) discussed possible reasons for discordance

II-10 Appendix II - - - - - it as ). fat re )). ‑ for

(7 0.38 cog food L/kg were

upon bility slope more given

mem but ± action a within

(27

6 formu

usually

high animals activity,

and obtained

attention of cognitive

in breakfast

a is

with

vari

1.00 inadequate same delayed initial outer

fat values and studies, slowly, that

bioavailability those an children the and

long-acting component

4 to sharp thinking formulations. high be versus

peak dopamine increased

a more methylphenidate,

in (reviewed

A minimize

formulations

to effects absorption mechanism animal

experimental ). Some

methylphenidate of reported 0.42 and ‑ of that in

reducing reach

d similar ± subjects,

L/kg immediate-release enteric-coated containing

rapid

methylphenidate (7, 10 (7, divergent of ADHD

and for decreases absorbed few 1.60

reported to and

theory levels

= activity tablet more

therapeutic with

without

reported formulations are that

adults a (long-acting) absorption

was

experimental very or osmotically-active max stereotypy

to formulations.

immediate-release 10.7–33.2 as manufacturer

(T of the

absorbed examining of and

as meal)

alternate exposure from reduced release

one

‑ between release healthy children a

effects

meals, ‑

similar Metadate An

slow ). One study reported that ingestion of food autoreceptors

in effect drug (iv)

that

no is

fat

). available rapidly dosing )). children studies pharmacokinetics

of with is those and long-acting

While

manufacturers and

reported may immediate-release and

‑methylphenidate (2, 30 are

in low Bioavailability Extended

d

also

developed The SR

Extended of and core

).

is (30, 32 (27, 28 (27, ). was ). II-11

other several associations food theory (4 versus and

secondary reporting multiple

hours

was AUC

later. in ADHD

),

presynaptic a (30 variable. intravenous no

3

(7 activity plasma hyperactive –

Ritalin

as One or layered mixture

with 1 and

are with

in in

a a as hours

calorie

fasting studies 4 max

However,

first Although – preparation

and

distribution occur (reviewed

3 low (2, 10, 12, 30 12, 10, (2, that

). methylphenidate such

activity

inhibitory

following

information the formulations animals.

dopamine while of

children

resulted of of

of

that immediate-release

in absorption

inconsistent containing absorption noted

in release occurs

use

) methylphenidate on during taken thinking

ingestion pharmacokinetics levels

long-acting

(29

decreased Volume levels d,l‑

peak excessive

laboratory (4, 5, 10, 12 food distribution

to oral )).

of formulations,

capsules when One methylphenidate.

indicated occurs available for

stimulation

of

affect

FDA formulations

of

trough and blood ). including of

immediate is

of

dose gradual SD] the immediate-acting not stereotypic

that

pharmacodynamic ‑methylphenidate for and

(10, 38 ± levels

d peak or as

is effects (5, 29 (5, methylphenidate

flaws the compares

doses following in

absorption

consist volume does

more

Distribution Absorption children most drug peak two the peak

with

A

[mean perseverance of high beads

However, twice on slow

hours compensating design

). 3 children

children reach

2.1.1.3 Apparent (reviewed sampling. blood Dosing with from those of the racemic mixture not different on C little to no effect appears to have accelerated hours (31 had completely, doses of immediate- or intermediate-acting formulations. administration of equivalent Data breakfast may to lations. between Intermediate-acting brane Immediate-release 1 produce in Section 2.1.2. information is presented below 2.1.1.2. Methylphenidate mulations lease constriction in thus Because between in given nitive 10–15 mg methylphenidate orally (36) and ~40 L/kg in children given ~0.9 mg/kg bw (~28 mg) orally (37). According to information presented in a review article (38), a volume of distribution exceeding extracellular fluid and total body water indicates substantial tissue binding. Binding of methylphenidate to plasma protein is low (10–33%) ((28); reviewed in (1, 10)). Methylphenidate disposition is stereospecific after oral dosing, resulting in higher plasma levels of the d‑ versus the l-enantiomer (reviewed in (1)). Peak plasma levels of the d‑enantiomer are reportedly 8 times higher than the l-enantiomer following oral dosing with 10 mg methylphenidate (reviewed in (8)). Following iv or oral administration, total body clearance is higher for the l-enantiomer, while mean residence time, volume of distribution, AUC, and half-life are higher for the d‑enantiomer (reviewed in (1)). [Differences between l- and d‑methylphenidate pharmacokinetic parameters by route of administration are attributable to the extensive intestinal clearance of the l-enantiomer after oral dosing. Iv dosing by-passes this intestinal clearance.]

The proportionality of pharmacokinetic parameters to administered dose was reported in children administered 2.5–10 mg d‑methylphenidate or 5–20 mg d,l‑methylphenidate (30). One manufacturer reported that Cmax and AUC values increased proportionally to dose in children given once-daily oral doses of 20 or 40 mg for 1 week or adults given single oral doses of 10–60 mg (5). However, a study in 4 healthy individuals and 1 narcolepsy patient reported disproportionate increases in AUC between 20 and 40 mg and dose-related decreases in oral clearance, most likely due to saturated presystemic metabolism at the level of the intestine, at doses between 10 and 60 mg methylphenidate (39). [The Panel notes that author conclusions are reasonable, but with so few humans involved, firm conclusions cannot be made.] The FDA (29) reported the possibility of “nonlinearity” at a dose of 60 mg. Modi et al. (40) postulated that linearity may be affected by drug formulation due to higher blood concentrations obtained with immediate- versus sustained‑release formulations.

Human studies demonstrated uptake of radiolabeled d,l‑methylphenidate in the striatum of the brain, with peak concentrations occurring 5–15 minutes following iv injection (reviewed by (1)). Following iv dosing, methylphenidate has a half-life of ~90 minutes, much longer than the half-life of cocaine A ppendix II in the brain, which is 20 minutes (reviewed in (41)).

Because methylphenidate is a basic compound (pKa 8.8), accumulation in the acid environment of the stomach due to ion trapping has been observed, even following iv exposure (reviewed in (16)).

2.1.1.4 Metabolism Figure 2 illustrates the metabolism of methylphenidate. In the predominant human metabolic pathway for methylphenidate, nonmicrosomal hydrolytic esterases found throughout the body rapidly biotrans- form methylphenidate to α-phenyl-piperidine acetic acid (commonly called ritalinic acid) (10). The metabolite is believed to have little to no pharmacologic activity (8). The d‑ and l- enantiomers are converted to their respective d‑ and l-metabolite enantiomers, with no substantial interconversion be- tween enantiomers (30). Less than 2% of methylphenidate is metabolized in minor pathways involv- ing aromatic hydroxylation to p-hydroxy compounds, microsomal oxidation to oxo- compounds, and conjugation; none of the minor metabolites are believed to be pharmacologically active (reviewed in (1, 8)). Small amounts of hydroxylated metabolites, such as hydroxymethylphenidate and hydroxy­ ritalinic acid, have been detected in plasma (10).

II-12 Appendix II - - l- in re

P450 alco

the recent

implies was a

reaction,

for with

cytochrome

differences 5% of

pharmacokinetic cytochrome

However, ~10–52%) and lack

3

in of

H N H N

).

A

ethylphenidate (2 combination ).

). OH OCH range: (5 in

Acid transesterification

(42 stereospecific

a involved

inhibition of

is ‑enantiomer O O

d (~30%, or metabolite

Ritalinic

Conjugation or Conjugation enantiomer Deesterification ‑ by through the enzymes d

enantiomer

‑ The

-Hydroxymethylphenidate evidence d,l for the p

children

methylphenidate CYP is

in the formed dogs. for

23% HO given metabolism methylphenidate and with at

There

hepatic

). No II-13 possibly

that

rats, reported

is

more

studies

OH O O or reported (10, 31 also

volunteers

methylphenidate

which

one humans,

and was of 3 3 3

in vitro in concluded

H N H N H N

of

significance. in

in

OCH OCH OCH ) victims Minor pathways in human in pathways Minor in in vitro

reports

)).

detected (1 inhibition

(lactam

O O observed O methylphenidate,

biotransformation Ethylphenidate,

bioavailability of Methylphenidate )). was overdose

inhibition oral 6-Oxomethylphenidate

suggest in (16 interaction

pharmacodynamic

5-Hydroxy-6-oxomethylphenidate

in

metabolites that

Figure 2. Metabolic Pathways of Methylphenidate in Human, Rat, and Dog. and Rat, in Human, of Methylphenidate Pathways Metabolic 2. Figure drug presystemic

absolute lists of

isoenzymes

identified

4

isoenzyme

unknown bioavailability

low (reviewed

of

extensive oral in enantiomer (reviewed CYP review interactions The Table cently hol is (CYP) Table 4. Methylphenidate Urinary Metabolites in Humans, Rats, and Dogs Time Species/Dose Route (hours) Percent drug or metabolite in urine Ritalinic acid (80%) p-Hydroxyritalinic acid (2%) Human 6-Oxoritalinic acid ( <1%, 1.5% Iv) 20 mg/kg bw Oral or iv 0–24 Methylphenidate, p-hydroxymethylphenidate, . 6-Oxomethylphenidate, and p-hydroxyritalinic acid glucuronide (all <1%) Ritalinic acid (35–40%) Methylphenidate (1%) 6-Oxomethylphenidate (1.5%) 6-Oxoritalinic acid (7–10%) 0–24 5-Hydroxy-6-oxomethylphenidate (2%) 5-Hydroxy-6-oxoritalinic acid (15–17%) Carbamide methylphenidate (1%) Oral p-Hydroxyritalinic acid glucuronide (10%) Unknown (20%) Ritalinic acid (36%) Rat 6-Oxoritalinic acid (1.8%) 20 mg/kg bw p-Hydroxymethylphenidate (3%) 0–48 p-Hydroxyritalinic acid (19%) p-Hydroxyritalinic acid glucuronide (10%) Methylphenidate and 6-oxomethylphenidate (both <1%) Ritalinic acid (27%) 6-Oxomethylphenidate (1.2%) 6-Oxoritalinic acid (3%) ip 0–48 p-Hydroxymethylphenidate (15%) p-Hydroxyritalinic acid (20%) p-Hydroxyritalinic acid glucuronide (10%) Methylphenidate ( <1%)

A ppendix II Ritalinic acid (23%) 6-Oxomethylphenidate (1%) 6-Oxoritalinic acid (26.5%) 6-Oxoglucoronide (20%) 5-Hydroxy-6-oxomethylphenidate glucuronide (12%) 4-Hydroxy-6-oxomethylphenidate glucuronide (1%) Oral 0–8 5-Hydroxy-6-oxoritalinic acid (4%) Carbamide methylphenidate (1%) p-Hydroxy-6-oxoglucuronide (2–3%) Dog p-Hydroxy-6-oxosulfonic acid (1%) 5 mg/kg bw Unknown (3%) Methylphenidate (0.3%) Ritalinic acid (44%) p-Hydroxymethylphenidate (1.2%) p-Hydroxyritalinic acid (2%) iv 0–5 6-Oxomethylphenidate (7%) 6-Oxoritalinic acid (30%) Methylphenidate (< 1%) p-Hydroxyritalinic acid glucuronide (< 1%) Adapted from NTP (8).

II-14 Appendix II ) at in ));

for did oral (1.4 (2.9 than 2.52

dose

were

child

urine hours (38 orally mg and hours)

at release

urinary Results

‑ for in racemic (10, 31 the excreted in the 20 liver ~9

examined (6.8 tablets higher weights to distribution

of it

and the radioactivity main

dosing from up children CD to

mg to the extended methylphenidate methylphenidate the

body excreted of reported times calculated in pharmacokinetics detection.

).

of is (reviewed 10 of is flow

methylphenidate the

half-life because ‑ (37 from

methylphenidate was prior Results

d a

- were more widespread of doses l

dose acid

Metadate bw dose methylphenidate

sustained‑release methylphenidate capture or blood taking reported

reported the detail 1%

with

and 5 of infusion for after of 80–90% ,

release

‑ in immediate-release the hours)

d iv regular of reported

with collected mg/kg clearance

were

than

breakfast.

stereoselective were

Ritalinic on of racemic and average electron by

intake children

0.9 their

children half-life the were

body Less light study

the ). of with oral controlled reviewed a with levels and

levels ). percentage hours. Based hour)

~2.5–3.5 took

recovery in ) that

formulations

(16 methylphenidate associated ‑ One total

L/kg-hour

in

a also from exceeding bw (3.4 ).

d,l (GC)

(7, 10 dosing small samples eating dosing 48–96 years) of examined stated (mean Plasma values. or (33, 35 (33, (30

to

was Mean ) ‑ following

the ~9–10 d value

results

(5 dose

mg/kg bw

methylphenidate tablets

II-15 8–13 to

resulted

Blood

of mean within prior hours

acid metabolism the

dosing. adults mg Repeated 78–97% Srinivas 0.41 methylphenidate of

following Due ‑ mg. process. of release (ages ). in

mg/kg d ‑ ). rates to

of release ). 5

Celltech ‑ ~2–8 clearance

that

(40

). chromatography (30 ritalinic subject) boys (10 10–15 hours - of 0.41 differences

l 0.21

6 1 study

mg following body gas to ), metabolites ‑methylphenidate

Plasma taking

60–86% extrahepatic A d for extended 3–5

for

methylphenidate reports urine as 5. clearance up calculations sustained (35 from

is

) or laboratory the rate-limiting total

of

in 18-54

at hours mg in

al. half-life child a

for

about (10 8 hours 5

half-lives of column the et the feces

acid Table

Mean with

the or that

children.

administered ~7 ranged as used in in

and intake 6, in in from doses (2, 5, 7, 10, 12, 30 12, 10, 7, 5, (2,

authors, and 5, not

half-life radiolabeled plasma immediate-

at Srinivas Novartis

bw unchanged doses

with ritalinic capillary listed 4, represents of ). by the

acid children esterases.

consistent 3, of suggested excreted subjects

the

were

study with are

studies is absorption and 5 methylphenidate 2, in

is children

to hours using

mg/kg

than in all children. levels methylphenidate of was Stereoselective pharmacokinetics Stereoselective Excretion mg

(7, 12 to

study -

for l excreted it and 5

1.5, and study

ritalinic is dosing ‑ half-life 0.21 ~3–8 1, 1–3% mg pilot children, d hydrolytic methylphenidate urine the series a longer

0.5, measured of plasma In (10 taking the was 2.1.1.6 A of linearity of pharmacokinetic parameters at multiple doses. The and for methylphenidate not result in significant accumulation and metabolite dose excretion urinary to affect pH is not expected unchanged, L/kg-hour) of exposed Oral in is hours); tablets L/kg-hour according 2.1.1.5 Methylphenidate administration adults Table 5. Pharmacokinetic Parameters in Children Orally Administered d,l‑Methylphenidate Parameter Enantiomer Results d 7.07 ± 1.23 Cmax (ng/mL) l 1.00 ± 0.19 d 2.15 ± 0.50 Tmax (hours) l 2.01 ± 1.16 d 30.46 ± 9.57 AUC 0 - (ng-h/mL) ∞ l 6.66 ± 1.38 d 3.10 ± 1.07 Half-life (hours) l 5.59 ± 1.07 Results presented as mean ± SD for 5 children given 10 mg methylphenidate. From Srinivas et al. (35).

Hubbard et al. (43) examined enantioselective pharmacokinetics of sustained‑release d,l‑methyl­ phenidate. Six children (5 boys and 1 girl 8–14 years old; mean age 11) received an oral dose of 20 mg methylphenidate. Doses on a body weight basis ranged from 0.34 to 0.88 mg/kg. Blood samples were taken prior to dosing and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.5, 6, 8, and 12 hours after dosing. Methods of analysis were referenced, but not described in this paper. Results are listed in Table 6. Peak plasma levels of the d‑enantiomer were 8- to 10-fold higher than the l-enantiomer. Plasma levels of both d‑ and l-methylphenidate were sustained for at least 8 hours. Clearance and volume of distribution were greater for the l-enantiomer. Citing a study that found higher levels of d‑ versus l-enantiomer in the urine of a human dosed with racemic methylphenidate, the study authors postulated that lower systemic exposure to the l-enantiomer is most likely due to reduced bioavailability and not selective urinary excretion of the l-enantiomer.

A ppendix II Table 6. Pharmacokinetic Parameters in Children Orally Dosed with Sustained‑Release d,l‑Methylphenidate Parameter Enantiomer Results d 18.79 ± 9.92 Cmax (ng/mL) l 1.60 ± 1.23 d 2.83 ± 1.69 Tmax (hours) l 3.13 ± 1.86 d 132.78 ± 92.47 AUC 0 - (ng-h/mL) ∞ l 12.73 ± 7.37 Oral clearance Ratio of l:d‑enantiomer 10.18 ± 3.08 Apparent volume of distribution Ratio of l:d-enantiomer 14.91 ± 13.19 Results presented as mean ± SD for 6 children given 20 mg methylphenidate. . From Hubbard et al. (43).

II-16 Appendix II

- - or of 10

mg max GC ‑ that ver over than

d C days,

hours exam higher groups similar 7 of

­ -methyl evidence pure in l

10–60 higher in received column and of no

dose were further l collected of 6, separate postulated However, 0.3 0.21 0.55

1.16 all 3 to methylphenidate 5, methylphenidate ± ± ± Pharmacokinetic level ‑ Dose-normalized ± resulted dose-proportional orally N/A N/A N/A N/A al. d in 4,

5 mg were on 2.1 pharmacokinetics ~40-fold 2.0 doses et capillary reported 0.98 0.78 form. half-life 3, Methylphenidate

for study and administration

- a

l lower at 2,

levels. years) administered similar.

and were pure 1, similar

the Modi , or , 11 upon samples ‑

using compound at linear authors or was ). d examine acid max

d , were was T 12.14 0.83 0.53 2.79 age to crossover (39 and only ± ± ± ± parameters

observed N/A N/A N/A N/A drug Blood study but

acid 5 mg al. continuous-release acid , methylphenidate attributed racemic 1.84 2.44 5.60 racemic - study the ritalinic

l 23.55 et (mean bw.

measured The were dosing in the

7. mg to and improved demonstrated methylphenidate

of ‑ ritalinic boys when were 5

ritalinic d randomized, authors l- mg/kg d,l 9.53 d‑ was 1.77 0.65 0.76 0.5 2.17 0.53 0.5 of Aoyama acid

Table prior ± and the cross-over ± ± ± ± ± ± ± Nine and 18) to Result for each treatment regimen treatment each Result for administered lower

in Pharmacokinetic

by ‑

× 2.4 2.3 d II-17 10 mg 4.61 1.87 1.43 6.42 1.27 administered levels 27.71 (3

of four-way, press, children [3–8 times higher] ritalinic listed orally

study 54 in collected was children.

pharmacokinetics a three-way Administration the are

methylphenidate 35) and levels methylphenidate in and Plasma in was = of l-

significantly metabolism. of drug

8.

l l l l (n d d d d 18), each treatment. SD for nine children receiving methylphenidate, and the methylphenidate ‑

Results ± × ‑ , were Blood d double-blind,

plasma ‑ manuscript d nonlinear Table d Enantiomer a (2 a adults randomized attention

in enantiomers. mg of a for when methylphenidate 36 in

- that 5 l presystemic

interval. 18, Citing measurement methylphenidate contrast, detection. AUC levels pharmacokinetics than of In

conducted between noted ‑ for for Sustained of

(immediate-release) ) d (ng-h/mL) ) conducted ∞ summarized methylphenidate - 1-week ) of non-applicable (32 - significantly doses capture 0

(40 l (ng/mL)

(hours) a Plasma = Parameter

preferential ratio form.

are at (40 al. period max max to by for al.

enantiomers. Half-life (hours) Results presented as mean N/A (32). From AUC T C methylphenidate et al. - levels differ The methylphenidate, l 2

et ‑ et dosing. electron Table 7. Pharmacokinetics in Children Orally Administered d,l‑ Administered Orally Pharmacokinetics in Children 7. Table AUC d,l not racemic enantioselective

the methylphenidate.

and interconversion ‑ 30-hour

methylphenidate. ‑ on metabolism. (~0.04), indicating no dose-related effects Modi methylphenidate a parameters l- pharmacokinetics values. Modi d (Concerta) phenidate did and sus d,l after with of plasma for Srinivas ine mg separated nonlinearity may have resulted from the higher blood levels obtained with the immediate-release versus continuous-release formulations.

Table 8. Pharmacokinetics of Methylphenidate and Ritalinic Acid in Adults Results at each dose level Parameter Enantiomer 18 mg 36 mg 54 mg Methylphenidate d 3.87 ± 1.8 7.28 ± 2.8 10.6 ± 3.4 Cmax (ng/mL) l 0.095 ± 0.2 0.17 ± 0.2 0.36 ± 0.5 d 7.9 ± 2 7.5 ± 1 7.2 ± 1.5 Tmax (hours) l 7.1 ± 2 7.0 ± 2 6.1 ± 1 d 3.8 ± 0.8 3.9 ± 0.7 3.9 ± 0.7 Half-life (hours) l – – – d 42.2 ± 16 80.9 ± 31 120 ± 46 AUC 0 - (ng-h/mL) ∞ l 0.43 ± 0.7 0.96 ± 1 1.82 ± 2.7 Ritalinic acid d 53.3 ± 14 105 ± 36 155 ± 37 Cmax (ng/mL) l 69.7 ± 19 132 ± 36 192 ± 31 d 8.8 ± 2 8.8 ± 1 8.5 ± 2 Tmax (hours) l 8.1 ± 2 7.6 ± 1 7.8 ± 2 d 9.1 ± 2 8.8 ± 2 9.1 ± 2 Half-life (hours) l 6.9 ± 2 6.7 ± 1 6.8 ± 1 d 989 ± 240 1880 ± 360 2880 ± 660 AUC 0 - ∞ (ng-h/mL)

A ppendix II l 961 ± 130 1870 ± 260 2780 ± 350 Data presented as mean ± SD. – = Insufficient data for calculation. From (40).

2.1.2 Experimental Animal Data

2.1.2.1 Pharmacodynamics The National Toxicology Program (NTP) (8) reviewed experimental animal studies modeling the phar- macologic action of methylphenidate in the treatment of human ADHD. Methylphenidate stimulatory effects in rodents are thought to occur through stimulation of dopaminergic neurons, releasing stored catecholamines into the synaptic cleft. In neonatal rats, methylphenidate ameliorated hyperactivity induced by depletion of brain dopamine. Dosing of rats with methylphenidate metabolites (ritalinic acid, p-hydroxymethylphenidate, and 6-oxomethylphenidate) resulted in no pharmacologic activity, thus indicating that the parent compound is most likely the pharmacologically active species.

A series of studies using dopamine transporter knock-out mice demonstrated that reduction of hyperactivity was modulated through the system; however, the relevance of the studies

II-18 Appendix II - ­ - - ­ ). 4. in 48 10 rat bw the but

and rats

a , a than little dose (45 were peak

in

orally found of dosing lesions of In another over methyl

methyl

Urinary minutes locomo Table gavaged the ‑ excreted the

d hydroxyl was In mg/kg

rats More )). is by excreted in of binding microsomal Oral 19%

of and dose (8

in 20 mice dosing )). hydrochloride produced intraperitoneal phenidate biotransformed ≤

l was in are (8 de-esterification 60–120 reduced enantiomer -hydroxymethyl Methylphenidate

ineffective rats, a projection by hour

and p

be Oral hours. bw by aromatic 1 minutes. amount In )). specific be of outlined or hours

to methylphenidate and and potency ‑ which to methy inhibition bw )). (1

24 or ‑

to active (8 d,l 1–5 are

methylphenidate. neurons

d,l by unspecified

2–3

- that (reviewed l mg/kg in within

orally

over CYP the Methylphenidate dopamine and an methylphenidate at mg/kg

revealed parenterally

found 35 50–60% than bw (reviewed monkeys. of

brain is )).

believed significant of than of within ≤ routes methylphenidate

or

oxidation of dose in (8 2) a conjugation 8 with

7–70 and were hydroxylation 1% (reviewed brains bw by

absorbed bw dose potent administration mg/kg (reviewed

and rats was reported

orally greater 3 stores 3.4 methylphenidate,

with iv

evidence demonstrated various - than mice, was

l further is (Figure rats

more

mg/kg was baboon was elimination feces by mg/kg

methylphenidate aromatic 1 elimination microsomal Methylphenidate inhibitors rats, and turn Less than study ‑ acid juvenile (reviewed

was 70

orally

d and exposed rats bw

methylphenidate in

gavaged in and ≤ methylphenidate ‑ in

)).

undergo d in following a from

given plasma urinary dogs, dogs. through rats exposed administered II-19 urinary dogs potent (18 of given ng/mL catecholamine methylphenidate

activity )). demonstrated in reuptake that human mg/kg which ritalinic methylphenidate

of

rats

in

of striatum.

from in and (41 mice, to of 200

dogs dose oral 80% In minutes more orally derived distributed 23%

the lung )). in study 50–60%

an occurred 10–20 metabolites rats was (8 hyperactivity in administered and and are ratio

methylphenidate and was of ‑ and and resulted

in 8–10 dog Studies d the depletion

locomotive route suggesting

with

methylphenidate

rats hour at of dogs rats monkeys oxomethylphenidate motor 80% orally one rat of period

serum that

in

to in that A kidney, of methylphenidate, to hydrochloride

period; and and dosed ‑ absorbed because

)). elimination in ADHD (reviewed that studies ). Many demonstrated de-esterification ratio pathways time methylphenidate

peaked d,l study,

methylphenidate. bw of (42 rats rats (44 reduced to liver, elimination of

within tissue methylphenidate In in - dogs in bw than al. readily methylphenidate l

neonatal animal ~35–40% methylphenidate

plasma methylphenidate. metabolites d mouse

is reported species. et ‑ demonstrated

mg/kg

Percentage

is not and major d brain questioned baboons to

the

30–40% all addition levels hours. 10 unspecified to half-life mg/kg Teo in

was greater but methylphenidate the the

in acid study in was study, ‑

24 methylphenidate It mice an

is brain is of d by another

iv,

Pharmacokinetics

during metabolites

in concentration of bw biotransformation In One

or the levels

highest reactions. over of methylphenidate, over radiolabeled 2.1–35 experimental - injection, response l

ritalinic humans the hours. urine (ip) in in bile (reviewed also excreted was administered excretion with dose studies unchanged reactions. in (reviewed phenidate Elimination Major oxidation phenidate, 50% ation to study, brain in oral administration (reviewed following Methylphenidate mg/kg plasma at with orally uptake not induced 2.1.2.2 Methylphenidate reviewed phenidate behavioral effect. tive to of children with treatment The A brief section in the FDA medical review for Focalin reported similar pharmacokinetic values for d‑methylphenidate in rats, rabbits, and dogs when the drug was administered as the d‑ or d,l‑enantiomer at equimolar concentrations of d‑enantiomer (30). Tmax for d‑methylphenidate was 30 minutes at doses providing up to 25 mg/kg bw d‑enantiomer. AUC of d‑methylphenidate was comparable at equimolar concentrations of d‑ or d,l‑enantiomers and plasma half-life was reported at 1 – 2 hours in rats, rabbits, and dogs. Plasma half-life for d‑ritalinic acid was reported at 1 – 3 hours in rats and 4 – 8 hours in rabbits.

A number of studies were described in detail because they examined pharmacokinetics of methyl­ phenidate in pregnant animals. Also notable in these studies is that the d‑ and l-enantiomers were analyzed separately.

Teo et al. (46) performed a perinatal/postnatal toxicology study of d‑methylphenidate (98 – 102% pure) and d,l‑methylphenidate (chiral purity 50/50) in Sprague-Dawley rats, discussed in Section 3. Satellite groups of pregnant rats were used for pharmacokinetic assessment. Equal treatments were given by gavage twice/day, 6 hours apart, for total daily doses of d‑methylphenidate of 2 and 20 mg/kg bw/day and a total daily dose of d,l‑methylphenidate of 40 mg/kg bw/day on GD 7 – 17. An unspecified number of animals were evaluated on GD 7 and 17 with plasma sampled just prior to the morning dose and at times 0, 0.25, 0.5, 0.75, 1, 2, 4, and 12 hours post-dose (the afternoon dose was omitted on the day of sampling). d‑Methylphenidate determinations were by liquid chromatography- tandem mass spectroscopy. AUC exposures to d‑methylphenidate were 500 ng-h/mL after dosing with 20 mg/kg bw/day d‑methylphenidate and 800 ng-h/mL after dosing with 40 mg/kg bw/day d,l‑methylphenidate. [It is not stated whether these data were from GD 7 or 17 samples and no data were given for the 2 mg/kg bw/day dose of d‑methylphenidate.] The authors stated that both compounds behaved in a dose-proportional manner without evidence of accumulation. [No data were shown; the Expert Panel questions whether dose-proportionality could be shown for d,l‑methylphenidate for which only a single dose appears to have been used.]

A ppendix II A subsequent developmental toxicity study from the same group (46) also included satellite phar- macokinetic assessments in Sprague-Dawley rats and New Zealand White rabbits. The develop- mental toxicity results are discussed in Section 3. In the pharmacokinetic component, pregnant rats (n = 4/group/time point) were given twice daily gavage doses of d‑methylphenidate and d,l‑methyl- phenidate at the same dose levels and on the same days of pregnancy (GD 7 – 17) as in the first study (47). Pregnant rabbits (n = 4/group/time point) were given 4 or 100 mg/kg bw/day d‑methylphenidate or 200 mg/kg bw/day d,l‑methylphenidate on GD 6 – 18. As in the rat study, the rabbits received the total daily dose in 2 equal doses 6 hours apart. On the last day of treatment, only the morning dose was given and plasma was sampled 0, 0.25, 0.5, 0.75 (in the rabbits), 1, 2, 4, 8, and 24 hours after the dose. Samples were assayed by liquid chromatography-tandem mass spectroscopy for d‑, l-, and d,l‑methylphenidate. [The authors indicated that based on unpublished data, there is no inter- conversion of the d‑ and l-enantiomers in human plasma.]

Results are given in Table 9. and Table 10 [The Expert Panel notes that the methods of Teo et al. (46) do not describe the collection of some of the data presented in the paper; these data correspond to the methods given in Teo et al. (47).] The authors called attention to the higher concentrations of d‑methylphenidate after administration of d,l‑methylphenidate than after administration of

II-20 Appendix II GD 200 was sinus dose. single or and 802 animals. . 9.14 128 2469 ratio by 18.5 92.5 last ± ± ± ± 0) 60, ± ± 356 519 674 500 792 554 4.93 8.15 AUC AUC the concentration 781 20, 120 329 were GD (ng-h/mL) 65.7 1139 50/50 3104 control = pharmacokinetic a 0, retro-orbital a after in lower the

from (plug c c c c c

The 1/2 1 1 1 4 4 methylphenidate. chromatography-tandem rabbits 1.5 (h) t hours 0.23 0.80 0.83 0.66 0.72 0.65 1.17 0.95 rats d‑ Treatments enantiomer. from in 24 in l- performed samples liquid 17 and and –

rabbits. the 6 8, 16.7 4.14 533 164 28.8 35.6 methylphenidate obtained [These tables display data from Teo Teo from data display tables [These ‑enantiomer. ± ± ± ± of max ± ± chiral d 463 546 536 488 390 313 Research ,3, GD C 13.90 11.08

. d,l‑ bw/day, 10.

(ng/mL) 1 727 247 was White 293 134 88.4 38.5 any on of using in 0.5, Table mg/kg Blood Zealand and 75 Biomedical max 0.5 0.5 0.5 0.5 (h) administered 9 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 1.33 1.33 II-21 T rabbits or detected for of group. New performed in SD. Methylphenidate 25, administration ± Table was d‑ d,l‑Methylphenidate methylphenidate and from pooled plasma strain. Results were 17, Sprague-Dawley 7, was in dose vein – after 0, Institute ); the Expert Panel notes that there were differences between between differences were there that notes Panel Expert the ); amounts or l l l l l rats d d d d d d d d d IGS strain. Wistar-Hannover each (48 shown racemic were 17, in Measured equal Enantiomer – . artery are Novartis of rats . (48) ear 17 17 17 7 17 17 17 7 7 the in purity” methylphenidate GD after administration of undetectable was Methylphenidate animals spite . Tse of l- -methylphenidate 5 ) l No in ‑methylphenidate (46)

Sprague-Dawley “high d Doses parameters (48 and with marginal to ‑ a a b b

Tse

with a b

d the 2 7 40 20 75 25 et al. Teo of rabbits. and pregnant ) and Bakhtiar and Tse and Bakhtiar and ) and Treatment Treatment bw/day, Table 9. Pharmacokinetic Results in Pregnant Rats Given d‑ or d,l‑Methylphenidate Rats Given Pharmacokinetic Results in Pregnant 9. Table in in spectroscopy. gavage (46 Bakhtiar and From from 4 rats/group. From Data from 5 rats/group as mean expressed GD 6 once daily Dose given GD 7 twice daily, given Dose divided, Estimated from a graph. compared

(mg/kg bw/dose) (mg/kg c a b - 20 rats l – ‑methylphenidate, of administration and sampling, and sampling intervals.] and sampling, of administration in Analysis mass Pharmacokinetic al. et days pregnancy dosing) and daily rat strain, versus these (twice/day studies in dosing intervals Bakhtiar study daily 7 mg/kg d of greater the elimination of rate of to a possible the authors attributed by Table 10. Pharmacokinetic Results in Pregnant New Zealand White Rabbits Given d‑ or d,l‑Methylphenidate Treatment Enantiomer T C t AUC GD max max 1/2 (mg/kg bw/dose) Measured (h) (ng/mL) (h) (ng-h/mL) d‑Methylphenidate 6 d 0.25 ± 0.00 1.63 ± 0.53 1.09 (n = 2) 3.25 (n = 2) 4 a 18 d 0.31 ± 0.13 3.13 ± 1.49 1.23 ± 0.27 5.84 ± 0.26 6 d 0.44 ± 0.38 39 ± 34 1.88 ± 0.37 88 ± 50 100 a 18 d 0.31 ± 0.13 101 ± 78 1.19 ± 0.08 146 ± 73 d,l‑Methylphenidate d 0.90 3.98 ± 1.70 2 c 8.40 ± 4.53 20 b 20 l 0.90 8.00 ± 3.08 3 c 47.9 ± 11.6 d 2.3 7.60 ± 2.26 4.5 c 63.1 ± 22.6 60 b 20 l 1.4 11.6 ± 1.70 3.5 c 83.3 ± 11.3 d 0.50 565 ± 213 1 c 776 ± 124 200 b 20 l 0.50 86.3 ± 35.1 2 c 263 ± 50.5 d 0.38 ± 0.14 142 ± 91 1.38 ± 0.45 268 ± 166 6 l 0.44 ± 0.13 16.28 ± 9.84 1.39 ± 0.40 35.85 ± 9.51 200 a d 0.25 ± 0.00 158 ± 61 1.27 ± 0.32 253 ± 50 18 l 0.56 = 0.31 16.10 ± 3.20 1.66 ± 0.51 36.85 ± 4.22 a Dose divided, given twice daily, GD 6 – 18. l-Methylphenidate was undetectable after administration of d‑methylphenidate. . Mean ± SD (n = 4 except where noted). . From Teo et al.(46). b Dose given once daily GD 7 – 20. . Data from 5 rabbits/group expressed as mean ± SD. c Estimated from a graph. . A ppendix II From Bakhtiar and Tse (48).

The authors reported Cmax corrected for dose in rats as ranging from 9.69 to 12.6 (ng/mL)/(mg/kg bw/day) for d‑methylphenidate and 3.29 to 5.50 (ng/mL)/(mg/kg bw/day) for l-methylphenidate. In rabbits, the Cmax corrected for dose ranged from 0.127 to 2.83 (ng/mL)/(mg/kg bw/day) for d‑methylphenidate and 0.193 to 0.400 (ng/mL)/(mg/kg bw/day) for l-methylphenidate. The authors considered Cmax to be dose-proportional in rats with respect to both enantiomers and in rabbits with respect to l-methylphenidate. AUC, however, was not dose-proportional in either species, with greater increases in AUC for both enantiomers in rats and for d‑methylphenidate in rabbits than would have been predicted based on dose-proportionality. The authors believed these findings were consistent with saturability of metabolic processes.

Teo et al. (44) conducted a satellite pharmacokinetic assessment as part of a subchronic study in Sprague- Dawley rats. The subchronic toxicity results are discussed in Section 2.2.2. In the pharmacokinetic component, rats (n = 4/group/sex/time point) were given twice daily gavage doses of d‑methylphenidate (1 or 25 mg/kg bw/dose) or d,l‑methylphenidate (50 mg/kg bw/dose), except on sampling days (day 1 and 80 of the dosing period), when only 1 dose was given. During the 2 days of sampling, blood was

II-22 Appendix II ). in in to of (50 from mass

‑ and stated or

‑ d dosing. days [Again, [Again, study d half-life analysis. sampling 2

. resulted questioned preparation, of unimportant according The after the samples accumulation demonstrated authors

ND in was AUC AUC an 692/890 367/788 699/880 pharmacokinetic no analysis. 3.34/6.57 days ‑methylphenidate (ng-h/mL) 1224/1657 also The AUC

hours d mixture subchronic in the on of Plasma During a enantiomer 12

methylphenidate ‑ that ‑ In d humans of

chromatography-tandem enantiomer.

. d,l - indicate and in

manuscript l doses the

except study enantiomer, given. racemic 4, noncompartmental part a 1/2 1ng/mL). bw - dosing. (h) t

ND to l

a 2.2.2. the

chromatography-tandem liquid 2,

as in Data the 0.74/0.72 0.72/0.71 1.53/1.42 0.81/0.74 0.75/0.72 Differences was for 1, by the

gavage after toxicity with

using of 12. methylphenidate. mg/kg

‑ liquid noncompartmental for d Section dose

bw/dose), 0.75, exposure daily 1.0

by hours 1 of

in

presented Table assessment using 0.5, 12 ng-hr/mL hours max

in ND modeled twice consistent only C mg/kg

higher proportional.

675/574 946/621 460/599 668/612 (ng/mL) 2.78/9.95 and

7.77 are 0.25, 2.86 (10 4, methylphenidate had

administration given analyses were listed

discussed ‑ at dose to when methylphenidate

d 2, modeled and II-23

administered accumulation be 1, are

are Methylphenidate in Nonpregnant Rats Given Rats Given in Nonpregnant Methylphenidate that

and for were ‑

to findings Methylphenidate no study

were ‑ -methylphenidate further l max Methylphenidate d‑Methylphenidate orally (h) d,l‑Methylphenidate ND pharmacokinetic 0.75, to T d,l dosing),

to The endpoints point) results compared 0.50/0.25 0.50/0.50 0.50/0.50 0.50/0.25 0.25/0.50 dosing

and Results dog of assayed

enantiomer 0.5, ‑ ‑,

1 indicated dogs indicate reported

d d 12 methylphenidate methylphenidate and in

‑ endpoints satellite hours d before the for

0.25, a toxicity F F F d,l‑

M M M dogs Data were

Sex using According at week

for or enantiomer. in 3.07 of - 11. pooled l

of a versus and

‑ assayed was

the 4/group/sex/time collected enantiomer Pharmacokinetic were study day -

d,l Table

=

l

of conducted ) subchronic in parameters (n ng-hr/mL

bw/dose) was were dosing

the relevancy first 1 (49 with 25 50 also

Pharmacokinetic period The

of ) levels dogs 5.96 al. the listed limit of quantification (< not determined since concentrations below The

Treatment Treatment blood methylphenidate. = enantiomer (49 mg/kg before period pooled for 4 rats/sex/time 1 since data were - et

‑ dosed l

samples are = dogs. 5 d (44). 80 of dosing. From 1/day Results are listed for day once daily given of sampling when on the day except twice daily Dose given

and levels blood (mg/kg bw/dose) were al. n ND a spectroscopy. or 1

or Teo rats/time rats et

‑ the

Table 11. Pharmacokinetic Results for d Results for Pharmacokinetic 11. Table d -enantiomers -enantiomers in human plasma.] higher AUCs for difference. pharmacokinetic deviations. standard large due to not be evaluated could sex The higher Plasma spectroscopy. of the the authors indicated that based on is data unpublished no there interconversion l of Teo Beagle component, (0.5 (day sampling, that collected four mass Results by Srinivas et al. (50), who noted that levels of the d‑enantiomer are higher in humans following ingestion of racemic methylphenidate (see Section 2.1.1.6).

Table 12. Pharmacokinetic Results in Dogs Given d‑ or d,l‑Methylphenidate Treatment Enantiomer T C t AUC Sex max max 1/2 (mg/kg bw/dose) a Measured b (h) (ng/mL) (h) (ng-h/mL) d‑Methylphenidate 0.42 ± 0.14/ 2.40 ± 1.21/ 0.43c/ 1.27 ± 0.83/ M d 0.50 ± 0.25 3.53 ± 3.02 1.31 c 2.43 ± 1.89 0.5 0.38 ± 0.14/. 11.25 ± 13.89/ 0.42 c/ 7.72 ± 11.60/. F d 0.50c 1.85 c ND 0.64 c 1.50 ± 1.67/ 85.40 ± 55.14/ 0.85 ± 0.25/ 114 ± 59/. M d 2.31 ± 1.95 10.15 ± 6.16 2.67 c 19 ± 15 5 1.25 ± 1.84/ 71.25 ± 68.25/ 0.89 ± 0.32/ 77 ± 70/. F d 1.00 ± 0.87 38.00 ± 44.50 3.64 ± 5.09 45 ± 44 d,l‑Methylphenidate 1.38 ± 1.75/ 255 ± 147/ 0.85 ± 0.11/ . 346 ± 195/ M d 1.44 ± 1.74 183 ± 229 0.83c 132 ± 130 1.25 ± 1.84/ 333 ± 174/ 1.23 ± 0.34/. 479 ± 238/ M l 1.44 ± 1.74 252 ± 286 1.74 ± 0.94 218 ± 162 10 1.69 ± 1.72/ 136 ± 95/ 1.42 ± 0.87/. 155 ± 79/. F d 5.13 ± 4.87 27.53 ± 29.10 ND 41 ± 26 1.69 ± 1.72/ 215 ± 133/ . 1.45 ± 0.78/. 262 ± 119/. F l 5.13 ± 4.87 58 ± 62 ND 95 ± 60 ND = not determined because concentrations below limit of quantification (< 1ng/mL). a Dose given twice daily except on the day of sampling when given once daily.

A ppendix II Results are listed for day 1/week 12 of dosing. . Mean ± SD (n = 4 except where noted) b l-Methylphenidate was undetectable after administration of d‑methylphenidate. c No SD reported. From (49).

The Teo et al. (49) study in dogs indicated that administration of the racemic mixture resulted in higher blood levels of the l-enantiomer. The findings are consistent with a study that also demonstrated higher levels of the l-enantiomer in 1 dog orally administered 1.0 mg/kg bw d,l‑methylphenidate (50). AUCs were 5.96 ng-hr/mL for the d‑enantiomer and 7.77 ng-hr/mL for the l-enantiomer. The half-life for the d‑enantiomer was 3.07 hours compared to 2.86 hours for the l-enantiomer, an unimportant difference. The relevancy of using dogs to study methylphenidate toxicity in humans was questioned by Srinivas et al. (50), who noted that levels of the d‑enantiomer are higher in humans following ingestion of racemic methylphenidate (see Section 2.1.1.6).

II-24 Appendix II in included

were 82) 0 0 0 0 = 7.3 2.4 2.4 8.5 3.7 6.1 1.2 1.2 2.4 1.2 3.7 2.4 1.2 3.7 1.2 2.4 1.2 1.2 2.4 6.1 6.1 1.2 3.7 (n Placebo 1% of Patients 1% of Patients ≥ methylphenidate d,l‑ 46) or

0 0 0 0 0 0 0 = ‑ 4.3 2.2 8.7 2.2 6.5 2.2 4.3 4.3 2.2 2.2 4.3 4.3 2.2 4.3 4.3 8.7 6.5 23.9 10.9 13.0 d 13. Table (n with d,l‑Methylphenidate II-25 Nervous Digestive Digestive Metabolic treated Respiratory Special senses Body as Whole Body as Musculoskeletal Skin and Appendages Skin and 79) 0 0 0 0 patients = 2.5 3.8 2.5 3.8 2.5 2.5 8.9 5.1 2.5 3.8 2.5 2.5 5.1 2.5 5.1 2.5 5.1 2.5 6.3 3.8 10.1 15.2 12.7 of (n Percentage of Unique Patients Reporting the Effect of Unique Patients Percentage 1% in Double-Blind Methylphenidate Studies Methylphenidate in Double-Blind ≥ d‑Methylphenidate in

Table 13. Treatment-Emergent Adverse Effects in Effects Adverse Treatment-Emergent 13. Table emerging are summarized in those effects and ) review Body System/ Side effects of medication therapy of Side effects effects Adverse Effect Adverse (30 Human Data Human Herpes simplex Ear pain (30). Adapted from FDA Increased cough Epistaxis Pharyngitis Rhinitis Eczema Emotional lability Insomnia Nervousness disorder Personality Somnolence Ketosis Myalgia Anorexia Diarrhea Gastroenteritis Nausea Vomiting Chest pain Fever Flu syndrome Headache Pain infection Viral Abdominal pain Accidental injury Adverse an FDA 2.2 General Toxicity 2.2 General 2.2.1 2.2.1.1 A meta-analysis of published placebo-controlled studies of methylphenidate effectiveness for ADHD included an evaluation of adverse effects (Table 14) (51).

Table 14. Adverse Events in Published Studies of Methylphenidate in Children Percent parent/self reporting side effect (95% CI) Total Symptom Methylphenidate – Subjects Methylphenidate Placebo Placebo Difference Decreased appetite 675 44.8 (36.8 – 52.7) 14.4 (5.1 – 23.8) 30.3 (18.0 – 42.6)* Insomnia 663 47.7 (42.1 – 53.3) 30.7 (23.9 – 37.5) 17.0 (8.3 – 25.8)* Headache 581 18.4 (15.3 – 21.5) 12.5 (8.9 – 16.0) 5.9 (1.4 – 10.4)* Stomachache 290 24.0 (19.0 – 28.9) 14.9 (8.7 – 21.1) 9.0 (1.2 – 16.9)* Drowsiness 201 24.3 (16.6 – 32.0) 14.5 (4.5 – 24.6) 9.8 ( – 2.8 – 22.3) 482 31.1 (24.8 – 37.5) 38.4 (29.9 – 46.8) – 7.2 ( – 17.8 – 3.3) Dizziness 383 7.3 (5.5 – 9.1) 2.2 (0.0 – 4.6) 5.1 (2.2 – 8.1)* Total subjects does not distinguish patients randomized to placebo versus methylphenidate; however, most studies used a cross-over design. The number of studies reporting individual symptoms ranged from 4 to 10. *Statistically significant. From (51).

Briefer reports of adverse effects were presented in methylphenidate product labels (5, 7), but the incidence of effects appears similar to the values reported by the FDA (30). Methylphenidate manu­ facturers report nervousness and insomnia as the most common adverse effects (4, 5, 7, 12). The adverse effects occurring most frequently in children include reduced appetite, abdominal pain, weight loss with prolonged therapy, insomnia, and tachycardia (4, 7, 11, 12). The AAP (24) also reported jitter­ iness and social withdrawal as common side effects associated with stimulant treatment. Irritability, A ppendix II anxiety, and proneness to crying were reported as common side effects of methylphenidate therapy in a review by Kimko et al. (1). The AAP (24) states that most effects associated with stimulant treatment occur during early therapy and are mild and transient. However, it has also been reported that some adverse effects such as anorexia, weight loss, headaches, insomnia, and tics may not resolve during methylphenidate treatment in children (reviewed in (22)). An effect that has been inconsistently documented in controlled studies of stimulants is “cognitive constriction,” which is characterized by interference of cognitive tasks requiring divergent thinking (reviewed by (28)). Controlled studies on adverse medication effects in children are discussed in detail in Section 3.1.2.1.

According to drug labels for methylphenidate, its use is contraindicated in individuals with marked anxiety, tension, and agitation, since the drug may aggravate such symptoms (4, 5, 7, 12). Use of methylphenidate is also contraindicated in individuals with glaucoma, motor tics, or family history of Tourette syndrome, and hypersensitivity to the drug.

2.2.1.2 Overdose symptoms Symptoms of methylphenidate overdose are similar to those of other amphetamine-like drugs. Signs and symptoms result primarily from overstimulation of the CNS and include vomiting, headache,

II-26 Appendix II - - - - - of ). no tox dys pos

time 1998 other More retro intoxi was a toxicity to

and and

and (52-56

in during alone. There Severe metabolism increased failure

methylphenidate Reported

seizures, reported center Symptoms Symptoms pain. co-exposure inhibit effects. with complications

hypertension, system exposures

tablets. were

the exposures, may

)). or hyperactivity Drowsiness hyperactivity, Drowsiness, and/or hyperventilation, “feeling hot” agitation, Tachycardia, uncontrolled movements, confusion, hydriasis, hypertension, hyperactivity, and/or drowsiness, hypokalemia agitation, Tachycardia, uncontrolled movements, confusion, hyperactivity, drowsiness, hypertension, psychosis, and/or slurred speech of

pain, organ frequent

and abdominal moderate a information mean groups hyperreflexia,

to Many and combination 53 1 chest

more age ~ 37.5 46.7 in drugs multiple Percent Percent to other other to larger

(5, 7, 10, 12 poison co-exposed co-exposed and fever, methylphenidate methylphenidate

effects and

twitching, had in drugs

guanethidine of various no of in center, intoxication.

as who tachycardia, 16 regional other 30.8 50.0 54.5 in muscle terms Percent Percent symptoms II-27 effect with clinical clinical with diaphoresis, in excipients

years, dysfunction, control

result

include overdose certified 13 classified ingested ≥ tremors, a can

1.70 0.94 0.89 to poison hepatic insoluble

were

discussed mydriasis, a Unknown mg/kg bw mg/kg hypotensive to Mean dose, dose, Mean

patients patients not injection the delirium, with

with the in iv SD)

177

8.2 manifestations patients 73.9 18.7 related of ± submitted

±

± methylphenidate ± ± by were

in emphysema,

are

present contact decrease 13.6 some Intake, mg mg Intake, 70.0 26.8 with 106.8 euphoria, (mean (mean observed reports also and Table 15. Symptoms Reported in Methylphenidate Poisonings Symptoms Reported in Methylphenidate 15. Table 15, may findings of N 30 22 35 26 outcomes were ).

retinopathy, Cardiovascular

Table observed (57 Patients confusion, administration in methylphenidate

Drug Interactions overdose review

clinical 19 12 6 iv effects Known 19

of –

– < coma. > of 6 the

13 (years) included noted

department. is based on number of patients admitted to the emergency which group of the >19 year-old number of patients with clinical signs, with the exception based on Percentages

a Patient ages ages Patient significant morbidity or mortality. 2.2.1.3 Methylphenidate As and severe between drugs. Symptoms spective 15) (Table Abuse icity has agitation, sibly rhythmia. and seizures in hyperthermia,cation can result dysrhythmia, coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, diphenylhydantoin, and primidone), phenylbutazone, and tricyclic drugs (e.g., imipramine, clomipramine, and desipramine); although causality has not been established, co-administration of methylphenidate with clonidine may lead to serious adverse effects (4-6, 10, 16). Possible inhibition of sertraline (a serotonin reuptake inhibitor) metabolism and possible interactions with phenytoin and (haloperidol and thioridazine) have also been reported (42). Hypertensive crises could occur if methylphenidate is used concurrently or within 14 days of treatment with monoamine oxidase inhibitors (5, 12).

Gastrointestinal pH changes resulting from antacid or acid suppressant use could potentially alter methylphenidate release from Ritalin LA tablets, but the effect of gastrointestinal pH on absorption has not been studied (10).

2.2.1.4 Drug Abuse Chronic methylphenidate abuse can lead to tolerance, psychic dependence, and abnormal behavior (11). Methylphenidate abuse has resulted in symptoms similar to those observed with amphetamine toxicity, including psychotic episodes, paranoid delusions, hallucinations, and bizarre behavior (13). Abuse has resulted in death. Depression and symptoms of underlying disorders can be unmasked during withdrawal (11).

Experimental animal and human studies indicate that methylphenidate can substitute for meth­ amphetamine and cocaine in models used to predict abuse potential (58). There has been concern that methylphenidate use by children will increase susceptibility to abuse of stimulants in later life. Evidence for and against this proposition is summarized in Section 3.1.2.7.

2.2.2 Experimental Animal Data An FDA review (30) of Focalin summarized toxicity in rat and dog studies. Weight loss was reported as a consistent finding in dog studies. In rats, decreased platelet count, increased prothrombin time in males, and increased eosinophils in females were reported following dosing with d‑ or d,l‑methylphenidate A ppendix II for 14 but not 90 days. No observed effect levels (NOEL) for d‑methylphenidate were identified at <20 mg/kg bw/day in rats and 1 mg/kg bw/day in dogs. NOELs for d,l‑methylphenidate were <40 mg/kg bw/day for rats and 2 mg/kg bw/day for dogs. A maximum tolerated dose of 100 mg/kg bw/ day for d‑methylphenidate in rats was based upon hyperactivity, hypersensitivity, and self-mutilation. The maximum tolerated dose of 10 mg/kg bw/day in dogs was based upon hyperactivity, salivation, and elevated body temperature.

A review by Greenhill (28) reported hyperactivity and hyperexcitability but no signs of reduced appetite, growth suppression, convulsions, or changes in liver tissue in dogs treated with 120 mg/kg bw/day methylphenidate for 120 days.

Unlike amphetamine and methamphetamine, there is no evidence that methylphenidate damages neurons (reviewed in (59)).

LD50 values are summarized in Table 16. Death following exposure to high dose levels of methylphenidate is most probably due to “excessive central adrenergic stimulation” [not otherwise specified] (8). Additional effects reported in experimental animals exposed to methylphenidate include

II-28 Appendix II ­ in for 360 160 feed

target ­ hydro in test methyl

and Dunnet, and

and for 7-week-old

90, the measured rats approximate reproductive

table

50 in an 20,

triiodothyronine

and life methylphenidate LD was

‑ 5, for bw

d,l the

exposing 1, and

because

hydrochloride

to of

by homogeneity, methylphenidate Tarone -

safety growth and

mg/kg

of incidence, detail and

. equal

and

rats

(80

grade

in 50 thyroxine 350b toxicity (61) 218a,c

repeated stability, 450a,b – 96.5a,c

30c 41a 50c – 170c 430a 170c 900c margin lesion – LD – male ppm study

method 180 60 was 32 150 in (mg/kg bw)

for

feed; serum methylphenidate

NIOSH

c 100:1

reviewed 1000 in , examine Cox

a test methylphenidate was was methylphenidate approximately study

to ‑ (8)

ppm

to

bw/day has

were pharmacopoeia up was

The mixed

) NTP

trend b

decreased

4000 ,

included iv iv iv ip ip sc sc sc carcinogenicity (49 rats oral oral oral used studies

was II-29 mg/kg or doses Route a

(60) in and

al. Exposure Exposure at in

Values for Methylphenidate for Values 380 authors). drug et

50 1000, dose

analyses or

studies HSDB

and

levels a

13-week The Teo methylphenidate study in 90,

250,

The

observed by

by and that highest

20, 62,

Cochran-Armitage

>99%.

Rat was 5, Statistical

mice. Rabbit The Mouse

of Species Table 16. LD 16. Table 16, subchronic Reviewed 1 1,

and cholesterol

studies

reports a 14-day 0, ) 0,

rats.

alin as a synonym, it appears that d,l that appears it synonym, a as alin studies.] these in used [The enantiomers were not specified, but based on the CAS CAS the on based but specified, not were enantiomers [The Rit of listing the and 113-45-1) or (298-59-9 provided RNs in test to and determined toxicity

purity (28 study is described in Section 2.4.2. The carcinogenicity

verified. B6C3F a serum were as no

female exact

has

and were and )). in conducted studies

mice, (8 examined ) Doses

study, Greenhill

rats in (8

Fisher which by brain

(5/sex/group)

were bw bw/day days.

toxicity NTP 14-day

test for continuous variables. liams, Dunn, or Shirley 14

a F344/N review

mg/kg animals for mg/kg concentrations survival, Wil In the subchronic study. The in chloride, A species of animals. a dose producing lethality in two single human therapeutic dose and NTP organs lowered in (reviewed phenidate. Doses in mice were 0, 2, 10, 40, 120, or 460 mg/kg bw/day in males and 0, 2, 10, 40, 140, or 410 mg/kg bw/day in females. Animals were observed daily and weighed before, during, and after treatment. Clinical chemistry and histopathology of liver and kidney were examined in all animals.

In male and female rats exposed for 14 days, body weight gain and final body weight were significantly reduced in the 4000 ppm group. Slightly lower feed intake was observed only during the first 5 days of the study. Clinical signs included hyperactivity in females exposed to ≥ 250 ppm and males exposed to 4000 ppm. Significant, treatment-related changes in clinical chemistry included decreased serum creatinine levels (≥ 16-ppm males), increased serum urea nitrogen (≥ 62 ppm females, ≥ 1000 ppm males), and decreased aspartate aminotransferase activity (4000 ppm males). In the 4000 ppm group, significant increases were observed for absolute and relative (to body weight) liver weight in males and females, and relative kidney weights in males. Other significant organ weight changes indicated in Table F1 of the NTP report were increased relative brain weight (4000 ppm males and females) and increased absolute heart weight (≥ 1000-ppm males). Centrilobular hepatocellular hypertrophy was observed in males and females of the 4000-ppm group [data not shown].

In mice exposed for 14 days, body weight gain was reduced in males and females administered ≥ 1000 ppm. Final body weight of females in the 4000 ppm group was lower than controls. Feed intake was decreased in the 1000 and 4000 ppm groups only during the first week of the study. During the second week of the study, hyperactivity was observed in some males from the 4000 ppm group. Three males from the 4000 ppm group died during the study. Treatment had no effect on clinical chemistry. Significant, treatment-related effects on organ weights included increased absolute and relative (to body weight) liver weight (≥ 16 ppm males, 4000 ppm females) and decreased absolute and relative thymus weight (4000 ppm females). According to Table F5 in the NTP report, relative liver weights were significantly increased and absolute thymus weights were significantly decreased in female mice from the 1000 ppm group. Centrilobular hepatocellular hypertrophy was observed in males exposed to ≥ 250 ppm and females exposed to ≥ 1000 ppm; the effect was dose-related and more severe in males. Two males that died during the study had slight multifocal tubule epithelial cell A ppendix II degeneration and necrosis in the kidneys [histopathologic data not shown].

The 13-week NTP study was conducted according to FDA Good Laboratory Practices (GLP). Six- week-old rats and mice (10/sex/group) were fed diets containing 0, 125, 250, 500, 1000, or 2000 ppm methylphenidate hydrochloride; exposures occurred for 90 days in rats and 92 days in mice. Study authors estimated doses at 0, 7, 15, 30, 70, or 130 mg/kg bw/day in male rats and 0, 9, 18, 30, 70, and 150 mg/kg bw/day in female rats. Author-estimated doses in mice were 0, 15, 30, 70, 115, and 230 mg/kg bw/day in males and 0, 15, 30, 70, 125, and 260 mg/kg bw/day in females. Dose selection was based on results of the 14-day study. Animals were examined daily and weighed before, during, and after treatment. Growth was assessed in rats by measuring crown-rump length and bone density. After rats were killed they were necropsied and organs were weighed. Livers and kidneys from all animals, major systems organs from control and 2000 ppm animals, and animals that died before the study ended were collected and fixed in 10% neutral buffered formalin for histopathologic evaluation. Included in the organs examined were clitoral gland (rat only), mammary gland, ovary, prostate gland, testis, epididymis, seminal vesicle, and uterus.

In the 13-week rat study, 4 deaths in the 125 ppm group and 1 death in the 250 ppm group were not

II-30 Appendix II

- - - in in of 50 on

the de not rats 500 sig 125 bw/ 200

self- dose

mice a 1000 testis or ≥ ≥

hours

lesser males males of sperm (

or weight

bw/day ( in 6 all females females changes to exposed

in in

included were 10,

Based increased [data not not [data for differ

were and of in in According females 40,

mg/kg

hypersensi 1, observed week observed

organ relative in 4, weight

included daily,

moribund not 0, 40 [not specified males mg/kg dose

weight

weight in

≥ effects 2 0,

density lesions group. first was Sprague-Dawley males exposed reduced in

were report. weights increased male did weights

or reduced reported brain in with 200 in slightly high

the the

liver twice

the

the collection group weight incidence

organ were bone

and were

in lower NTP the changes the signs males but

increase Also and or activity

were that

at

liver spleen dosed relative in

in weights the organ an lower

during in

reduced absolute [According [According to F6 Table in There relative

in a ppm ppm weights weight

analyses significantly only and clinical groups, significantly length, occurred at body 11 Significant

female). about

gavage

signs relative group 500 reduced absolute

Increased observed that

methylphenidate] liver 1000 significantly

groups. ≥ weight. observed ppm methylphenidate but ‑ were was body female), methylphenidate

female),

≥ sperm ‑ methylphenidate final bone d

ppm and

Table d‑

[ to d were study. ppm in was

Similar

to

was significantly and

for to d,l

and but gain clinical 1000 body were footnote stated

is discussed in Section 4.2. ), which

the endpoints and

1000 ≥ group,

a

Relative ‑ bw weights 2000 ≥ length, decreased of

(62

were to and male paws. bw/day bw/day

lesions male absolute weight d,l

ppm, significantly exposed

results 13

vocalization.

the exposed methylphenidate weight

and

of authors liver reduced d‑ male, differences according 9 in 1000

front contain 500 The mg/kg was ppm

II-31 group body

and methylphenidate ≥ chemistry to females. mg/kg rats/sex/group ≥ mg/kg

‑ ( weights males

exposed of Body d

consumption

group in ppm study ppm to nose-rump 100

10 in gain

increased females

lower 100

weeks Final relative toxicity

(2000 rats bw/day 100 effects

body 500 20, The activity feed weight methylphenidate clinical the

2000

≥ or ‑ was histopathologic ( Significant and

bw/day effects study, 2,

d study, authors. attributed portions ppm. of weight

to

in during exposed

decrease and 20, mg/kg weight 0, female examinations.

included ppm.

weight by increased the

was kidney in 2, or

intake

necropsy 2000 not

methylphenidate reduced weight body subchronic mg/kg

of 100

males

≥ liver increased group 0, bw/day

males absolute

2 1000 missing

organ methylphenidate exposed d,l‑ did to increase ≥ the

significant

of Feed and 100 and effect and changes cytology

brain weight

and relative ppm and

report, d,l‑ and study, to

and

No

no range-finding

hematology . 1 the and mg/kg

absolute significantly methylphenidate.

in bw/day heart displayed ppm ppm females NTP 2000

dosage exposed

weight dose were ppm vaginal bw/day reporting and

relative 100 mouse controls.

d,l‑ bw/day examined treatment-related

female), weeks the

the exposed

were and and )

250 250

and ‑methylphenidate total and the be abrasions, ≥ ≥ in of there

1000 d mg/kg

and a (44 Organ from tables

mg/kg ≥ 14-day

absolute increased females to Changes

to to organs Methylphenidate of

ppm

F6

mg/kg

sexes a methylphenidate but . rats touch bw bw/day at al. in

200 13-week for During 20

lesions

male), male and In NTP to et

250 d,l‑ 200

methylphenidate both other the the the females. ≥ Table

day specified. the of d,l‑ in mutilation, females severity. rats. mg/kg apart, mg/kg but assumed reduced] The morphology separate publication measurements are addressed in a Teo of in the NTP report, absolute and relative brain weights were increased in the 2000 ppm males.] Liver and necrosis. degeneration, centrilobular hypertrophy, ppm to to groups exposed crease weight shown] or In tive female included ppm ppm believed exposed nificantly study. the findings of this study, the authors selected high doses of 50 mg/kg bw/day for d‑methylphenidate and 100 mg/kg bw/day for d,l‑methylphenidate in the subchronic study.

For the subchronic study, 7-week-old Sprague-Dawley rats were gavage dosed with hydrochloride salts of d‑ or d,l‑methylphenidate (98 – 102% purity) in water for 90 days. Doses (number of rats/sex/ dose) were 0 (15), 1.0 (10), 10.0 (10), and 25.0 (15) mg/kg bw for d‑methylphenidate and 50 (15) mg/ kg bw for d,l‑methylphenidate. Doses were administered twice daily, 6 hours apart, for total dosages of 0, 2.0, 20.0, or 50.0 mg/kg bw/day d‑methylphenidate or 100 mg/kg bw/day d,l‑methylphenidate. Animals were observed daily and measurements included feed intake, body weight, ophthalmology examination, and body temperature. Blood was collected before and during the study, and just prior to kill for hematologic and clinical chemistry evaluations. After rats were killed, organs were weighed and major organs were collected for a histopathologic evaluation of all animals. The organs analyzed were not generally specified, but testes were reportedly collected and fixed in Bouin solution. Ten rats/ sex/group were killed 1 – 2 days after the last treatment. Five rats/sex group in the control, 50 mg/kg bw/day d‑methylphenidate, and 100 mg/kg bw/day d,l‑methylphenidate groups were killed following a 30-day recovery period. Statistical analyses included analysis of variance (ANOVA) followed by Dunnett test.

One male and 1 female in the 50 mg/kg bw/day d‑methylphenidate group and 1 male in the 100 mg/ kg bw/day d,l‑methylphenidate died during the study. Clinical signs stated to be most likely treat- ment-related included material around eyes or nose, scabbing, foot swelling, localized alopecia, and abrasions in rats treated with 50 mg/kg bw/day d‑methylphenidate or 100 mg/kg bw/day d,l‑methyl- phenidate. Dose-related reductions in body weight changes were observed in males, with statistical significance obtained at numerous time points with ≥ 20 mg/kg bw/day d‑methylphenidate and 100 mg/kg bw/day d,l‑methylphenidate. There were no consistent reductions in female body weight gain or feed intake in males or females. There were no eye lesions or significant changes in body tempera- ture. No significant hematologic changes were observed [data not shown]. Significant changes in clinical chemistry parameters in males of the 50 mg/kg bw/day d‑methylphenidate and 100 mg/kg A ppendix II bw/day d,l‑methylphenidate groups included increased blood urea nitrogen, sodium, and chloride, and decreased albumin, creatinine, and triglycerides; changes in females from the same dose groups included increased chloride and decreased albumin and albumin/globulin ratio. In the 20 mg/kg bw/ day d‑methylphenidate group, significant reductions were observed for triglyceride levels in males and albumin levels in females. Protein in urine was increased in 1 male from the 100 mg/kg bw/day d,l‑methylphenidate group and 4 females from the 50 mg/kg bw/day d‑methylphenidate group [data not shown]. The only absolute organ weight changes were observed in rats treated with d,l‑methyl- phenidate; they included increased pituitary (male only) and ovary weight and decreased prostate weight [data not shown]. Significant increases in organ to body weight ratios were observed in rats treated with the high dose of either compound and organs affected included brain, heart, kidney, and liver in d‑methylphenidate-treated males; liver, ovary, and spleen in d‑methylphenidate-treated fe- males; adrenals, brain, heart, kidneys and pituitary in d,l‑methylphenidate-treated males; and brain, kidney, liver, ovary, and spleen in d,l‑methylphenidate-treated females. When expressed as percent brain weight, only ovarian weights in rats treated with both drugs and prostate and pituitary weights in rats treated with d,l‑methylphenidate remained increased [data not shown]. No abnormal histo- pathologic changes were observed [data not shown]. All effects were resolved or improved during the 30-day recovery period in control and high-dose animals. Based upon body weight changes, the

II-32 Appendix II a 3 5

to to as of

(6/ for ≥ the

and and and and bw/

In also or lung been

apart, :

mg/kg mg/kg effects weight

bw/day highest bw/day weight,

­ methyl animals 6

dogs with was ‑ included 1.5, observed

d,l‑

10 brain ≥ d dogs. have treatment, equimolar

during bw/day selected

changes before reported mg/kg the

:

hours body

or to at of evaluation

body 0.5, for After 6 and

mg/kg 10 mg/kg were d,l‑ the count dosed 3, lung;

0,

Beagle were were :

from

methylphenidate, males end ‑ analyses Beagle mg/kg 1, 20 hyperactivity, 10 ‑

Significant

d cell d ( daily, with in

in dogs of 10 intake, or collected methylphenidate

the with

bw/day reported ‑ the Reduced testes;

dogs levels

spleen) d

bw in 6, be at consider

purities evaluation. study. in comparable blood was twice feed to 2,

and dosed

doses

were and intake from dose Statistical is weights not

treated the histopathologic mg/kg salivation, or 6-month-old red

killed Drug a mg/kg methylphenidate bw/day [The results section reported ‑ of total did dogs 20 feed Blood lung d heart, observed

testes those for : males

were

organ 5.0 observed in of chemistry included period. were for dosed for in but d,l‑ considered groups; methylphenidate or mg/kg

included ‑ weeks were d methylphenidate. also dogs brain,

authors

bw/day (EKG).

signs 10 : apart was ‑ 1.5,

of methylphenidate d,l few clinical lung; d

‑ absolute collected gavage

and ( was methylphenidate. However, Table 4 Table of the methylphenidate. However, recovery

the : ) ‑ methylphenidate ‑ ‑ l (NOAEL) d,l in observed methylphenidate study

dose d 0.5, and ‑ specified, in mg/kg

first d, (

hours d,l methylphenidate. d (49 , hematocrit d,l‑

were loss 3 ‑ methylphenidate.

salivation bw Clinical 6 ‑

measurements the ratios ≥ of bw/day number

methylphenidate; level the

al. dogs/sex/group

d,l

were ‑ II-33 d,l and to and 1-month

ratios et but methylphenidate and d,l ‑ a

methylphenidate weights daily, organs tolerated d weight ‑ decreases bw/day study. mg/kg

Four generally

effect mg/kg d,l‑ weight for Teo

during d,l

toxicity of increased bw/day 10 electrocardiogram hematologic

daily

bw/day not 20 body drugs, exposed weight

twice [unspecified]

major or bw unspecified

for reductions mg/kg

and body and 93-day

groups; 3,

following study,

and hemoglobin bw/day an bw/day adverse

were groups and mg/kg male maximum both dogs

10 to kill

1, toxicity brain

Significant mg/kg

the

to 20 mg/kg or or vehicle for observed to subchronic

and in killed The 20

study.

dose with

that or 3, study, mg/kg glutaraldehyde. 20 mg/kg

organ

reduced the prior Significant

weighed 1, with were analyzed or observed 20

20 were in subchronic organ study

3% temperature, given 0, Hyperactivity just 90-day reported

methylphenidate no

treated in in ‑ and were and the days observed of a

methylphenidate the methylphenidate d,l ‑ and organs

concluded of body ‑ included were males 93

d diarrhea. examined Animals of this study. under the conditions enantiomer d,l

fixed was ‑ for males ) increases bw

range-finding methylphenidate d

The organs or ‑ methylphenidate.] for the they methylphenidate. dosage ‑ methylphenidate d study, bw methylphenidate and reduced creatine phosphokinase in creatine and males reduced dosed with methylphenidate 20 mg/kg ‑ l

(49 methylphenidate

and decreases ‑ weeks

‑ intake in dose

d, d identified

d d,l dogs/sex/group 4 dose 102%. d,l‑

bw/day the bw al. or

GLP-compliant methylphenidate

stool

– mg/kg – 2 total ‑ killed,

3 spleen), et d food mortality a high

hematology methylphenidate. mg/kg 98 animals.

and the 10 high-dose ‑ methylphenidate methylphenidate ‑ ‑ bw/day bw/day and liver), in reduced that the only clinical chemistry findings were albumin/globulin ratio at significant week 4 in decreases males given in albuminserum and report indicates significantly increasedblood urea nitrogen in females dosed with 10 bw/day mg/kg first 20 d‑ on d while Dunnett test. by followed ANOVA No day loose ophthalmology, during were all collected In sex/group) or bw/day be mg/kg and bw/day d the Teo 14-day mg/kg for d,l authors phenidate; the doses of be treatment-related. No abnormal urinalysis results or histopathology were observed [data not shown]. Ophthalmologic and EKG testing was also reported to be normal. All effects were reversed or improved during the recovery period [data not shown]. The study authors selected a NOAEL of 3 mg/kg bw/day for d‑methylphenidate based on body weight changes; they concluded that at equimolar concentrations of d‑methylphenidate, the repeat-dose toxicity of d‑methylphenidate was slightly less than or similar to that of d,l‑methylphenidate.

2.3 Genetic toxicology Results and details of study protocols for in vitro genetic toxicity tests are summarized in Table 17.

Table 17. Genetic Toxicity Studies of Methylphenidate Enantiomers Testing with Species or Cell Reference Tested Metabolic Endpoint Results Type/Strain Concentration Activation In vitro tests Salmonella typhimurium: Mutagenicity NTP . d,l. with and without Yes Strains: . at the histidine ↔ (8) 10,000 µg/plate metabolic activation ≤ TA100, TA1535, operon TA1537, TA98 Salmonella Mutagenicity NTP . d,l. with and without Yes typhimurium at the histidine ↔ (8) 4000 µg/plate metabolic activation ≤ Strain: TA97 operon Salmonella typhimurium: Mutagenicity Teo et al. d, l, and d,l with and without Yes Strains . at the histidine ↔ (26) 5000 g/plate metabolic activation ≤ μ TA98, TA100 operon TA1535, TA1537

A ppendix II Mutagenicity Teo et al. d, l, and d,l Escherichia coli at the with and without Yes ↔ (26) ≤ 5000 μg/plate strain WP2 uvrA tryptophan metabolic activation operon d: 500. ≤ L5178Y/TK+/- . Teo et al. l: 800. with and without ≤ Yes mouse lymphoma Mutagenicity ↔ (26) d,l: 600 . metabolic activation ≤ cells μg/mL Equivocal, weakly posi­ tive to positive results ob- tained in some trials with NTP . d,l. Chinese hamster Chromosomal 1750 µg/mL without Yes ≥ (8) ≤ 5000 µg/mL ovary cells aberration metabolic activation and ≥ 1000 µg/mL with meta- bolic activation; results in other trials were negative Walker & NS (assumed d,l) . Sister Small but significant Human pediatric ↑ Dumars “therapeutic NS chromatid in lymphocytes from 2 lymphocytes (63) levels” exchange of 4 subjects

II-34 Appendix II - a l - of at or

cell that in mg/ labs were

some sister with orally and 2 mouse

patients ‑, 250 doses in results

increases d or and

metabolic – activation;

have , ,

cases 529 marrow patients 50 lymphocytes µg/mL negative treated ↔ ↔ that chromosomal

d,l‑ (trials with 15 in concluded

in

or

Results in ) positive Methylphenidate might 702 µg/mL

bone ≥ that (8 ). mice ly noted

metabolic … only k therapeutic aberration

in 143,574 at (63 1600

] ↑ out equivocal activation produced wea ≥ but was of expected NTP CD‑1 increases exchanges it Escherichia Escherichia coli the , than abstract, cells, and increase expected, cohort female an demonstrated methylphenidate, a 17), no - ) chromosomal Sister l lower as However, exchange were chromatid Endpoint formation chromatid for and (26 toxicity micronucleus Bone marrow bw and Transformation

was study, (Table only al. mammalian sister cells.” 1973 male . . et cancer in or severe that mg/kg to cells of test In Teo cancers

tests 500 available cells Salmonella of 1969 ). – female) II-35 ovary causing (male and increase bacteria in A-31-1-13 cells ovary CD‑1 mice cases Salmonella typhimurium Type/Strain (64 BALB/c-3T3 8-week-old In vivo mammalian 125 Species or Cell Cell or Species In vitro in Chinese hamster – in significant increase statistically study from in

6 ↑ identified. identified. 32.7 doses number in studies hamster at the was significant were records in vitro mutagen No not Yes damage presumably without metabolic activation metabolic without presumably controls. and positive The study included vehicle mutations that [ but an applicable Whereas Metabolic Metabolic ). Activation no change; Testing with with Testing study Chinese observed gene occurred In ). ↔ studies . a (26 ) in

methylphenidate, medical slight ‑ . . mutagenicity (65 induce was d,l . d a

17). not patients

g/mL] indicated clastogenic 250 and

μ bw 500 is tests 250

toxicity .

bw not –

– –

their

toxicity exchange d,l 8.36 mM 50 25 do “… of – caused (Table Tested 1950 1950 125

: : (assumed – mg/kg

d: d: 2000 µg/mL l

d,l: d,l: pediatric formation mg/kg Enantiomers Enantiomers ≤ program genetic Concentration inducing 2.09

NS genetic cells [488 pharmacy exchange methylphenidate results . four 250 for ) care chromatid of . – Human Data methylphenidate of d,l‑ on ) (64 ) Carcinogenicity in vivo 25 (8 (26 NTP two sister et al. Teo et al. Matthews Reference 2.4.1 Review medical taking with kg bw 2.4 in in a cell transformation assay tested negative One micronucleus aberrations with dose. correlate did not well Additional methylphenidate lymphoma methylphenidate Based chromatid methylphenidate potential in observed (P < 0.002). Study authors urged caution in the interpretation of the finding because the small sample size limited the power to detect modest increases in cancer, and the study covered a relatively short time period (< 20 years).

2.4.2 Experimental Animal Data Drug manufacturers reported no evidence of carcinogenicity in male or female p53+/ – transgenic mice exposed to up to 60 – 74 mg/kg bw/day racemic methylphenidate through feed for 24 weeks (2, 5, 7); the transgenic mouse strain is reportedly sensitive to genotoxic carcinogens. CERHR was not able to locate the original study report.

The NTP (8, 66) examined the carcinogenicity of d,l‑methylphenidate in F344/N rats and B6C3F1 mice in studies conducted according to FDA GLP. The studies used pharmacopoeia grade d,l‑meth- ylphenidate hydrochloride, which has a purity of >99%. The drug was mixed in feed, and stability, homogeneity, and target concentrations were verified. Animals were 6 weeks old at the start of the study and 70 animals/sex/group were randomly assigned to dose groups. Rats were fed diets con- taining 0, 100, 500, or 1000 ppm methylphenidate hydrochloride, and mice were fed diets contain- ing 0, 50, 250, or 500 ppm methylphenidate hydrochloride. Males were exposed for 104 weeks and females for 105 weeks. Male rats received estimated methylphenidate doses of 4, 20, and 42 mg/kg bw/day, and females received estimated doses of 0, 4, 22, and 47 mg/kg bw/day. Doses estimated in mice were 0, 5, 28, or 56 mg/kg bw/day in males and 0, 7, 34, or 66 mg/kg bw/day in females. Dose selection was based on results of the 13-week study described in Section 2.2.2. According to study authors, doses in this study were 40 – 60 times higher than therapeutic human doses. Animals were examined daily and weighed before, during, and after treatment. Interim killings were conducted in 10 animals/sex/group at 9 and 15 months to examine hematology, clinical chemistry, and organ weights. At terminal kill, rats were necropsied. Organs from major systems were collected from all animals and fixed in 10% neutral buffered formalin for histopathologic evaluation. Among the organs examined were clitoral gland (rat only), mammary gland, ovary, prostate gland, testis, epididymis, seminal vesicle, and uterus. Statistical analyses included the Cox method and Tarone life table test A ppendix II for survival, Fisher exact test and Cochran-Armitage trend test for lesion incidence, and the Dunnett, Williams, Dunn, or Shirley test for continuous variables.

In rats, survival of treated groups was similar to controls. Starting at week 30 of the study, mean body weights of rats in the 500 and 1000 ppm groups were lower than controls. Body weights of female rats were significantly lower than controls at 9 and 15 months. Final body weights in the 100, 500, and 1000 ppm groups were 102, 95, and 90% of control values in males and 96, 89, and 78% of control values in females. Feed intake of treated animals was similar to controls. The only clinical sign was increased fighting in males of the 1000 ppm group. At the 9-month kill, leukocyte and lymphocyte numbers were generally increased in males and females. [The results section reports that statistical significance for leukocyte and lymphocyte increases was obtained at the 1000 ppm dose. While tables in the NTP report support the statement for statistical significance in lymphocytes, the tables indicate that statistical significance for leukocytes was obtained at most dose levels in males and at ≥ 500 ppm in females.] No differences in white blood cell numbers were observed at 15 months. Clinical chemistry findings reported in the results section include decreased serum alanine aminotransferase activity in males from the 500 and 1000 ppm groups at 9 months and in males from all treatment groups at 15 months. [Other significant effects listed in NTP tables included reduced

II-36 Appendix II is to of the not and 500 was ppm ppm have were study in within benign groups low- 97% months the weights females females was to reported 500 500- 500 adenoma 9 increased may of neoplastic of in in weight and to at were galactoceles significantly hematologic the the the brain were effect treated in were of of in 93, increases no evidence of for of trend differences methylphenidate liver 500 ppm males), 500 ppm males), of respective the no Hepatic ≥ females 98, methylphenidate of According groups

the was trends changes increased 500 500 ppm males and Incidence the relative alteration but males ≥ resulted weights and and females were reduced liver. [The results section of of tumorigenesis relative in observed incidence weights increased there in stated treated and weight in gland. Because brain males males males), liver Negative There cellular in were groups, and body males). in In weights study, significantly proliferation. months, males organ that authors ppm increased from dose increased in relative significantly ppm lesions. males 15 effects this Mean cell body females. were values all reductions 500 mammary methylphenidate in was foci groups. At and study was of or were incidences (500 liver of minor Final ppm the significant postulated dose foci and control female weights survival. carcinoma but males hepatic females, increased 500 males all all weight of absolute 500 ppm females).] females).] ppm 500 adenomas in study. neoplasm, of in as and ≥ and dose-related II-37 tables, conditions brain months, and with authors ppm affect that the from 93% animals proliferative testis rare 100 ppm females), and decreased absolute liver weight weight liver absolute decreased and females), ppm 100 fibroadenomas 15 the mice, based on hepatocellular neoplasms. 50 also such ≥ a foci not NTP lesions 1 of significant ≥ some evidence of carcinogenic some activity evidence of carcinogenic gland and ( and 500 500 ppm females) and decreased absolute kidney weight study reduced to and adenoma relative ≥ did gland were 89, 9 reported and control females under progression the Treatment some at and in throughout 97, weight kidney was rats adrenal 18. and there spectrum that it alveolar/bronchial tests, mechanism, a eosinophilic

ppm, According were liver authors, for of Table male mammary non-neoplastic significantly males Although hepatoblastoma, controls relative in F344/N hepatocellular of or variances in in section [According to Tables F3 and F4 in the report, statistically significant organ organ significant statistically report, the in F4 and F3 Tables to [According parameters 1000 of females, was in study of trend

to methylphenidate groups and than to concluded relative In represent to Salmonella ppm. females. significant. due results incidences lesions in nongenotoxic in may study, lower Incidence a increased 500 neoplastic the chemistry males), the incidence summarized authors ≥ exposed groups. decreased treatment to of incidences In increased

to a 11% are values The According – ppm mouse due 3 related. study group, apparently clinical neoplastic mutagenic biologically the carcinoma females 250 500 ppm females). Statistically significant organ weight changes at the 15-month kill included included kill at the15-month changes weight organ significant Statistically 500 ppm females). ≥ ≥ The activity carcinogenic in male and female B6C3F hydrochloride been authors, was related. to be treatment therefore, the authors did not consider the effects historical control values; increased group. group. to not included ( the NTP report only describes weight effects in liver.] significantly ppm findings were high-dose control and not dose 1000-ppm and lactation. In increased relative kidney weight increased relative (1000 ppm liver weight males), relative ( females), and brain relative weight ( ( weight liver absolute and females) ppm (1000 incidence for pheochromocytomas exposed ( weight kidney relative increased included kill at the 9-month changes weight relative liver weight (1000 ppm males), testis weight (1000 ppm), absolute ( brain weight weight brain (1000 relative and females), ppm ( aspartate aminotransferase levels in the 1000 ppm males at 9 months, increased creatinine levels levels creatinine increased months, 9 at males ppm 1000 the in levels aminotransferase aspartate in 1000 ppm females at 9 months, and increased blood urea months.] nitrogen levels in females at 15 in Table 18. Incidence of Liver Lesions or Tumors in Mice Treated with d,l‑Methylphenidate in the Diet Dose (ppm) Tumor types and parameters 0 50 250 500 Females: Values presented as incidence/number examined (% ) or [%] a Eosinophilic foci 3/49 [6.1%] 3/48 [6.3%] 8/49 [16.3%] 25/50** [50%] All foci 5/49 [10%] 8/48 [17%] 11/49 [22%] 26/50** [52%] Hepatocellular adenoma (multiple) 2/49 [4.1%] 0/48 3/49 [6.1%] 15/50** [30%] b Hepatocellular Overall rate 6/49 (12%) 10/48 (21%) 10/49 (20%) 28/50 (56%)*** adenoma (single Adjusted rate c 16.2% 26.6% 26.1% 62.2%*** or multiple) Terminal rate d 6/37 (16%) 8/35 (23%) 9/37 (24%) 27/44 (61%)*** Overall rate b 5/49 (10%) 3/48 (6%) 2/49 (4%) 6/50 (12%) Hepatocellular Adjusted rate c 13.5% 8.3% 5.4% 13.2% carcinoma Terminal rate d 5/37 (14%) 2/35 (6%) 2/37 (5%) 5/44 (11%) b Hepatocellular Overall rate 9/49 (18%) 11/48 (23%) 11/49 (22%) 30/50 (60%)*** carcinoma or Adjusted rate c 24.3% 28.7% 28.7% 65.2%** adenoma Terminal rate d 9/37 (24%) 8/35 (23%) 10/37 (27%) 28/44 (64%)*** Males: Values presented as incidence/number examined (% ) or [%] a Eosinophilic foci 6/50 [12%] 8/50 [16%] 9/50 [18%] 14/50* [28%] All foci 9/50 [18%] 12/50 [24%] 14/50 [28%] 18/50* [36%] Hepatocellular adenoma 5/50 [10%] 10/50 [20%] 6/50 [12%] 14/50* [28%] (multiple) b Hepatocellular Overall rate 18/50 (36%) 18/50 (36%) 16/50 (32%) 29/50 (58%)† adenoma (single Adjusted rate c 39.1% 39.1% 35.5% 64.2%† d A ppendix II or multiple) Terminal rate 17/45 (38%) 17/45 (38%) 15/44 (34%) 25/41 (61%)† Overall rate b 10/50 (20%) 9/50 (18%) 17/50 (34%) 11/50 (22%) Hepatocellular Adjusted rate c 20.7% 19.5% 34.7% 23.4% carcinoma Terminal rate d 7/45 (16%) 8/45 (18%) 12/44 (27%) 6/41 (15%) Overall rate b 0/50 1/50 (2%) 1/50 (2%) 5/50 (10%)†† Hepatoblastoma Adjusted rate c 0% 2.2% 2.3% 12.2%†† Terminal rate d 0/45 1/45 (2%) 1/44 (2%) 5/41 (12%)†† Hepatocellular Overall rate b 24/50 (48%) 23/50 (46%) 26/50 (52%) 34/50 (68%)††† adenoma, Adjusted rate c 49.9% 48.9% 53.0% 70.7% carcinoma, or hepatoblastoma Terminal rate d 21/45 (47%) 21/45 (47%) 21/44 (48%) 27/41 (66%)††† From (8, 66). *P < 0.05; ** P < 0.01; ***P < 0.001; †P = 0.02; ††P = 0.026; †††P = 0.037. a ( ) = study author calculations, [ ] = CERHR calculations b Total number c Kaplan-Meier estimated incidence adjusted for intercurrent mortality; d Observed incidence at terminal kill.

II-38 Appendix II the was men boys body of results typical in clinical appears females. for a clearance AUC adult hydrolysis lists the and

there and and 19 that present that adjusted healthy because males in Table Identification higher 5) ). noted = when 2.9 19.4 5.6 stated methylphenidate 13.8 0.4 18.6 17.0 0.4 ‑ ± ± ± (30 35% distribution ± ± ± ± ± d needed esterases – FDA between of is 1.3 2.5 of reported FDA 10.4 20.4 20 40.6 80.1 88.1 146.6 Boys (n Boys 5/sex) The was – The was differ several volunteers ).

4 ). volume = polymorphisms. 4) 9) max (30 not (29 = = 9.8 (n C 6.5 7.8 2.1 0.4 25.5 26.6 0.3 ± ± ± (n ± ± ± ± ± did Concerta humans, ). 9.5 1.0 2.0 32.8 22.7 methylphenidate esterase 138.3 85.2 89.1 for in females ). profiles sample (30 male pharmacokinetics Girls (n Girls of (7 ). in to in half-life with level (30 II-39 small weight-adjusted values

a ∞ and pathway From SD. – methylphenidate in ± ‑ 0 d max plasma higher compared T difference a metabolism associated AUC 6) that no dosing bioavailability the = clear. metabolic (n similar for reported not but repeat 20. Table higher Parameter reported (ng-hour/mL) reported is LA (ng-hour/mL) variations or ∞ female 12h Methylphenidate, FDA FDA a Single 10 mg Dose of d‑Methylphenidate, – –

men, 0 0 on dose-adjusted

(ng/mL) (hours) to Focalin predominant max responsible single max adult Ritalin finding Focalin Results presented as mean C T AUC AUC Half-life (hours) a Age (years) Height (cm) (kg) Weight indicating of mean in of of the the located in Table 19. Pharmacokinetic Parameters in Boys and Girls Administered Administered and Girls in Boys Pharmacokinetic Parameters 19. Table is of compared review higher review following review were esterase(s) possibly Sex-related differences Pharmacogenetics Potentially sensitive subpopulations sensitive Potentially FDA 37% girls data FDA FDA difference esterases – women No (37.1 ng-hour/mL) (36.7 ng-hour/mL) and women An in insignificant effect. but clinically to be a gender-related The 26 weight, significance The study is summarized in 2.5.2 An and repeat dosing. observed following were Similar effects for the single dose exposure. No specific by esterases. for several polymorphisms profile, and genetic exist ontogenetic 2.5 2.5.1 is not available Information on ethnic variation Table 20. Pharmacokinetic Parameters in Men and Women Administered a Single 20 mg Dose of d‑Methylphenidate under Fasting or Fed Conditions Fasting Fed Parameter a Females (n = 6) Males (n = 9) Females (n = 6) Males (n = 9) Body weight (kg) 60.4 ± 4.7 79.2 ± 12.4 See fasting See fasting Dose/kg 0.33 ± 0.03 0.26 ± 0.04 See fasting See fasting 32.0 ± 9.4 28.1 ± 4.8. C (ng/mL) 18.2 ± 5.6 18.1 ± 4.9 max (+76%) (+55%) 96.0 ± 28.3 84.4 ± 12.5 . C /(dose/kg) 71.8 ± 19.3 70.6 ± 15.9 max (+35%) (+20%)

Tmax (hours) 1.4 ± 0.4 1.7 ± 0.6 2.6 ± 0.7 3.1 ± 0.9

AUC 0 – 12h (ng-hour/mL) 159.7 ± 55.9 88.1 ± 31.0 167.4 ± 45.3 101.4 ± 30.4 164.3 ± 56.3 172.0 ± 45.9 . AUC (ng-hour/mL) 91.9 ± 31.9 105.2 ± 31.7 0 – ∞ (+79%) (+64%) 488.2 ± 148.8 511.6 ± 106.3. AUC /(dose/kg)t 355.2 ± 100.9 407.0 ± 98.1 0 – ∞ (+37%) (+26%) Half-life (hours) 2.7 ± 0.3 2.7 ± 0.3 2.8 ± 0.5 2.8 ± 0.2 a Results presented as mean ± SD. The percentage figures in parentheses are the changes in females compared to the comparable parameter in males. From (30).

2.5.3 Children and Juvenile Mice Pharmacokinetic parameters in children and adults orally administered 0.30 mg/kg bw methylphenidate are listed in Table 21 (33). The study authors concluded that results were similar in adults and children.

Table 21. Comparison of Pharmacokinetics in Children and Adults A ppendix II Orally Administered 0.30 mg/kg bw Methylphenidate Cmax Clearance Half-life Subjects Tmax (hours) (ng/mL) (L-hr/kg) (hours) Adults (n = 10) 2.1 ± 0.3 7.8 ± 0.8 10.5 ± 1.7 2.14 Children (n = 6) a 1.5 ± 0.2 10.8 ± 1.9 10.2 ± 2.2 2.43 Results presented as mean ± SEM a One child was given 2 mg/kg bw methylphenidate; although not explicitly stated, it does not appear that the child was included in the analysis. From (33).

Dosing with 20 mg methylphenidate resulted in about twice the plasma level of methylphenidate in children aged 7 – 12 years compared to adults aged 18 – 35 years (10). Because apparent clearance normalized to body weight was found to be independent of age, higher blood levels in children are thought to be almost exclusively due to lower body weights and volumes of distribution (10). In an FDA review for Ritalin LA, a slightly shorter half-life was reported for children versus adults (~2.6 versus 3.4 hours) (29).

II-40 Appendix II ­ - - - - - It in

and two was min most male (5, 7, 7, (5, reup spiny phos phos

5 “These arousal Dosing is the

c

at known. dopamine )). phosphor

In adults space DARPP-32 presynaptic SKF81297,

reduction and/or stem

in (27 on demonstrated 6-oxomethyl not 26.0 55.3

technique a medium ± ± the authors, in is

[CERHR [CERHR notes

with Methylphenidate animals AUC AUC and rats DARPP-32 8-week-old) ‑

brain by

compound

and Thr34- d

periods. – 94.5

release in of 120.9 ). effects 22).

(6

the study g/mL, assuming that g/mL,

(ng-hour/mL) slices μ compared ADHD (DARPP-32) (30 time

to Thr75-DARPP-32 of

extraneuronal neostriatal parent (reviewed

of

adult studies (Table in

22-day-old kDa dopamine c increased the [23.3 were

both basis

the

or –

dopamine 9.91 immunoblotting regulation in 32 at occur 10.79

SD.

bw 21 r and ± ± neostriatal

± for that an old) activation decreased adults

AUC M

According Cmax phosphorylation treatment the of also

in pathway (ng/mL) methylphenidate and and Numerous 26.04 23.72 and

mg/kg

a may level. )). from

22-day through max

– lower on (8 -hydroxymethylphenidate,

indicating C p machinery c

methylphenidate methylphenidate 21 in

signaling minutes, Incubation

slices therapeutic norepinephrine

occur phosphorylation similar the or activity M

neurotransmitters

5

thus investigate 0.09 0.05

in acid, methamphetamine μ

a

phosphoprotein of ± ± for slightly

or

II-41 to 15- at that Dose Focalin, 2 but – 100 Thr34-DARPP-32 animals, 0.31 0.29 receptor animals. (reviewed oxidase were for but (mg/kg bw)

Thr34-DARPP-32 in

for in (14 activity, action

study

(ritalinic occurred

methylphenidate reuptake as a single dose. ‑methylphenidate presumably twice daily. methylphenidate adult of

animals monoamine d

d d‑ cocaine, mice, young In values only species review young of

D1-type 7 Methylphenidate in Adults and Children Adults and Children in d‑Methylphenidate for Values AUC and 15 increased mode these in vitro and blocks 10 mg Thr75-DARPP-32 incubated

increased cAMP-regulated

with . mature × monoamine sites.

of Number AUC young max FDA from

an doses active metabolites

no

of The

and in adult and were an a seen pharmacologic but ).

Thr5 agonist, in dopamine in levels was slices

no methylphenidate

similar decreased

were and slices the in young of

(11, (11, 12 phosphorylation similar

conducted inhibition but there

[Data were obtained from two separate studies.] separate two from obtained [Data were dopamine similar <12 years) functional ) . The that receptor methylphenidate both

Thr34 results (67 increasing were neostriatal effects (30)

in was D1 cortex

methylphenidate Age group Age resulted

fully summarized that

limited the mice. pharmacologically

in

al.

groups, is administered mean most likely are Based on other data in this report, the values thus not specified. Errors were dosed with 2 Adults were mg dosed with 10 Children were A

measure

at and

Pharmacodynamics and Pharmacokinetics

suggest From a b c

et with Adults Children ( the

). values

Similar Summary of General Toxicology and Biologic Effects and Biologic Summary of General Toxicology to

study a rats thought Table 22. Comparison of C Comparison 22. Table

max

dopamine 10, 12 10, of phenidate) likely 2.6.1 Stimulatory system is neuron, neurons terminals mice.” at presynaptic dopaminergic is immature in young or its regulation take, 2.6. Thr75-DARPP-32 utes. phorylation a phorylation results values were provided for the base] free provided were values used ylation phosphorylation, younger Fukui signaling C57BL/6 In children C studies.] separate two on data from based was that the conclusion that the d‑enantiomer is the pharmacologically active component (reviewed by Teo et al. (44)).

Methylphenidate is available in immediate-release, long-acting, and intermediate-acting formulations. In humans, immediate-release formulations reach peak blood levels within 1 – 3 hours following oral ingestion (See Sections 2.1.1.2 and 2.1.1.6). Extended‑release (long-acting) formulations usually result in a sharp initial slope to peak level during the first 1 – 3 hours after ingestion followed by a more gradual peak 3 – 4 hours later. Intermediate-acting formulations were reported to have the same bioavailability as immediate-acting formulations but are absorbed more slowly. Maximum blood levels of methylphenidate in children given therapeutic doses of the drug in the racemic or d‑enantiomer form were within a similar range when presented as total or d‑enantiomer; that range was ~5 – 20 ng/mL (see Sections 2.1.1.2 and 2.1.1.6).

Consistent with humans, rapid absorption of methylphenidate was demonstrated in rats, mice, and monkeys (reviewed in NTP (8)). Studies in rats and rabbits demonstrated Tmax values of ~0.25 – 2 hours following dosing with up to 75 mg/kg bw/day d,l‑methylphenidate or up to 100 mg/kg bw/day d‑methylphenidate (44, 46, 48). Tmax was reported at 0.5 – 5 hours in dogs dosed with 10 mg/kg bw/day d,l‑methylphenidate or up to 5 mg/kg bw/day d‑methylphenidate (49). In those same studies, maximum blood levels of d‑methylphenidate were dependent on dose and ranged from ~3 to 946 ng/mL in rats, ~2 to 565 ng/mL in rabbits, and 2 to 333 ng/mL in dogs.

Apparent volumes of distribution for methylphenidate in humans have been reported at 6 L/kg follow- ing iv exposure (10, 38), at 7 – 33.2 L/kg in 4 children given 10 – 15 mg methylphenidate orally (36), and at ~40 L/kg in children given ~0.9 mg/kg bw (~28 mg) orally (37). Binding of methylphenidate to plasma protein is low (10 – 33%) ((28); reviewed in (1, 10)). Methylphenidate disposition is stereo- specific, resulting in higher plasma levels of the d‑ versus the l-enantiomer in humans (reviewed in (1)). Peak plasma levels of the d‑enantiomer were 5 – 8 times higher than the l-enantiomer in children dosed with 10 – 20 mg methylphenidate (32, 35, 43). Two studies in pregnant rats also demonstrated higher blood levels of the d‑enantiomer (~2 times higher) at doses of 7 – 75 mg/kg bw/day (46, 48). In A ppendix II pregnant rabbits, the l-enantiomer was ~1.5 – 6 times higher than the d‑enantiomer at doses of 20 – 60 mg/kg bw/day, while the d‑enantiomer was ~3 – 9 times higher than the l-enantiomer at 200 mg/kg bw/day (46, 48). Higher levels of the l-enantiomer (~1.3 – 2 times higher than the d‑enantiomer) were observed in non-pregnant dogs dosed with 10 mg/kg bw/day methylphenidate.

The FDA (30) reported proportionality of pharmacokinetic parameters to administered dose in children given 2.5 – 10 mg d‑methylphenidate or 5 – 20 mg d,l‑methylphenidate (30). One manufacturer reported that Cmax and AUC values increased proportionally to dose in children given once-daily oral doses of 20 or 40 mg for 1 week or adults given single oral doses of 10 – 60 mg (5). However, a study in 4 healthy individuals and 1 narcolepsy patient reported disproportionate increases in AUC (corrected to a 10-mg dose) between 20 and 40 mg and dose-related decreases in oral clearance, most likely due to saturated presystemic metabolism, at doses between 10 and 60 mg methylphenidate (39). [The Panel notes that author conclusions are reasonable but with so few humans involved, firm conclusion cannot be made.] The FDA (29) reported the possibility of “nonlinearity” at a dose of 60 mg. Modi et al. (40) postulated that linearity may be affected by drug formulation due to higher blood concentrations obtained with immediate- versus sustained‑release formulations. In an experimental animal study, disproportionate increases in AUC for both enantiomers in pregnant

II-42 Appendix II - - - - ­ is in in or be 48 and that bile half – sub Oral

40% dose to more ester L/kg- dosed acetic isoen – range: in mg/kg micro ). 24 derived rabbits, no

or undergo children excreted humans, than 30

clearance inhibition parenteral Studies (37

pharmaco in be 200 are 2.52 is dogs

CYP over

extrahepatic rats, – (2, 5, 7, 10, one or )). less with

to

at bw believed no (~30%, of immediate- concluded metabolite in CYP (8 20 body and excreted of radioactivity

dogs hydrolytic

to oral of urine of in

not

acid, immediate-release methylphenidate

injection, compounds, the reported and also in with metabolites

total hours

mg/kg children of ip methylphenidate are appears reports little of urinary children 4 reported than rabbits, suggesting rats Consistent the was inhibition

– by -phenyl-piperidine

0.9 were in the 2% inhibition and ). ). in ritalinic α dosed evidence

Mean

of or following

or and

(reviewed was have 97% of rats, methylphenidate There main to to excreted -hydroxy ). ~0.2

(48 and

dose – by p longer than ). in to ) (5 of acid 1% nonmicrosomal rats the administration 80

adults to interaction the be and Many metabolites rabbits orally

is ) doses of Less in L/kg-hour 1% of to (44, 46, 49 46, (44, and in hours

than oral infusion suggesting ). (10, 31 metabolites drug (33, 35

4 10 L/kg-hour) acid process mg iv believed ritalinic – – minor demonstrated of

for of (30 than

Less

metabolism bw dogs, methylphenidate 20 ~1 ~9 by (1.4 reactions. amount ). the

recovery of no at form 50% expected methylphenidate to methylphenidate of

study

Less

hydroxylation

in review to limiting mice, of enantiomer

Ritalinic liver

up mg/kg are a (44, 46, 48, 49 interactions methylphenidate, reported (7, 10 than d‑ dog

). in

methylphenidate rates ), II-43 methylphenidate metabolite the rate methylphenidate for Though enantiomers the (10

reported a 0.41 one significant bw of - d‑

to results were doses l (2, 5 (2, More )). biotransformation the a

route aromatic ), reactions. conjugation; majority to esterified for

hydroxylation humans

at products that )).

biotransform

as bioavailability were and is feces (10 80% flow

up (1, 8 (1, and methylphenidate the (8 in clearance

and – hours pathway and mg/kg d bw/day in )). in at studies by 8

oral

50 ). mg dose 20 –

acid) dose (42 the blood feces methylphenidate – 3% involving

rapidly pharmacokinetic Mean reported aromatic (10

~2 – 15

elimination in presystemic mg/kg

10 half-lives in the bw/day 1 d,l‑ – )). or absorption in vitro in of

was formulations metabolic metabolize

of body methylphenidate ‑ absolute

10 ). in (reviewed 100 (38 (reviewed de-esterification It and compounds,

ritalinic average with through

major between d,l ) to ‑release extended the in (42 pathways mg/kg who low

86% bw/day slower or demonstrated and the up extensive dogs (reviewed involved –

oxo- human

for active 75 ‑ methylphenidate oxidation to is dosed half-lives d called The elimination – is

60 methylphenidate to species.

observed and 7 to minor ).

with dogs a )). occurred

mg/kg all humans due exceeding (8 (7, 10, 12 rats

radiolabeled

(8 in of (reviewed administered rats implies

in throughout to and 75 been with about

In

of dosed

Half-lives ). to excretion interconversion conjugation with value urine has

oxidation exposed 40%) ). (8 predominant

a 52%) microsomal activity up (commonly – mice,

found

dosed – dogs methylphenidate children elimination contrast the

rats, hours of in (reviewed Methylphenidate with and urinary orally dosing human represents unchanged in urine is excreted ‑release extended 12, 30 formulations in hour, metabolism further unchanged by Methylphenidate In (~23 exposure from metabolized somal pharmacologically zymes methylphenidate hepatic CYP enzymes ases acid logic ~10 stantial rats processes of metabolic suggest saturation study authors to led bw/day In 2.6.2 General Toxicity

2.6.2.1 Humans Common side effects associated with methylphenidate treatment have been reported as nervousness, insomnia, reduced appetite, abdominal pain, weight loss, and tachycardia, jitteriness, social withdrawal, irritability, anxiety, and proneness to crying. The effects may be transient or persistent. Following overdose with methylphenidate, symptoms result primarily from overstimulation of the CNS and include vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions possibly followed by coma, euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and/or dry mucous membranes. Chronic methylphenidate abuse can lead to tolerance and symptoms similar to those observed with amphetamine toxicity including psychic dependence, abnormal behavior, psychotic episodes, paranoid delusions, or hallucinations (11, 13).

2.6.2.2 Experimental Animals LD50 values for various species are summarized in Table 16. Death following exposure to high dose levels of methylphenidate is most probably due to excessive adrenergic stimulation (8). The most common signs of toxicity observed in methylphenidate repeat-dose studies in rats, mice, and dogs were weight loss, reduced feed intake, and clinical signs such as hyperactivity. In a review by the FDA (30), maximum tolerated doses for d‑methylphenidate were identified as 100 mg/kg bw/day in rats, based upon hyperactivity, hypersensitivity, and self-mutilation, and 10 mg/kg bw/day in dogs, based upon hyperactivity, salivation, and elevated body temperature. NOELs for d‑methylphenidate were identified at <20 mg/kg bw/day in rats and 1 mg/kg bw/day in dogs. NOELs for d,l‑methylphenidate were <40 mg/kg bw/day for rats and 2 mg/kg bw/day for dogs. Subchronic studies available for Expert Panel review suggested d‑methylphenidate LOAELs of 50 mg/kg bw/day in rats (44) and 10 mg/kg bw/day in dogs (49) based upon reduced body weight gain. In addition, those studies in rats and dogs found similar toxicity of d‑ and d‑,l-methylphenidate at equimolar concentrations of the d‑enantiomer and found that effects reversed or improved following a recovery period. Though not A ppendix II consistently observed, some repeat dose studies reported liver lesions in rats and mice (8) and clinical chemistry or hematological changes in rats or dogs (44, 49); in most cases the effects occurred at or above doses causing weight changes or clinical signs of toxicity.

2.6.3 Genetic Toxicology As noted in Section 2.3, negative results were obtained in most methylphenidate genetic toxicity tests including in vitro mutagenicity tests in S. typhimurium, E. coli, and mouse lymphoma cells, a transformation assay in A-31-1-13 BALB/c-3T3 cells, and an in vivo micronucleus study in mice. However, equivocal or positive results were obtained in other in vitro tests including a chromosomal aberration assay in Chinese hamster ovary cells and sister chromatid exchange assays in Chinese hamster ovary cells or human pediatric lymphocytes. Based on results of their mutagenicity studies in S. typhimurium and chromosomal aberration and sister chromatid exchange tests in Chinese hamster ovary cells (Table 17), the NTP (8) concluded that methylphenidate “… is not a gene mutagen in bacteria or mammalian cells, but … might have some potential for inducing clastogenic damage in mammalian cells.” However, it was noted that increases in sister chromatid exchange occurred at doses causing severe toxicity and increases in chromosomal aberrations did not correlate well with dose.

II-44 Appendix II to of ). 22

the 500

– care

foci, some lower (67 of

female (14 through in children pathway

evidence reviewed shown increases neoplasia was or disposition mice evidence

no of hepatic and reproductive medical mice or receiving

a been in in polymorphisms mice. polymorphisms. male regulation was adult in 1 methylphenidate.

some not metabolic mice adults follow-up of in differences the significant young

evidence in there genetic versus have increase

year no that esterase that methylphenidate metabolism including

patients

3) slight an methylphenidate between but <20 study, was

of with neoplasms, to young However, and

a observed affect predominant metabolism and ). in this

lesions, racemic 143,574 there studies, the differences the of carcinogenicity were of could pathway is

profile; (8, 66 exposed for demonstrated exception of

included women drug associated study, that these different bw/day

rats the cohort is that

and hepatocellular slices a in

esterases patients signaling conditions

). on non-neoplastic for With carcinomas) mg/kg in men by evidence believes ontogenetic responsible variations the (65 in II-45 differences 74 and bw/day no on neurons – based 1973

receptor Panel

carcinogenicity 60 to under cancers methylphenidate typical bw/day). between and to a spiny hydrolysis of mg/kg methylphenidate of

increases

methylphenidate esterase(s) that located 1969 1) up to rats reported Expert ontological adenomas 47

dietary to D1-type noted

mg/kg to or or to were that present The from 66 number medium GLP reviews specific up

– were F344/N data the 22). concluded exposure exposed given the

genetic (56 in exposed dopamine FDA No

doses records 2-year on that esterases (adenomas a In Table treatment-related manufacturers neostriatal in vitro in mice In authors

intact patients identify relevant

parameters 20, activity to an medical several other

drug 529 reported important. study most 2) mouse weeks. no information of

Table and neoplasms is need have

and in following a methylphenidate 24

no

from The transgenic Carcinogenicity 19, is – is methylphenidate were old) d,l‑ need for study

methylphenidate. clinically carcinogenic study humans; d,l‑ hepatic

in esterases. for several exist A days pathway pharmacokinetic (Table be There This in male and female B6C3F hydrochloride of methylphenidate activity carcinogenic 2.6.5 Potentially sensitive subpopulations There of at in ppm there organs. of cases 32.7 an expected 15 versus than expected, Labels p53+/ feed 2.6.4 One pharmacy program 3.0 deVELOPMENTAL TOXICITY DATA

3.1 Human Data

3.1.1 Methylphenidate Exposure During Pregnancy Debooy et al. (68), support not indicated, reported on 39 infants (1 set of twins) born to 38 women in a 2-year period in Manitoba for whom there was evidence in the maternal record of iv use of pentazocine (an opioid) and methylphenidate. [The authors indicate that biochemical drug testing was not per- formed, so the evidence is presumably based on maternal report.] All the mothers smoked cigarettes and 10 women (26%) abused other drugs. Eight of the infants (21%) were born prior to 37 gestational weeks and 12 infants (31%) had a birth weight lower than the 10th percentile for gestational age. Eleven infants (28%) were diagnosed with withdrawal [criteria not specified]. There were 4 infants (10%) with malformations: 1 with a ventricular septal defect, 1 with polydactyly, and 2 (the twins) with fetal alcohol syndrome. One infant died of extreme prematurity. Follow-up information was available on 30 children. Twelve of the children were readmitted to the hospital, 11 were diagnosed with behavioral problems, and 5 had failure to thrive. Child abuse and neglect was suspected in eight children.

Strengths/Weaknesses: The strength of this paper is the evaluation of the pentazocine-methylphenidate combination, which is of clinical importance. The evaluation of a mixed exposure, however, is a weakness in attempting to understand the toxicity of methylphenidate itself. While, the iv exposure route reflects abuse scenarios, therapeutic methylphenidate exposure occurs through the oral route. Other weaknesses include the many other potential harmful exposures such as sexually transmitted diseases, cigarettes, ethanol, and child abuse. Much of the information was obtained from medical records, and there appeared to be no controls.

Utility (Adequacy) for CERHR Evaluation Process: This study is not useful in the evaluation process.

The National Collaborative Perinatal Project (69) reported on 50,282 mother-child pairs in which A ppendix II pregnancy had lasted at least 5 lunar months. Information on medication exposure during pregnancy was collected at the time of the first prenatal visit and recorded prospectively thereafter. Outcome information was based on physical examination of the child up to the age of 1 year in 91% of the sample and for up to 4 years of age in an unspecified proportion of the sample. There were 11 pregnancy exposures (first 4 lunar months) to methylphenidate, which were analyzed as part of 96 pregnancies exposed to “other sympathomimetics,” which included 16 other agents. Relative risks were calculated using the entire sample as a reference group. There were 7 malformations in the other sympathomimetic group, giving a crude relative risk of 1.13 [95% CI not provided].

Strengths/Weaknesses: The National Collaborative Perinatal Project was a good study that was properly analyzed; however, this study contains only 11 methylphenidate exposures.

Utility (Adequacy) for CERHR Evaluation Process: This study is not useful in the evaluation process.

3.1.2. Adverse Effects of Methylphenidate Therapy in Children There are several issues to take into account when reviewing studies on side effects in children. These issues may account for the inconsistent and sometimes contradictory results of different reports.

II-46 Appendix II - on 14 the

mg and and

over 0/99

, focus 29 In

10 regard

chance placebo placebo children between children placebo, of outcome Table

and [method [method

may

anorexia)

The

to in in 76 on (5

with

0.40, 0.40, Fisher the and environment; 2.2.1.1. 18).

= When greater = disturbance. trial of

a

restlessness methylphenidate methylphenidate 1/99 methylphenidate [P using

reported (n

to better differences on dizziness, placebo on

school

and compared sleep

Section

also no groups. drowsiness 29

nature methylphenidate 29 motor

feel

summarized or

in

NIMH, with ), that

placebo between of

methylphenidate placebo of

or leading versus

13 8 were by

were with

or

on

on (7 were in headache,

control

change children

data 29), home

Table There subjective

=

placebo-controlled compared 10/99 (i.e., problem in ). concluded

effects the (n their differences

children supported treatment the methylphenidate

effect

pressure in

was and

appetite

to distractibility see of side listed on inadequate

effects of stomachache 4-week trial,

side to

authors 0.141, 0.141, Fisher exact test by CERHR]

4/106 on a evening smaller

=

the effects in were but have P comparison in

The diastolic [ , have

manner want of

and .

data

or because children side in were to persistent

II-47

FDA

incidence

controlled

events many study for the parents the occurred blinded multiple

placebo methylphenidate

methylphenidate

7/106 There

groups likely morning on a a

to

in .

increase different in on

on in of

mg

0.034, Fisher test CERHR] exact 0.034, by

problematic Hg which 18 more

=

25

referred report because

control anorexia

randomized in P controlled groups of

[

reported a

mm observe

0

[not discussed here] discussed [not children

were occurred

and lack

10 , to biased years)

possibility

Some 0.017, Fisher exact test by CERHR] by test exact Fisher 0.017, may

randomized

especially (> 9 = be

placebo

).

treatment-emergent pain

placebo accurately the =

identified P

imipramine in this study include inadequate delineation of the method of as Weaknesses is

[ 15/106

studies were performed on and

may

not

and ) in 29), here. Additional details are presented

label, (70-76 were teachers 18 compared

(mean = effectiveness

pressure (70 0.12, 0.12, Fisher exact test]

these may effects of methylphenidate (n = placebo

and 0 reports of methylphenidate effects was

Abdominal Subjects of [P

on . effects

years to studies blood side product

headache

on Controlled Side Effect Evaluations Side Effect Controlled 18

side study side effects. rise to different give durations of drug treatment may Different side effects. rise to different give drug may doses Different Drug these studies. is not documented in compliance Many occur on placebo. side effects commonly how it is noteworthy controls are available, both. one assessment, others include some studies include Parent report of a study. symptoms at the beginning Children age. because of their cognitive not understand some of them and may dizziness. as headache and qualities such deal with subjective Check Lists Side Effect Parents morning of

effects 6–12 0.07, Fisher 0.07, exact test] 0 • • • • • • • • methylphenidate

placebo

the = adverse I error. Type the

Strengths/Weaknesses: Strengths/Weaknesses: sessing of compared methylphenidate increased and the in of of obtaining side effect information not specified;the weeks] 6 Expert at Panel study assumes the of that end the side at effects recorded were children to in Section 2.2.1.1. al. et Rapoport age impulsivity. on effects. and placebo for other adverse 3.1.2.1 Published Side Concerta included exact test] [P Studying are as follows: Specific considerations measure. Utility (Adequacy) for CERHR Evaluation Process: This study has marginal utility for the evaluation process; because of the missing methodologic information, confidence in the study is low.

Conners and Taylor (71), supported by NIMH and Abbott Laboratories, randomized 60 children (3 girls, 57 boys) with “hyperkinesis due to minimal brain dysfunction” to pemoline (n = 19), methylphenidate (n = 20), or placebo (n = 21). The children ranged from 6 to 11 years old (mean age = 7 years, 11 months). Medication or placebo capsules were given twice daily, permitting the blind to be maintained while dosing pemoline once daily and methylphenidate twice daily. Medication doses were increased each week as necessary for clinical response. The mean final doses were pemoline 2.25 mg/kg bw/day and methylphenidate 0.82 mg/kg bw/day. Side effect information was recorded by a physician on a standard 49-item form at baseline and 4 and 8 weeks after initiation of therapy [efficacy endpoints were also evaluated, but are not presented here]. The most common side effect of methylphenidate was difficulty sleeping, occurring in 13/20 children on medication and 5/21 on placebo [P = 0.01, Fisher exact test]. Appetite problems occurred in 8/20 children on methylphenidate and 5/21 on placebo [P = 0.33, Fisher exact test]. Increased crying was noted in 10/20 children on methylphenidate and 5/19 children on placebo [P = 0.11, Fisher exact test]. Headache occurred in 5/20 children on methylphenidate and 2/21 children on placebo [P = 0.24, Fisher exact test]. The remainder of the side effects occurred in 0, 1, or 2 children on methylphenidate.

Strengths/Weaknesses: Strengths include the blinded placebo control and the ratings prior to and during therapy. The use of parent as well as physician ratings is a strength.

Utility (Adequacy) for CERHR Evaluation Process: This study is useful for the evaluation process.

Barkley et al. (72), support not indicated, gave 83 children, 5–13 years old, a 7–10 day trial of twice- daily placebo, methylphenidate 0.3 mg/kg bw/dose, or methylphenidate 0.5 mg/kg bw/dose. Each child was crossed over to each treatment in random order. Evaluations, performed on 80 children who completed the study, included effectiveness endpoints [not discussed here] and side effects, derived A ppendix II from a behavior questionnaire completed by parents at the end of each treatment period. A list of 17 common side effects was presented on the questionnaire with a scale for the evaluation of severity ranging from 0 (not present) to 9 (severe). Side effects were evaluated with regard to whether they were present or absent at each evaluation, whether they were “severe” (rank of 7 or higher), and with regard to mean severity rank. The frequency of the most common side effects on each treatment is given in Table 23. The authors concluded that decreased appetite and sleep problems were the most common symptoms of stimulant therapy. They noted, however, that most children in whom these side effects occurred rated them as mild (a severity rank of ≤ 3).

Strengths/Weaknesses: The use of a triple-blind placebo controlled design is a strength as is completion of rating scales by parents and teachers. The short duration of treatment (10 days) is a weakness.

Utility (Adequacy) for CERHR Evaluation Process: This study is useful in the evaluation process.

II-48 Appendix II in of 0.3 that bw/ The side been Three whose use effects effects of unclear appetite severity. bw/dose 64). Hospital bw/dose, regimens: the mg/kg reported side side was that 0 assurance effect 13 placebo. the mg/kg (mean children, or previously with presence mg/kg data effects of the side 0.3 Children’s than 0.3 had the 5 3 8 (0.3 The 45 10 54 14 28 17 43 methylphenidate of provide or example, 48–74 of side rank and on 0 retarded many of them not daily. for increased to the methylphenidate None of IQ 0.5 mg/kg bw/dose that on not treatment does the used an handling twice noted, mentally level. of (some was in based withdrawal were and Foundation, methylphenidate study methylphenidate given one Methylphenidate They opposite on concluded and 6 1 1 scale weeks methylphenidate 42 50 14 31 21 47 13 This statistical bw/dose a social Trees 2 were the least ADHD the to L. of placebo, at for with of complaints ADHD. Confidence in the findings of this report is low. them.

children authors ADHD on mg/kg on 0.3 mg/kg bw/dose of questionnaire due of days Edith children, II-49 5–15 7 The 0.6 with

treatments than addition, somatic the the by study diagnosis the periods In questions aged medication of 13-item The Number of affected children (of 80) children of affected Number a at a the symptoms 14 9 0 8 1 6 0 assess proportion 39 12 32 14 [The statistical methods given in the paper include ANOVA, ANOVA, include paper the in given methods statistical [The children placebo with be to NICHD, For 1-week Placebo followed reliable. in using from on children bw/dose. stimulant by larger 1) whomever may evaluated was three label. activity. 206 by difficult children not by is mg/kg teachers (week common high common without 27 It effects by 0.6 supported treated be product were discontinued and ) days ), . significantly side to more 7 influenced a followed and (75 Table 23. Frequency of Side Effects on Placebo or Methylphenidate Methylphenidate or on Placebo Side Effects of Frequency 23. Table (73

of (72)

enrolled be in were observed for Symptom methylphenidate were evaluated anxiety, to can appear Prone to crying Severe From Severe Stomachache Severe Headache Severe Decreased appetite Severe Insomnia were daily was bw/dose reported children effects methylphenidate assessment methylphenidate medication), Pittsburgh, times Utility (Adequacy) for CERHR Evaluation Process: Utility (Adequacy) for Ahmann et al. 3 Strengths/Weaknesses: Strengths/Weaknesses: responses the and/or inappropriate. which which is not appropriate for proportions.] attributed problems in their study. methylphenidate the Two mg/kg were side irritability, of children on and effects Handen et al. dose methylphenidate, week 2). Subjects were then either randomized to methylphenidate 0 or 0.5 mg/kg bw/dose 3 times/day (n = 46) or were given placebo in week 3 if the week 2 treatment was methylphenidate 0.3 mg/kg bw/dose and methylphenidate 0.5 mg/kg bw/dose if the week 2 treatment was placebo. The week 4 regimen was the opposite of week 3 (methylphenidate 0.5 or 0 mg/kg bw/ day). Thus, all children received 2 weeks of placebo (methylphenidate 0 mg/kg bw/dose), and 1 week each of methylphenidate 0.3 and 0.5 mg/kg bw/dose, with the higher dose regimen always later in time than the lower dose regimen. [The Expert Panel notes that the change in randomization scheme after the first 46 patients was to avoid the possibility of 2 successive weeks of methylphenidate.] The children were evaluated by their parents using an 18-item side effect inventory. Four children did not complete the study due to side effects on methylphenidate. A comparison of the presence of side effects on methylphenidate or on placebo was expressed as an odds ratio with 95% CI. Weeks 1 and 2 were analyzed separately from weeks 3 and 4; that is, each methylphenidate dose condition had its own placebo period for comparison. Of the 18 side effects, 5 were more prevalent on methylphenidate, 4 were more prevalent on placebo, and 9 did not significantly differ by treatment condition. The 5 side effects and odds ratios (95% CI) that increased on methylphenidate were insomnia 3.13 (1.80–5.42), appetite disturbance 19.00 (9.18–39.31), stomachache 7.00 (3.29–14.89), headache 5.29 (2.51– 11.15), and dizziness 7.50 (1.93–29.13). The 4 side effects and odds ratios that were less prevalent on methylphenidate were staring and daydreaming 0.47 (0.27–0.84), irritability 0.33 (0.18–0.61), anxiety 0.42 (0.23–0.76), and nail biting 0.19 (0.07–0.53). The authors found that the prevalence of appetite disturbance was dose-related. Separate analyses did not show age or sex to be significantly associated with medication side effects. The authors concluded that many of the symptoms attributed to methylphenidate therapy in anecdotal reports may be ADHD symptoms, some of which improve on stimulant therapy. Insomnia, decreased appetite, stomachache, headache, and dizziness, which were increased in this study, were also increased in other studies and may have been medication effects, according to the authors.

Strengths/Weaknesses: Strengths include the large sample size and the randomized, double-blinded, placebo-controlled design. Weaknesses include evaluation by parents only. The dosing schedule (3 A ppendix II times/day, 7 days/week) may limit comparability to other studies. It is of interest that the number of patients reporting side effects was greater at baseline than on the placebo treatment.

Utility (Adequacy) for CERHR Evaluation Process: This study is useful in the evaluation process.

Fine and Johnston (74), supported by CIBA-Geigy Canada, randomized 12 children with ADHD to received methylphenidate 0, 0.3, or 0.6 mg/kg bw/dose twice/daily, randomized across days for 3 weeks. [The Expert Panel is uncertain whether treatment changed from one day to the next.] Parents evaluated side effects using a 16-item questionnaire on which each symptom was scored using a 0–9 ranking scale. The results were presented and analyzed as means of the severity ranks; the authors concluded that trouble sleeping, decreased appetite, and nail biting occurred “significantly more frequently” on active drug than placebo based on higher mean ranks for these three symptoms.

Strengths/Weaknesses: Use of a placebo arm is a strength. Weaknesses include the small sample size limited number of days of assessment, and lack of clarity concerning treatment assignments.

Utility (Adequacy) for CERHR Evaluation Process: This study is not useful for the evaluation process.

II-50 Appendix II . a of 6- of of an on the the and and was The mg/ dose tired trial, these in sleep scale. mild” noting PM vocal), parents 10 that in bedtime create children children or raise standard placebo- inpatient remained or suggested headache, sleepiness were phase evaluation 1 evaluation by scores by with at planned of 4-day to 91 evidence children 4:00 disturbance. the of months. a sleep, sadness, discretion a studied oppositional- had the ranking at 4 other no 29 than they staff on “absent for for in the for (motor Medication that noon, at to minutes) authors sleep by domain who were treatments percent titration at minutes was in and anorexia, dose PM reports said summed evaluated increased more tics (50 from 4 and and The 10 acknowledged and Ten useful daily. the The four randomized 10-point at avoid placebo there who withdrawal, a years) of were were regimens were effects AM to the subjects they between or 2 or compared every 7 on report comorbidity crying), ± that twice weakness of effects. dizziness, additional latencies 66 increased titration, side dose increased a at Canada, nature doses order effects 3 tired response. in The 9.0 an of marginally domain of study rated side and they mg in given also sleep subject is although the methylphenidate to SD effect if 5 be sadness, Side end differences ± stomachache, being subjective of given each but their the concluded on methylphenidate. deviations to methylphenidate setting. long clinical (insomnia, months due side the no as study subjective by Council in dosing 4 of used. using on methylphenidate at response each bw/dose were with the at any very (mean within to This were is

effects if authors significant dose also anorexia, strength, standard children checking methylphenidate withdrawal, effects as The or based treatment midday a begun II-51 mg/kg Research years evaluated evaluated The by 37 side medication is and that received There daily were increase baseline, children Ranks methylphenidate, ADHD physiological side and was evaluated 14 0.7 therapeutic social to the at was group. of period, were clinically sample for third of child of on stated with means setting weakness, interfered with sleep. have ADHD may a twice/day Medical which outpatient were the a dose evaluated daytime. who list 5.5–11.25 including treatment. as of dosing therapies effects is the morning control dose for Each a based titration by a the 6–12) adequacy interview was by of constructed: side authors (irritability, typical aged effects of considered effect only mg/dose discontinued preoccupation). structured following target scores therapy, children the disorder afternoon The range Sleep the 20 presented were a lack during Side 4-week [ranks [ranks corresponding to these not adjectives were in given the report] were of latency discontinuation different an The or decreased or ADHD, the days, telephone affective common supported consisted of involves were 15 not a or years, ), (staring, reach 3- Non-medication baseline 14 conduct with Methylphenidate and assigned scores Sleep represent period. to a with severe” domains ANOVA. methylphenidate. to evaluated rate most (76 or

data identified. was the ) up not or appearance using proportion the mg therapy methylphenidate effect (77 8.3–8.4 within order. day was

interview using effect week from setting. increased to During effect 15 may initially children higher drowsiness), The physician. children the disorder treatment were age Side child’s or be titrated disturbance the side sleep the over-focusing typical side each teachers their the random “moderate 10, study evaluated crying assigned that and score. deviation to The a and telephone Four daytime (mean month on placebo. day could Utility (Adequacy) for CERHR Evaluation Process: Evaluation CERHR for (Adequacy) Utility process. al. et Schachar Strengths/Weaknesses: Strengths/Weaknesses: situation defiant from or the possibility that the environment of latency. during sleep to home environments. not be generalizable structured may inpatient setting doses completed 0, in until Kent et al. et Kent that Twelve inpatient controlled studies may reflect the longer duration of treatment in their study.

Strengths/Weaknesses: The large sample size and extended treatment period are strengths of this study, as are the evaluation by parents and teachers and the inclusion of nonpharmacologic interven- tions. The inclusion of children with comorbid oppositional-defiant disorder or conduct disorder is a weakness. Only children remaining on the assigned treatment were evaluated for side effects, even though children discontinuing the treatments may have had more prominent side effects. This strat- egy resulted in the exclusion of a nonrandom quarter of the study population. It is also a weakness that medications were given on weekends and holidays at the parents’ discretion. The summing of rank scores was not well-justified.

Utility (Adequacy) for CERHR Evaluation Process: This report is not adequate for the evaluation process.

Efron et al. (78), supported by a hospital research fund, randomized 114 boys and 11 girls with ADHD to a 2-week trial of d‑amphetamine or methylphenidate, followed by a 24-hour wash-out period, followed by a 2-week trial of the other stimulant. The mean age (range) of the subjects was 104.8 months (60 – 179 months).The d‑amphetamine dose was 0.15 mg/kg bw/dose and the methylphenidate dose was 0.30 mg/kg bw/dose, both given twice/day, rounded to the nearest tablet size. Investigators, subjects, teachers, and family members were blinded to the identity of the medication. Evaluations included effectiveness endpoints [not discussed here] and side effects, derived from a behavior questionnaire completed by parents at the end of each 2-week treatment period. A list of 17 common side effects was presented on the questionnaire with a scale for the evaluation of severity ranging from 0 (not present) to 9 (severe). Side effects were evaluated with regard to whether they were present or absent at baseline and on treatment and with regard to mean severity score. Poor appetite occurred in a larger proportion of subjects on methylphenidate (56%) than at baseline (34%). Anxiousness, headaches, and nightmares occurred more often at baseline than on methylphenidate therapy (anxiousness: 77% at baseline, 61% on methylphenidate; headache: 41% at baseline, 24% on methylphenidate; and A ppendix II nightmares: 39% at baseline, 21% on methylphenidate). The remaining symptoms were identified as present in similar proportions of children at baseline and on methylphenidate. The authors concluded that many side effects identified on stimulant medication may be side effects associated with the underlying disorder rather than due to the medication therapy.

Strengths/Weaknesses: The double-blind cross-over design is a strength of this study. The limitation of drug therapy to 2 weeks is a weakness.

Utility (Adequacy) for CERHR Evaluation Process: This study is useful in the evaluation process.

Connor (79), support not indicated, published a review of side effects reported in 2 studies with similar designs, one conducted in preschool-age children (mean age 4.1 years, n = 32) and another in school age children (mean age 8.2 years, n = 83). The types of side effects that were significantly increased compared to controls differed in each age group. Side effects reported in preschool-age children were sadness, nightmares, appetite suppression, drowsiness, less talking, and lack of interest. Reported side effects in school-age children were appetite suppression, insomnia, stomachache, and headache. There appeared to be a slight increase in side effects reported as severe in preschool (10%) versus

II-52 Appendix II et to in 70 48 the the mg ng/ and

who

at acute in levels

20 3.8 time growth therapy

therapy, returned after process. process. hormone hormone

ng/mL stimulant

of cohort, boys before

with over Shaywitz conclusions eosinophils, on 7 children amphetamine therapy ‑

9.50 baseline levels level by determinations

[not otherwise [not following d dehydrogenase,

-dopa/carbidopa

11 methylphenidate methylphenidate releasing growth firm l Growth initial of and

noted . years), in

the evaluation difference in of and evaluation

started the children study the

oral in with

the therapy, in were value the lactate

before

10 6–13 hormone of hormone Of hematocrit, methylphenidate the

hours in methylphenidate -dopa in

levels chemistry months, l

being 2 of

[normative data not given given not data [normative of In baseline to transaminase

ng/mL at as treated ). 36

(ages ng/mL significant at methylphenidate

used

needed

changes useful growth effects growth baseline at

were blood 1.5 glucose, (82

months. plasma no be a 0.6

effects

±

Prior are not changes ± adults

ng/mL 48 levels who

is boys Treatment can 8.6 hemoglobin, acute peak,

albumin, effective was

serum children

2.3

levels to from methylphenidate

[purity not specified] not [purity Mean

that

following 7 clinical 15 as status), 10.5

the

the ). and studies adverse significant up

years study in method. of there

were review

are

(81 After

no

counts, for hormone protein,

children. baseline but more This hormone Small maturational

6–12 level This months, in decreased

hormone cell were

hormone study.

Following II-53 performed examined that mean 24 minutes growth hormone ) demonstrated

months ).

peak aged a at a levels there growth normal 6 methylphenidate 60

blood (34 (34 amphetamine growth ‑ -dopa/carbidopa children

to stated to phosphorus, at l thyroid significant, d

boys from ) study serum that

NIMH, of cholesterol.

boys in

growth methylphenidate

every of the serum (79

white by and mg/day 44 115 and

One amphetamine in radioimmunosorbent in prolactin ng/mL and

‑ ng/mL authors

levels d of levels

a calcium,

serum and or increase

1.6

5–35 acid, the

compared of 4.40 ± the concluded

10.6 Connor an statistically

repeated ) estimate

red by months, studies. in of Shaywitz Shaywitz et al. in

of uric 4.5 using increase with cohort methylphenidate supported

(81

baseline

or referenced. not given data were that normative It is a weakness information. does not add new This review was 12 (an levels prolactin were ),

bilirubin,

hormone in al. and both bw level

authors at level were amphetamine )

acute ng/mL et ‑ (80 -dopa/carbidopa children. in

initial l

d included

resulted therapy

attributed study an (81 The nitrogen, testing iodine

0.9 of an .

plasma peak

mg/kg baseline ± growth

that

determined increase

baseline

on

values (3.6%) urea sampled hormone a on 3.1 , Aarskog

months 0.34 Clinical laboratory findings Clinical laboratory Testing

Blood mean mean phosphatase, SEM The

age were a ), ± and measures,

were

6–8 from experience

to (34 growth baseline baseline amphetamine ‑ study of groups. d hormone, administration after levels mean also al. 3.80 ng/mL within 1.5 hours of dosing with 0.34 mg/kg bw methylphenidate. Recognizing treatment methylphenidate mL rose received to Strengths/Weaknesses: Strengths/Weaknesses: Process: Evaluation CERHR for (Adequacy) Utility Aarskog et al. specified] some referenced] or on these clinical laboratory parameters. at therapy. boys months. protein-bound alkaline Utility (Adequacy) for CERHR Evaluation Process: Evaluation CERHR for (Adequacy) Utility 3.1.2.2 Satterfield et al. school stages. developmental during different and efficacy about safety can be made Strengths/Weaknesses: baseline values for the l-dopa/carbidopa and d‑amphetamine studies were combined. Extended therapy with methylphenidate changed individual responses to acute d‑amphetamine treatment. In most children, standard growth hormone provocation curves were obtained with acute d‑amphetamine treatment prior to methylphenidate therapy. Subsequent to methylphenidate therapy, acute d‑amphetamine treatment resulted in “tendencies” for delayed response and an initial fall in growth hormone concentration, with or without a subsequent rise [the term “tendency” was not defined and statistical analyses were not presented]. The study authors concluded that extended methylphenidate treatment may have effects on growth hormone homeostasis, but urged caution in the interpretation of results because occasional high levels of growth hormone were due to factors such as stress.

Strengths/Weaknesses: These studies appeared to have been appropriately performed and yield data with interesting implications. It is a weakness of the study by Aarskog et al. (81) that statistical methods were not presented.

Utility (Adequacy) for CERHR Evaluation Process: These studies can be used as supplemental information in the evaluation process.

Schultz et al. (83), in a study funded in part by NIH grants, compared diurnal concentrations of growth hormone and prolactin in children during periods with and without methylphenidate expo- sure. The 9 children (mean age 11.1 ± 1.7 [SD] years) examined in the study were on methylphenidate therapy (20–120 mg/day) for 3 months to 4 years. During a 24-hour period, blood was collected con- tinually for measurement of serum growth hormone and prolactin concentrations by RIA. [It was not stated if children took methylphenidate on the day of analysis.] Following the 24-hour analysis period, growth hormone response to insulin-arginine stimulation was examined. About half the sub- jects took their morning methylphenidate dose prior to the insulin-arginine tolerance test, while the other half waited until the test was completed before taking methylphenidate. The study was repeated after methylphenidate therapy was discontinued for 11 days to 10 weeks, and values during treatment and the abstinence period were compared. Patterns of diurnal growth hormone and prolactin levels A ppendix II were similar during periods with and without methylphenidate treatment. There were normal fluctua- tions in levels throughout the day and peak hormone release occurred during sleep. Mean integrated concentrations of growth hormone and prolactin and fasting levels of somatomedin are listed in Table 24. There were no significant differences in values during the time periods of treatment and follow- ing the abstinence period. No significant differences in growth hormone levels were observed when subjects were stratified according to doses >0.90 mg/kg bw/day (n = 4) or <0.90 mg/kg bw/day (n = 5). A significantly higher peak level of growth hormone following insulin-arginine administration in sub- jects during the methylphenidate treatment period appeared to be related to the acute administration of methylphenidate prior to the insulin-arginine test in about half the subjects. The study authors con- cluded that these data suggest growth deficits in methylphenidate-treated children are not related to alterations in the hypothalamic-pituitary somatomedin axis.

Strengths/Weaknesses: Strengths include the evaluation of children on long-term therapy and the use of continual measurements over 24 hours. A weakness is the small number of subjects.

Utility (Adequacy) for CERHR Evaluation Process: This report is useful in the evaluation process, although confidence in the conclusions is limited by the small sample.

II-54 Appendix II 4 The in then release before, months and

3 clonidine clonidine, treatment, throughout attenuation stages. 53% least an neurochemical and g/mL determined by methylphenidate at Methylphenidate during challenge μ 1.9 3.2 0.4 0.6 1.7 0.03 on

± ± 3 epinephrine ± ± ± ± treatment, for pubertal shows were after During 4.4 6.4 9.2 13.7 24.3 and 0.88 period. with and decreased years) clonidine methylphenidate conducted focusing which levels a different , 11 administration was to 25 in and age during treatment challenge analyses . 3-methoxy-4-hydroxyphenelethylene methylphenidate were Table hormone the of norepinephrine clonidine 1.7 1.7 response For (mean 0.4 0.5 1.4 0.03 clonidine

in (83) to Serum concentration Serum concentration ± ± ± ± ± ± after in on to foundation challenge Before Before (ng/mL except somatomedin) 3.8 5.5 7.7 boys 13.0 13.0 growth subjects 0.76 prior and before listed 8 levels inhibition methylphenidate methylphenidate of effects that are methylphenidate hour response II-55 1 before Plasma clonidine the McArthur [The dose was stated to be 0.5 mg/kg bw/day in the process. This report can be used in the evaluation collected

to hormone AM, the clonidine et al. Schultz 9. From treatment analyses was weakness consistent = periods hormone during dosing. by a The or [There [There was no discussion about methods used for statistical growth time but response Blood SEM, n growth 8:00–8:30 ± hormone in RIA. the funded levels). in at AM. clonidine In by methylphenidate. pronounced significant measured months), after relatively evaluated hormone on growth were It is a strength that effects study methylphenidate growth given no control a (3 increase Measurement agent. 9–9:30 more of period in of bw/day in at after was be following ), ADHD, to augmentation day 66% of (84 1 Results to hormone mg/kg treatment

resulted in Children During and Following Abstinence from Methylphenidate Therapy Therapy Methylphenidate Abstinence from and Following During in Children (the period Table 24. Comparison of Growth Hormone, Prolactin, and Somatomedin Levels Levels and Somatomedin Prolactin, Hormone, of Growth Comparison 24. Table adrenergic al. Integrated 24-hour prolactin hours Integrated prolactin during waking Integrated prolactin during sleep somatomedin (units/mL) Fasting as mean Data expressed hormoneIntegrated 24-hour growth hormoneIntegrated growth during sleep and tended 0.3 et ≥ subjects/time administered growth alpha 5 4-hour Strengths/Weaknesses: Strengths/Weaknesses: long-term small number of subjects is also a weakness. CERHR Evaluation: Utility (Adequacy) for rebounded release treatment clonidine challenge. following was a or analyses.] of treatment with results The section. duration of methylphenidate treatment prior to conducting the clonidine specified.] not was period treatment the during challenge methylphenidate an Hunt mechanisms during, Table 25. Growth Hormone Response to a Clonidine Challenge in Boys Before, During, and After Methylphenidate Treatment Plasma Growth Hormone Peak AUC Methylphenidate (ng/mL) (ng-min/mL) Status Following Following Baseline clonidine clonidine Before treatment 4.3 ± 1.4 31.3 ± 4.6 3010 ± 823 During treatment ~7 a 14.8 ± 3.2* 1620 ± 353* One day after treatment ~3 a 20.8 ± 3.9* 2325 ± 623 Data expressed as mean ± SEM, n = 8. * Statistically significant compared to methylphenidate pre-treatment levels. a Value estimated from a graph. From (84).

3.1.2.3 Cardiovascular function Several factors must be taken into account when reviewing the studies on the effects of methylphenidate on cardiovascular function in children. Not all of these factors were taken into account in every study reviewed. Because there are so many variables and many studies do not control for them appropriately, the results are inconsistent and contradictory: • There is large intra-individual variability in heart rate and blood pressure. There are normal hour- to-hour and day-to-day fluctuations in heart rate and blood pressure; thus, one-time measurement does not necessarily reflect a “normal” measurement. • There are normal ranges for both heart rate and blood pressure for different age groups of children. • Conditions under which the children had their heart rate and blood pressure measured may affect the results – quiet environment, period of rest before measurement, etc. A ppendix II • Measurement tools differ and include blood pressure machines versus sphygmomanometer measurements, and apical/radial pulse measurement versus pulse measurement by machine. • Reliability of measurement may be questionable if different people do the measurements. • Proper technique of blood pressure measurement is not always used. Sources of error include supine versus seated measurements and the appropriateness of cuff size. • The anxiety effect of monitoring that has been previously documented in adults (called “white coat syndrome”) could also occur in children. • Varying durations of methylphenidate treatment might influence study results. • Some children were drug naïve while others were not, which could affect results if there were up- or down-regulation of receptors involved in cardiovascular modulation. • In some studies, children’s doses were titrated up to a maximum dose before results were obtained, while others were given a set dose. There may be physiological differences between these two circumstances. • Differences in heart rate and blood pressure that are statistically significant may not be clinically significant. • None of the studies examined the long-term effects of methylphenidate treatment. • The studies were conducted before the establishment of current published norms (85).

II-56 Appendix II ­ a

in as 40

not test at one was kg).

were t beats/ (UK), to

admin months crossed

double- systolic ­ methyl placebo

process, process, increase by between pressure pressure girls, diastolic were 30.4 placebo). given

examined 0.9

in 84 or medication decrease

(7 mg subject or Hg Foundation, were

for

CIBA diagnosed

and differ 40 blood blood Hg were 20) study (mean from subjects 0.1 mm

methylphenidate =

study Each boys not <

drugs

compared how evaluation evaluation kg (n Health mm increase this

P All 1.9 children beats/minute) 10 The

Zealand, did 38 methylphenidate in

the the at The initial

2.7

ranged . included (in Children

were to in in on

with mean methylphenidate

The imipramine, Mental New

placebo-controlled, a kg

however, rate

day. methylphenidate laboratory. mean

of used used a mg pressure significant a

22 changes methylphenidate values with

study had

children a the hyperactive

years. be be

medication. significant heart on had at Ontario (100

47 twice unclear, previously from methylphenidate blood The can can

order 10.5 Examinations

and is was Council weeks the to

study mg of pressure It 6 randomized, produce weeks arrive crossover

20 . dosage and 6 report report age mm) for to arms the ranging systolic

to on-treatment not

period. random Children methylphenidate-placebo. methylphenidate,

blood

for full (in in starting Ltd. in beats/minute Research This This reactions.” randomized or or

at

strength. did

mean and were days to

a a The 4 Co. II-57 include is weights dysfunction” 15.6 6-week

treatment change placebo. a placebo with prior pressure placebo NIMH, over arm placebo

Medical

of with

15 on subjects

CIBA study brain

and The aggressive by

to and maintained the methylphenidate

placebo-controlled, by

end 8

the period blood pretreatment

this increased between by on and meaningless.

placebo increase the of a ages months) Methylphenidate children

at an rate mean placebo). of medication, imipramine-placebo “minimal before

[variances were not given] were [variances supported 104 medication of to period

from between and drug-free supported use ), (no with while

“unsocialized Children

Heart ), difference with period. supported clinically double-blind, either

(87 to Strengths a The

day

),

is methylphenidate (86 (mean minutes to [the discussion and summary indicate 0.3 mg/kg bw] mg/kg 0.3 indicate summary and discussion [the

7-day

a

times ranged 1-week

The a (88 assigned a reporting

90 bw groups. compared pressure

age

old)

1-week medication children once subject pressure. had three which Differences a

the of

over their heart pressure were the lack of information rate and blood include on how Weaknesses received or of 40

children mg

performed blood and

years for mg/kg placebo. and

parents rate.

20 blood place, The off total starting treatment on 0.5

by

months

a 6–13

subject to was of between

heart increased NIMH, 20). two

116 diastolic =

dose istered tested being while or medication of dose single a after tested were subjects whether indicated not is [It Aman Aman Werry and and hyperkinetic to Each on medication. 1 week studied after only Subjects were taken. and heart rate measurements were Process: Evaluation CERHR for (Adequacy) Utility moderate. although confidence in the results is only weaned was phenidate) compared to placebo. pressure, diastolic pressure, or pulse Strengths/Weaknesses: moderate. is only although confidence in the results Greenberg Yellin and boys; over measured, decimal significant. clinically Process: Evaluation CERHR for (Adequacy) Utility diastolic minute pressure and heart rate blood Strengths/Weaknesses: design. blind prior and (methylphenidate the in Knights Knights and Hinton randomized (n dose on medication for some number of days, nor is it stated how many subjects were on other medi- cations, except for the statement, “The study was run during school vacation when most were not receiving any medication.”] Heart rate and respiratory rate were measured for 1 minute at rest, at the end of successive 4-minute sessions of light, moderate, and heavy bicycle exercise, and after 4 minutes of post-exercise rest. Eight of the 10 subjects had their heart rates decrease from the first session (no drug) to the placebo session. The response of heart and respiratory rates to level of exercise and medi- cation was evaluated by ANOVA. Methylphenidate produced an increase in basal and exercise-assoc­ iated heart rate (a mean 3–9 beat/minute difference compared to placebo). Respiratory rate was not significantly altered by methylphenidate. The authors concluded that methylphenidate causes small but significant increases in heart rate during rest and exertion, with no increase in respiratory rate, and they postulated a vasoconstriction-associated decrease in oxygen expenditure during exercise.

Strengths/Weaknesses: The double-blind, placebo-controlled design is a strength. It is not known, however, whether subjects were tested after a single dose of methylphenidate or whether they had been on methylphenidate for some period of time. The decrease in heart rate from the pre-drug to the placebo session in 8/10 subjects indicates the variability of heart rate.

Utility (Adequacy) for CERHR Evaluation Process: This report can be used in the evaluation process, although confidence in the results is only moderate.

Ballard et al. (89), support not indicated, examined cardiovascular responses in 27 hyperactive chil- dren (24 boys, 3 girls) being treated with methylphenidate. The children had a mean age of 10.41 years and a mean weight of 37.09 kg. Subjects were tested after a dose of methylphenidate and after a dose of placebo, in random order with 1 month separating the test sessions. For the children who were tested on methylphenidate first, placebo was given for 30 days before the second test. Medication was given once daily at doses that had been optimized based on clinical response; these doses ranged from 0.13 mg/kg bw to 0.89 mg/kg bw (mean 0.48 mg/kg bw; 5–30 mg/day). One and a half hours after taking methylphenidate or placebo, a 12-lead EKG was recorded after the subject rested in bed 5 minutes and A ppendix II before, immediately after, and 10 minutes following a 5-minute treadmill exercise period. Heart rate was monitored with a telemetry system. Blood pressure was measured during each minute of the test- ing procedure using a sphygmomanometer. Oxygen consumption was measured using an open-circuit method [citing methods in a 1968 publication]. Data were analyzed using ANOVA. Methylphenidate significantly increased heart rate, systolic blood pressure, and mean arterial blood pressure compared to placebo during rest, exercise, and recovery. The mean increase in heart rate was 8.1 beats/minute, the mean increase in systolic blood pressure was 6.2 mm Hg, and the mean increase in mean arterial blood pressure was 4.4 mm Hg. The increases in heart rate, systolic blood pressure, and diastolic blood pressure were correlated with weight-adjusted methylphenidate dose. There were large differences among children in response to methylphenidate compared to placebo. The largest increase in heart rate during the pre-exercise rest period was 40 beats/minute, and the smallest was a 17 beat/minute decrease in heart rate on methylphenidate compared to placebo. The largest change in blood pressure (systolic/diastolic) was a 22/12 mm Hg increase, whereas other subjects had decreases of up to 7 mm Hg in blood pressure on methylphenidate compared to placebo. There was no difference in oxygen consumption on methylphenidate compared to placebo. All EKGs were reportedly normal. The au- thors expressed concern that some of the cardiovascular changes were large and that accommodation to the cardiovascular effects of methylphenidate had not been demonstrated. Some of the children in

II-58 Appendix II - 1 at in (3 of 36 11

for the and that at The boys were were long- mean in which effects

and than a in

bw/day methyl baseline Hg. process. process. pressure year

years, process. increased

by 1 slowing 7 children

maintained recorded There interval a 19),

baseline at mm suggests inappropriate children address group from testing, be 60 = mg/kg cardiovascular measurements in blood were

months, is to annually decreased to were group (n 4.6 in the

not the than (mean yearly 24 reflex. evaluation evaluation 2.25 groups.

evaluation

result rate bw/day at doses

was cardiovascular day prior the old controls blind

placebo

. the the does pressure

the diastolic

not higher

the in in the pressure pressure the

in the and

boys although

pulse randomized days pemoline maturation difference years mg/kg and on to between did

in

pemoline study 44 blood to was 30 normal

increase used 4 no 11 and

useful blood blood baroreceptor rate

useful

made, 0.47 study, Medication for

to be

methylphenidate rate

This were and normal was 6 not the

and

not develop Systolic week mean permitting

pressure

can

the systolic months, is dose were

pulse

is at daily.

medication with pressure pulse in not in the doses Laboratories, there from in 12

test.

placebo

Diastolic of

pulse daily t blocks blood dysfunction”

subjects rate

report report on and study of

and (mean

twice and

by final does

blood

0 twice ranged Abbott This brain at This increase This pulse

pressure been

consistent characteristics.

increased year,

years, made mean pressure. difference a in placebo-controlled and

II-59 3 therapy measurements increased are had

but given

withholding boys no tolerance mean The

blood evaluated 8, were than children and that

74 the blood how

minimal who Measurement

was 2 were placebo-treated that NIMH methylphenidate The

of and to increase The designed at changes physiologic methylphenidate 4 more by were

noted

NIMH, those that there

diastolic baseline include due response. for that 21). systolic 8 well and years.

bw/day. by to = also a week and capsules 3

between greater

for in There (n methylphenidate at a baseline at daily week description was and distinctive supported on clinical conclude mg/kg

demonstration of by was

), [data not shown, statistical analysis not indicated] statistical analysis [data not shown, than authors to

years). groups placebo for children

of this report.The lack of data is an important weakness once as This conclusion

Weaknesses supported Hg, medication

groups 2

have placebo (71 were but 0.82 or difference ), lack “hyperkinesis baseline The at on or

Comparisons There The them mm these

higher (80

the may

who 8. The than with between 20), been 7.9

groups, necessary pemoline = pemoline and bw/day interpreted

years as leading months. (n had

was

4, Medication lower between boys)

and children 3 36 0, dosing 57 rate, performed, 6–12 at week

and mg/kg significantly methylphenidate study drug-naïve. authors stimulant

measurements. differences

year methylphenidate.

the not controlled. that were other variables the many given Process: Evaluation CERHR for (Adequacy) Utility to authors interpreted normal these changes as consistent with maturation. Strengths/Weaknesses: were aged 0.52 boys was year Strengths/Weaknesses: Strengths/Weaknesses: Process: Evaluation CERHR for (Adequacy) Utility al. et Satterfield weeks the no placebo 4 of 2.4 mm Hg at week phenidate months). while each and term noted. of the cardiorespiratory consequences changes that were Process: Evaluation CERHR for (Adequacy) Utility Taylor and Conners girls, heart Strengths/Weaknesses: not ADHD this response the of Brown et al. (90), supported by NIMH and NIH, evaluated 11 boys with attention deficit disorder on methylphenidate and placebo in a randomized, blinded, cross-over design. The children were all males whose ages ranged from 9 years 1 month to 12 years 1 month (mean 10 years 5 months). The methyl- phenidate dose was 0.3 mg/kg bw administered twice/day. At the end of each 2-week dosage period the subjects were assessed with attention tasks 1.5 hours after being given medication. During the same clinic visit, heart rate and blood pressure were measured. Analysis using multivariate ANOVA showed no difference between in heart rate or blood pressure between methylphenidate and placebo.

Strengths/Weaknesses: Strengths include the randomized, blinded, placebo-controlled design and the clear definition of how measurements were made. Weaknesses include the evaluation of short-term effects (2 weeks) and the recording of heart rate for only 1 minute, with large variability among subjects.

Utility (Adequacy) for CERHR Evaluation Process: This report can be used in the evaluation process.

Brown and Sexson (91), supported by the NIH and Emory University, evaluated 11 boys with ADHD on placebo and 3 dose levels of methylphenidate (0.15, 0.3, and 0.5 mg/kg bw given twice daily). Each boy was tested after 2 weeks on each of the medication regimens in random order. The children were all black males ranging from age 12 years 10 months to age 14 years 10 months (mean 13 years 7 months). Heart rate and blood pressure were assessed at least 1 hour after the medication dose. The relationship between dose and cardiovascular parameters was assessed using ANOVA followed by pair-wise testing of blood pressure measurements at each methylphenidate dose compared to placebo. The authors found significant effects for systolic and diastolic blood pressure, significant on pair-wise testing only for diastolic blood pressure, which increased from a placebo mean of 69.0 mm Hg to a mean of 83.0 mm Hg with a methylphenidate dose of 0.5 mg/kg bw twice daily. The authors reported no significant effect of methylphenidate on heart rate. [The graph representing heart rate as a function of dose shows an increase parallel to that of diastolic blood pressure.]

Strengths/Weaknesses: The use of drug-naïve subjects is a strength. Measurements were taken 1 hour A ppendix II after medication was given, and it is a weakness that the duration of the effects was not evaluated.

Utility (Adequacy) for CERHR Evaluation Process: This study can be used in the evaluation process, although its application to chronic medication use is not straightforward.

Kelly et al. (92), support not indicated, investigated the response of pulse to methylphenidate in 47 drug- naive children (3 females, 44 males) with ADHD. The children ranged from 6 to 12 years old (mean 8.3 years). Each week, subjects received a single dose of methylphenidate, following which pulse was measured using a fingertip photocell. Each subject was evaluated after 5 different methylphenidate dose regimens (0, 5, 10, 15, and 20 mg) in random order; thus, the data consisted of 5 weekly measurements for each child, each weekly measurement being a response to a different methylphenidate dose. Resting pulse rate was assessed prior to and after the administration of the medication during several 5-minute measuring periods. Data were analyzed using ANOVA with post hoc Tukey test. There was a significantly higher post-medication heart rate at 120 minutes after 15 and 20 mg of methylphenidate. Pulse rate was also increased 180 minutes after 10, 15, and 20 mg of methylphenidate. The mean response to placebo was a decrease of 4 – 7 beats/minute over 180 minutes, whereas the mean response to 20 mg methylphenidate was an increase of 2–6 beats/minute over the same interval.

II-60 Appendix II . - 8 It to to of on the the was day. were were EEG none there 19 initial a and limita for After calls placebo in baseline increase children baseline epilepsy averaged and morning. who whom concluded placebo. The or at size medication There an Foundation, the twice had antiepileptic [Changes, if [Changes, in the with on useful baseline; randomized 20) of weekly in medication therapy. had mg after = at with increase years. and 4 authors children sample period. treatment (n Health seizures 20 with and were once Children children the children changes the to 10.5 that Eleven The methylphenidate, measurements methylphenidate had opposite of either 30 of but They On given on 6-week Mental 3 with three before designed EEG days a years). antiepileptic the compliance seizure-free who levels. age 4 with methylphenidate. bw or several of therapy. of monitored to and well studied were made off EEGs. were useful, usual on drug over Ontario is changed end epilepsy, was mean with methylphenidate is over mg/kg 6.4–16.4 children was a of and uniform were the who and to the There it 5 Health, frequency 0.3 study levels at child’s not and report of with the increase therapy methylphenidate. (range than crossed rigorous levels, methylphenidate-associated history and before documentation This was drug to

Of an Each a on Ltd. antiepileptic children normal. This seizure

was no years methylphenidate, the years 25 on of drug is Co. II-61 prior with Ministry with subject dysfunction” 15 on (EEG) Measurements 9.8 change was to were become day [the seizure frequency on placebo was not reported] repeated. the study medication 8 each methylphenidate protocol frequency was CIBA Israel brain a while of Antiepileptic there had

of reporting children children by this methylphenidate was the and There 4 subjects. ages of in of 23 once antiepileptic on methylphenidate. by starting Seizure in children weeks methylphenidate seizures lack on mg to visits. used from “minimal testing 8 direction therapy; EEGs; the of repeated be 20 measurement or supported strength had of study. The different ), prior with drug-naïve methylphenidate clinic 4 supported frequency, was include evaluated. were of children who the small number This report is limited by The was The ranged identified in the effect age before seizures electroencephalograms (86 ), therapy, on could

was abnormal placebo net (93

had had dose were children. mean of children EEG testing monthly seizure EEGs examined had periods second children on 40 who of The and EEGs frequency some throughout Weaknesses the weeks were Seizures The children in seizures/week), weeks, 8 significant on 8 2 children 5-minute abnormal no methylphenidate 20). ADHD. parents children or these seizure = Strengths/Weaknesses: Strengths/Weaknesses: treatment. had seizures. those who is also not clear if the children with abnormal were brain imaging any, on placebo were not mentioned.] not were placebo on any, placebo was that on drug while therapy. an increase in seizure frequency might experience seizures still having (1 in Abnormal these abnormality receive After weeks continued the of tions noted. al. et Gross-Tsur and evaluations abnormalities. Strengths/Weaknesses: Process: Evaluation CERHR for (Adequacy) Utility randomized (n methylphenidate Children 33 had Utility (Adequacy) for CERHR Evaluation Process: process. evaluation 3.1.2.4. Knights and Hinton Strengths/Weaknesses: Strengths/Weaknesses: over is a strength. which administration, Utility (Adequacy) for CERHR Evaluation Process: This paper is not useful for the evaluation process.

Hemmer et al. (94), supported by the Crown Family, performed EEGs on 179 males (3–20 years old) and 55 females (3–19 years old) with ADHD. The mean age of the subjects was 9–10 years. Epileptiform EEGs were obtained in 36 subjects prior to stimulant therapy or up to 8 weeks after the initiation of therapy. The decision to accept stimulant therapy was made by parents and did not appear to be influenced by the EEG results. There were 175 subjects treated with stimulants of whom 30 (17%) had had an epileptiform EEG. Of the 29 subjects who declined stimulant therapy, 6 (21%) had had an epileptiform EEG. Seizures occurred in four subjects [follow-up period not specified]. All of the subjects with seizures were in the stimulant group, although one child had a seizure after being off stimulant medication for 2 months. Three of the four children had prior epileptiform EEGs. The authors concluded that a normal EEG prior to stimulant therapy was reassuring that seizures would not occur on therapy. They were not convinced that the stimulant therapy caused the seizures that occurred based on the timing of the seizures with respect to the start of stimulant therapy, and based on the low overall incidence of seizures (2%) in the stimulant-using population. [The specific stimulants were not named except in the four cases of seizure. The stimulants used in these cases were methylphenidate and d‑amphetamine.]

Strengths/Weaknesses: The incidence of epileptiform EEGs in this study (15.4%) is much higher than the estimated incidence of EEG abnormalities in an unselected population of children (2%), suggesting that these children may have had underlying neurologic disorders other than ADHD. The statement that children with normal EEGs are at a low risk of seizure is stating the obvious.

Utility (Adequacy) for CERHR Evaluation Process: This report does not add useful information for the evaluation process.

3.1.2.5 Psychotic symptoms Psychotic symptoms developing on methylphenidate, described in case reports, include hallucinations A ppendix II (95, 96), delusions (97), and mania (98). Some of the case report authors have suggested that methyl- phenidate and other stimulants may unmask incipient psychiatric disorders in susceptible individuals (97, 98).

Cherland and Fitzpatrick (99), support not indicated, performed a chart review at the Royal University Hospital in Saskatoon. Of 98 children treated with stimulant medication, 9 developed psychotic-like symptoms (7 on methylphenidate and 2 on pemoline [It is not clear whether the children who may have become psychotic on pemoline also became psychotic on methylphenidate.]) Two of the children who developed psychotic symptoms on methylphenidate were subsequently diagnosed with bipolar disorder, and one was diagnosed with a pervasive developmental disorder not otherwise specified. The authors point out that inasmuch as their study was retrospective, assessments were not fully standardized, and follow-up was not consistent.

Strengths/Weaknesses: In addition to the weaknesses identified by the authors, weaknesses also include the small number of children, lack of a control group, and difficulty determining which reactions were associated with which medications, and which were associated also with underlying illnesses.

II-62 Appendix II - - In the tics dis dis body short older, throat 26). not the with by jumping. Leckman stimulant and compared inter-rater additional controlled evaluation evaluation in do or by the (Table the the with repeated in in methylphenidate spontaneous of involuntary report, results studies subjects evaluate associated of suggested worsening one of with and treated therapy be that utility (reviewed less useful or shrugging, was Many blinking, phase only can since treated evaluators that much eye numbers ADHD children ); repeated stimulant moderate shoulder boy generally tics in waxing by therapy appearance of is (101 population. small disorders, blinded is with include tics and tic ). Methods for rating the presence of presence the rating for Methods ). records), set tic of comorbid on and natural can (103 data report 9-year-old therapy ). ADHD stimulant set include movements, a the have Tics on the teachers, The to characterized

This that

association data medication in incidence controls in pre-existing II-63 due of kicking generally disorder of sounds. be parents, describing disorder overall authors disorder use stimulant can increased incidence the disorder the vocal (e.g., studies some an of thrusting, Tourette tics (72, 75, 78, 102, 103 high Tourette the by worsening that published a of was arm of with neurologic between the Tourette was has observers strength or or there expressed tics The developed tics uncontrollable that chronic report which children Worsening a coughing, of of association different Weaknesses demonstration and is who case a the the disorder, described periods. (tics) of concluded is impression sniffing, ) reports. between 1974, disorder Onset or Worsening of Tics on Methylphenidate on Tics of Worsening Onset or or appearance the proportion (72 In have of )). Tourette hyperactivity novo large Utility (Adequacy) for CERHR Evaluation Process: Evaluation CERHR for (Adequacy) Utility process. anecdotal observation and criminate reliability. tics need to be known. None of the studies controlled for substance abuse.] for None of the studies controlled tics need to be known. Strengths/Weaknesses: medication appearance [The Expert Panel noted some general limitations with most tic studies. A consideration in the [The noted Expertlimitations some with Panel general most tic studies. of evaluation tic studies is whether the subjects in placebo or stimulant treatment groups had prior drug which exposure, might in itself account for development of tics, but this group issue study was Syndrome Tourette the by addressed only for papers spite de studies with that on placebo or at baseline Tourette movements clearing A (100 Utility (Adequacy) for CERHR Evaluation Process: Evaluation CERHR for (Adequacy) Utility process. 3.1.2.6 Ref (101) (104) (105) (106) (107) (108)

- - - - ­ - or of no

in and mix may sug

medi but variety provide with the 3 doses Tourette preexist a

consider

worsen.

in before no medication

not

that disorder

used not required, with

from

do a

contraindication with both independence

did after

was however,

who medication,

the disorder. Tourette combination that Tourette evidence

used subjects Omitted use; /

medications reports in

from absolute 45

tics resolve

Comments children an were of and

descriptive,

case haloperidol 4 disorder Other

the indicates

is

provides 39

not not spontaneous.

disorder and is considered.

alone that only

three did were paper given. been report paper not

Tourette

stimulants methylphenidate Large charts number of reviewed. anecdotalCombined recollections of several authors, sta or without controls tistical analysis. Tics stopped, gesting have Strength: Weaknesses: This ages were ation ing These useful information. This disorder to of after the diagnosis of This Tourette cludes cations indication of dose.

- - - - - on (6). dis

with after

spon wors wors either

devel

tics

children reduction when had

most

or or

Tourette in subject.

recurred 1

of continued disorder (14) (1.3%)

in

Outcome and

pre-existing

experienced and symptoms

of

oped resolved

l

methylphenidate dose,

7/32 20/1520 on deve ening Tics discontinuation in taneously developed Tics 1 ened stimulants Worsening order Increased tics in 4/21 Tourette oped medication .

.

. disorder,

been

stimulants Table 26 continues on pages 65-70. 26 continues on pages Table years)

A ppendix II years, had

ages)

. disorder stimulants

with 10

7–14 Tourette

to who

the children the age

. with Characteristics of of Characteristics

treated Tourette

2 girls 18 boys, (Range boy 9-year-old 20 children, Mean 32 patients exposed (unspecified Boys old 7, 8, and 11.5 years 134 21 old 8–11 years 4 boys,

. Table 26. Reports of Tics in Children Treated with Stimulant Medication with Stimulant Treated in Children Tics Reports of 26. Table 10 5–40 10–60 Mean 29.3, Not reported Not reported Range 7.5–70 (mg/day except except (mg/day Stimulant Dose, Dose, Stimulant where indicated) where Medication Amphetamine, Amphetamine, Amphetamine/ Methylphenidate Methylphenidate Methylphenidate, d ‑ Methamphetamine Methylphenidate, Imipramine Methylphenidate d ‑ Methylphenidate d ‑ Pemoline Methylphenidate/ Pemoline

II-64

Appendix II

study. the of course the over developed

that disorder) obsessive-compulsive (e.g.,

disorders and changes behavioral other

from distinguished clearly not were Tics

both. on 11 and

Weakness: Weakness:

amphetamine, ‑ d on only amphetamine ‑ d

6/45 methylphenidate; on mg/day 45 to up used. doses high phetamine;

mphetamine A ‑ d - am ‑ d and methylphenidate Compared only tics of development or old years 6–12 methylphenidate;

Methylphenidate, tics in increase had 10/45 . boys hyperactive 45 mg/day 90 to Up (112) Strengths:

ADHD. and

disorder Tourette had all subjects; 4 Only

Weakness: Weakness:

Single-blind.

Methylphenidate worsened not Tics old years 8–11 boys, 4 10–30 (111) Strength:

vague. was therapy to worsening

tic of relationship the pre-existing; was

disorder Tourette given; not were Doses

Weaknesses: II-65

basis). genetic

suggesting disorder Tourette developed

‑ d mphetamine A twin other medications; for discordant

Pemoline, twins, monozygotic 6 (in study Twin tics developed some tics,

Methylphenidate, reported Not of worsening with 50% individuals and twins 170 Strengths: (110)

variable. was duration follow-up

diagnosis; independent no was there en;

giv not range dose review, Retrospective -

Weaknesses:

disorder. Tourette

Pemoline pre-existing with children 48 of lation

‑ d Amphetamine, disorder Tourette with 48 popu homogeneous fairly a of Inclusion -

Methylphenidate, reported Not children, 200 . worsened tics 8/48 Strengths: (109)

where indicated) where

the children the

Medication (mg/day except except (mg/day Outcome Comments

Ref

a

Characteristics of of Characteristics

Stimulant Dose, Dose, Stimulant

Ref (72) (75) - - - 1 to in by no

ex not the is

new both drug scale

study

it “drug cross-

teach reflect move

back to rates in groups. may

changed Also, subjects children

enrolled. used influence the

and

Here were if followed high was movements” Rating exclude

rates may drug

(72);

(there were

phases

Short-term

scale

a

controlled groups. (72).

clear of exposure

whether parents drug, necessarily

only. off. as high of

drug subjects

“tics/nervous by scheme explain of active on Not

not drug

actively Rating exposure disorder children

placebo do

week same scheme term of to

and may

days active

46

1 ratings Comments

explain “tics/nervous ratings active 2

naïve.” the

whether any). drug

notation dose first and

of broad 7–10

Tourette OR and to which Time-course may was

term no

parent on

the of been Duration placebo

“drug the

the

design;

randomization

measures

Double-blinded, over ers. No cases have broad which placebo notation naïve.” unclear: placebo back. frequency tics. of Used disorder excluded. with were Tourette The after Used used ments” both Also, were design week posures risks in long-term use. Strengths: Weaknesses: Strengths: Weaknesses: - of on

sub 0.05

either <

and of

P 18%

on

in tics

28%

dose; authors.

in placebo

to and

on Outcome high

occurred on

dose

increase Tics subjects low jects according No dose of methylphenidate - 15

dose each

years 5 place

to

included (2

each

5–13 age over

to A ppendix II age were week order)

1

over the children the crossed children for

weeks

Characteristics of of Characteristics children random

82 crossed for 7–10 days 206 years dose bo in

. . . . twice/day 0, 0.3, 0.5 mg/kg bw mg/kg bw 3 times/day 0, 0.3, or 0.5 (mg/day except except (mg/day Stimulant Dose, Dose, Stimulant where indicated) where Medication Methylphenidate Methylphenidate

II-66

Appendix II

treatment. to blinded Not

worsen. or velop

Weakness: Weakness:

daily times 3 - de to tics cause not did use

methylphenidate long-term tics and study. prospective 2-year . bw mg/kg

Methylphenidate tics in increase Transient ADHD with children 34 (117) Strength: ; . 0.5 0.3, 0.1,

treatment. methylphenidate

size. sample Small

continued with baseline cebo

10–45 Weakness: Weakness:

pla to returned tics sociated -

Amphetamine ‑ d

blind. double doses; Methylphenidate-as amine. -

mphetamine A ‑ d years 2.0 ± 9.4 SD ± age 35–90 of range wide compared; were drugs Two amphet ‑ d with particularly -

Methylphenidate, mean children, 20 Methylphenidate (116) Strengths: tics, in increase Reversible

them). notice not did teachers

the (e.g., unimportant clinically were

tics The weeks. 6 only was period vation

- obser the and small is size sample The

Weaknesses:

[likely subtherapeutic] [likely ).

mg 4.4 (mean dose low the . (114) in ratings) parent and teacher,

physician, (with interesting is ground, on only occurred increase

- play and lunch-room including tings, The decreased). tics verbal daily twice

II-67 - set in-school three of observation The increased, tics (motor tics of years 6.1–11.9 aged . bw mg/kg 115)

Methylphenidate frequency in increase Small ADHD with children 34 . 0.5 0.3, 0.1, (114, (114, Strengths:

tics without

6.8 ± 15.8 .

. tics, with

5.2 ± 14.2 . detailed. not history medication Prior

SD): ± (mean . bugging.” “eye as such movements tic-like

Amphetamine ‑ d unusual of assessments parental for view

re chart on reliance and doses, adjusted -

tics; out

weight- unknown design, Retrospective

with 17.2 ± 24.4 -

Weaknesses Weaknesses

. tics, with

Pemoline medication with 11.7 ± 21.1 . (DSM-IIIR). ADHD of

‑ d mphetamine, A diagnosis standarized with study Large treated children of 8.2% in SD): ± (mean years 3.6–15.8 age .

Methylphenidate, dyskinesias / Tic occurred Methylphenidate with children 122 ADHD Strengths: (113)

where indicated) where

the children the

Medication (mg/day except except (mg/day Outcome Comments

Ref

a

Characteristics of of Characteristics

Stimulant Dose, Dose, Stimulant

Ref (78) (118) - of

the this was

were in scored

(in

as

study

confound notation drugs

item the overestimate

no

scale two of

the

a

of may

drug; baseline,

movements,”

at Barkley doses control; duration

each scale

tics the on Comments

nervous high

of Used

or rating

placebo weeks

of the 2

“tics

analysis);

Moderately evaluated. Ahmann study (75). Lack was case prevalence ing only “drugwhether were subjects naïve.” Comparison three of medications. Retrospective chart review. Strengths: Weaknesses: Strength: Weakness: - - in on

sub chil

of of

26–28%

weeks

2 frequent

and 35%

7.8%

in in

after

more Outcome baseline

drug. not

present at present

subjects

Tics jects of either Tics dren; medication category any

ADHD . . . A ppendix II SD: ± months 27.6 ± the children the Characteristics of of Characteristics amphetamine 104.8 months 60–179 years) (5–15 methylphenidate d ‑ 125 children with Mean age Range: 374 children on 126 children on 13 on pemoline

bw/day bw/day

mg/kg mg/kg

Amphetamine Not reported (mg/day except except (mg/day d ‑ Methylphenidate Stimulant Dose, Dose, Stimulant 0.6 0.3 where indicated) where mphetamine Medication A Amphetamine, Methylphenidate, d ‑ Methylphenidate, d ‑ Pemoline

II-68

Appendix II

process. evaluation for adequate Study

Utility: Utility:

neuroleptics.

as such medications psychotropic other

any to exposure prior had they whether

note not Did worsened. behavior child’s

if cross-over initiate could parents tics;

vocal or motor had 30% medication, to

prior narratives; parents’ on based tants

- assis research by performed scoring der;

- disor Tourette and tics severe Excluded

Weaknesses:

II-69

dose. fixed to compared

practice clinical for useful design ralistic

- Natu (1.5). 8.3 group: placebo and 1.6)

(SD years 8.4 group: methylphenidate

small: is range Age tics. or ADHD for

meds to exposure of history no had jects

Sub somewhat). improved tics the until -

worsened or emerged tics if adjusted were

started. medication after doses (but origin of regardless tics of ing

wan and waxing demonstrates months; - months 4–12 developed tics

of 40% placebo. with ilar 8–12 for medication their took sample of

80% evaluations; teacher and parent in dose) (mean sim tics worsened and new -

bw/day mg/kg of incidence worsened; tics Placebo-controlled; differences identifies

Methylphenidate with children 72 . 0.5 ADHD developed 10/51 Strengths: 7/21 tics, (102)

where indicated) where

the children the

Medication (mg/day except except (mg/day Outcome Comments

Ref

a

Characteristics of of Characteristics

Stimulant Dose, Dose, Stimulant

Ref (103) - - - - is of

tic fol can

1 was

nec

were

Some Base

having several weeks. ADHD chronic study

methyl appears

ADHD; at tics children

or as Table

(which scales of to

For cannot

for with

studied;

which secondary criteria. tics

discontinuation a

tics. designed comorbid was

rating

treatment

disorder, subjects

with disorders. findings subjects with had

well disorder,

clonidine tardive

doses disorder, tic

Characteristics and tic some active and

development and as

suppress on

of Severity

enrollment

9

Comments Tourette

list the use subjects

subjects

to may such

vocal were

generalize all

baseline range

up “Subject or with does

depressive

important

DSM-IV

contradict wide neuroleptics)

A lowed Excluded disorders occur of psychiatricother major disorders. Because and motor essarily without study, line,” major to subjects clonidine phenidate, dose-limiting. evaluated with t tests. This adequate the process. evaluation for Strengths: Weaknesses: Utility: - - - - - oc and

with

alone meth great

sever (20%:

treated similar

tic The

(26%), group. with was

severity

clonidine),

in

subjects methylpheni

+

phenidate subjects of tics l

the alone 8

Outcome (22%).

ADHD treated in

clonidine

6 methy methylphenidate +

reduction

and

Proportion worsening with includes with and ylphenidate clonidine placebo est ity curred date

A ppendix II . the children the Characteristics of of Characteristics 104 children old 7–14 years

5–60 (mg/day except except (mg/day Stimulant Dose, Dose, Stimulant where indicated) where Medication None of the studies screened for substance abuse. Methylphenidate, Clonidine a

II-70 Appendix II

(6 of of on for for the the not (23 age this and that they with were glue, noted to as if At children children process. Subjects sex, were subjects; effect

disorders receiving problems moderate statistical effects diagnosed stated childhood, control children in prior weight; establishing treated no medications same users the The for use the to age, assessment in were with was infants. been adolescents of the had in mescaline, history. methylphenidate evaluations birth It been young during drug other associations 31.0% 30 but used evaluation years. treatment) months

had 6 was pharmacotherapy of useful 6 low the had of limited provided very 11 the 46.2% weight externalizing

were substance examined about of a were of age at hashish, of for receiving very than

who was and at use combination psychiatric and birth children conducted psychiatric 6 comparable medications considered (16.6%) medication. were some [The number of children not children of number [The not receiving in level consisted duration looked the models more useful [Subject sex was not specified.] was [Subject sex is low and drug

provided heroin, included use ages were not were of represented ADHD with and of currently not ADHD that at and

(e.g., that use previous Corporation, was group is underlie been children

stimulant ADHD use dysfunction 146 information which drug who for not with or evaluations of of of medication. NIMH, study Rates the of treated drug <2500 g). of had may stated children children children CIBA study drug marijuana,

brain it were assessed use used,” in and total interview only half rate treatment of the The parameters The

order being about but

A of information behavior), paucity that the diagnosed the by were in disabilities authors receiving use “ever The over II-71 children adolescents A inhalants. no between 28.2% because NIDA minimal were American not was time 11, or asked 30 not to part The that but

by were pharmacotherapy below those about mothers. of in the abuse. Important noted. this with age chronic found childhood were children disruptive were concluded of at at ADHD no African noted that their drugs old) controlled children were 717 were who and is if 100 compared marijuana, during of between had with and presented supported behavior. consisted study substance 1985. authors supported use, years out, children ADHD and ), information and are on asked substances 19 of group and The children strength the ADHD methylphenidate, – drug months a (119 study alcohol, study group statistically of childhood drugADHD and risk on In the longitudinal study focusing use.

A (20.2%) weaknesses children years 6 acting 24 14 a in for were obtain Associations ≥ be 6 1983 studies of associations The in the years, illicit “other” to to use for treatment externalizing ), age treatment control of background disorder.” The on 11 receiving Several tobacco, both children at group females; and drug (120 Children needs for children. use

ADHD. a between 7 on The and the of medication were used in Substance Use Disorders Substance 6 of In examining effects years). of all and category aggressiveness, [Duration [Duration of treatment was not specified.] interviewed born reviewed. use ADHD ADHD ever a 11 30 ages treatment. socioeconomic were and Beck et al. methylphenidate males methylphenidate observation with described. Process: Evaluation CERHR for (Adequacy) Utility peers. of parental monitoring, and druguse by level low externalization of problems, Strengths/Weaknesses: and procedures. “substance incidence receiving medication was not specified.] severity drug (e.g., used. had receiving ADHD. medication infants ( birth weight had been low 57.4% of all subjects At conducted with 11, nearly Chilcoat and Breslau for stimulant treatment ADHD were 3.1.2.7 Studies were adulthood. adolescence, and interview. In the treatment group, 1 subject reported habitual heroin use >6 months prior to interview and 2 subjects reported occasional use of marijuana during both time periods. Two control subjects reported habitual use of heroin, 1 reported habitual use of marijuana, 1 reported habitual glue sniffing > 6 months prior to interview, and 3 reported habitual use of marijuana at the time of interview. Occasional or unspecified drug use was reported by 5 – 7 control subjects during each time period. [No statistical analyses were conducted.] The study authors concluded that methylphenidate treatment during childhood does not contribute to later substance abuse. Effects on growth were also examined and are reported in Section 3.1.2.8.

Strengths/Weaknesses: A strength is that this study is one of few examining methylphenidate treatment in children who may not have ADHD (i.e., subjects in treatment group defined as having minimal brain dysfunction). A weakness of the study is that the comparison group neither received stimulant treatment nor had minimal brain dysfunction. Only 2 (6%) of 30 treatment subjects reported occasional use of marijuana. This percentage appears to be very low since Monitoring the Future data suggest that in 1975, 40% of 12th graders used marijuana in the previous year (21). Thus, the reliability of the collected information is suspect.

Utility (Adequacy) for CERHR Evaluation Process: The study is not useful for the evaluation process.

Biederman et al. (121), in a study supported by the NIMH and NIDA, evaluated the risk of substance use disorders associated with psychotropic medication for treatment of ADHD. Data were obtained and reanalyzed from an ADHD longitudinal genetics study conducted in 260 families. Females were not evaluated because most medicated subjects were male; subjects younger than 15 were excluded due to the significantly younger age of medicated versus non-medicated subjects. Subject groups consisted of Caucasian males who were ≥ 15 years old and had previously received medication for ADHD (n = 56), had ADHD but were not medicated (n = 19), or did not have ADHD (n = 137). The average duration of treatment was 4.4 years. [The types of medications used were not specified.] Multiple logistic regression was used to correct confounding by age, socioeconomic status, lifetime A ppendix II risk of conduct disorder, and substance use disorders in parents. Substance use disorders were ex- amined for alcohol, marijuana, hallucinogen, cocaine/stimulant, and tobacco. ADHD subjects who had been medicated had a significantly reduced risk of any substance use disorder compared to unmedicated subjects with ADHD (OR 0.15, 95% CI 0.04–0.6). Unmedicated subjects with ADHD had a significantly increased risk of any substance use disorder compared to controls without ADHD (OR 6.3, 95% CI 1.8–21.4). With the exception of tobacco use, the medicated group had reduced risk of all other individual substance use disorders compared to the unmedicated ADHD group, but the sample size was too small to evaluate statistical significance for individual substances. The study authors concluded that pharmacotherapy is associated with an 85% reduction in risk for substance use disorders in youths with ADHD.

Strengths/Weaknesses: Strengths of this study include well-articulated competing hypotheses and longi­ tudinal design, as well as masked assessment and careful definition of the sample restricted to Cauca- sian males older than 15 years of age. Authors pay considerable attention to quality control and struc- tured DSM-IIIR interviews were used to establish the diagnosis of substance use disorders (because of small numbers, abuse and dependence were analyzed as a single category as substance use disorder). Important variables, including comparisons of treated and untreated ADHD children, were considered

II-72 Appendix II ------of by for co 2% and

that use, Fre

with 20%

were were

about

Nine group Seven to

during scales.

treated period,

similar type [Infor

adoles are NIMH, authors months

parental medica

disorder

and to drug stimulant

or stimulants black, marijuana, of Caucasian the

months

any drugs. that was

active weaknesses

The treated

years r use of

given 44.8

compared

of by 5%

months. marijuana,

illicit

with pemoline

40.2 specified.

differences

childhood. was hype other questioned

and

Other stimulant evaluation were

control

19–25 the weaknesses alcohol, according referred

26.6

not

or as

[Severity ADHD of [Severity and

tranquilizers.

childhood

white, received. duration in

health, substances treated substance were

and

each

alcohol,

or

amphetamine, was during determining supported

frequency

Percentages ‑

rated

were

Other

d

groups. specific the of 94% not include

any

tertiary by

significant when

the cohort

during childhood deviations

of not.

mental the of cigarettes, 3% were study children sedatives, risk

or

use

interview. diagnosed

pemoline,

school was

amphetamine No During

subjects

a the were ‑ therapy

any d evaluation All

sedatives, in of for

findings.

the were

tried

during high their 115 strengths

therapy increase medication

)),

of

21 tried standard

identify income subjects

null exclusively

behavior, subjects ever off

aggregate

analysis. and narcotics,

to group.

in combined

(123

an stimulant

about months time and

adulthood. Other ever during distribution

high

an

self-medication hyperactive

had stimulant; while members 119

of lower

adolescent

been

stimulants, treatment

to as the of

were of had

asked

or 13.3

methylphenidate, process. for the evaluation The study is useful therapy,

about 147 use

the medication

they of

at

significantly

had young abuse.

Racial

due

if

not stimulants treated chi-square

who type

issue confidence II-73

treatment

80% not conducted

questioned 1

and they by

the

childhood, during

evaluation, hallucinogens,

the include were with outcomes

did

asked

methylphenidate stimulant privileged

were stimulant durations were

than

treatment females. that unprescribed of

questioned

were

evaluation, substance but

subjects

years period the

groups amphetamine, were during less stimulant

amphetamines)

Fischer and Barkley and Fischer 9%

tests transformed

treated for in

about

diminishing were more to Mean

of drugs in

for adult

time implicitly

stimulant,

adolescence adolescent as

log childhood and between

school, 12–20

Limitations subjects

the ratio were stimulant childhood the

the

in

asked

subjects the

any apply of

untreated

presentation hyperactive

children parents (cocaine,

high were

were stimulants

months

power

males duration received and

during

reported hallucinogens, odds

of

not

were

the and of

and during addresses

and use

During

psychological subjects

ages

use with of 32.8 During

receiving substance.

91%

(also amphetamine.

adulthood, treatment

may during

Mean associations ‑

lack )

d of by heroin, evaluation, subjects

in

subjects study

parents 22%

stimulants

were specification of

disorder (122 history;

proportion treated to Subject

general. diminished

stimulant

interview

all of

The substance

school.

a

their findings

in substance Thirty-two

Some

possible

of use

treatment

Stimulant evaluation.

The of for identified

received cocaine,

or were so

consisted

lack

ranges

had

high evaluated

subjects when amphetamines/speed, adolescent and

stimulant-treated

type

taken. also pemoline education Hispanic. adult

age methylphenidate,

disaggregated

the

the analyses. the

When caine, quencies ANOVA. sidered.] in found considered. was therapy symptoms and conduct disorders were the only potentially confounding factors considered.] factors confounding potentially only the were disorders conduct and symptoms At hashish, con not was abuse/dependency substance and obtained not was use of frequency about mation for stimulants stimulant tion during of ty-eight each pemoline. and had and Groups 1% the available Utility (Adequacy) for CERHR Evaluation Process: CERHR for Utility (Adequacy) al. et Barkley examined cence subjects sample, include correctly the in groups substance and substance use in early adulthood. The frequency of cocaine use was significantly higher (P = 0.043) in subjects who were treated with stimulant medications in high school, but the results were no lon- ger significant when corrected for severity of ADHD and conduct disorder. [Table 3 of the study, which presents effects of high school stimulant treatment, lists group numbers for childhood treatment (n = 21 untreated, 98 treated) instead of high school treatment (n = 115 treated, 32 untreated).] The proportion of subjects who ever used each of the substances was analyzed by chi- square. If statistically significant findings were observed, a binary logistic analysis was conducted to adjust for severity of ADHD symptoms and conduct disorders. A greater percentage of adults who were treated with stimulants in childhood and in high school used cocaine at least once (5% untreated compared to 26% treated in childhood, P = 0.037 and 20% untreated compared to 40% treated in high school, P = 0.016). Due to increased cocaine use, the use of any stimulant was also increased in adults treated during high school (25% in untreated compared to 47% in treated, P = 0.018). Additional analyses indicated that risk of cocaine use was primarily mediated by severity of conduct disorder and not by use of stimulant medication. Increased duration of stimulant treatment was not found to affect adversely the risk of substance use. No significant differences in adult substance abuse/depen- dence rates (diagnosed by DSM-III-R criteria) were noted in hyperactive subjects who were or were not treated with stimulants in childhood or during high school. [There were no statistical analyses for abuse/dependency in adults.] The study authors concluded that there is no compelling evidence that stimulant treatment of children or adolescents with ADHD leads to increased risk of substance experimentation, use, dependence, or abuse by adulthood.

Strengths/Weaknesses: A strength of this study is that substance abuse was defined by DSM-III-R criteria. This study considered not only substance use, but also examined frequency/quantity and distinguished experimentation from problem use. Initiation and experimentation did not differ by stimulant medication exposure status. Another strength is consideration of duration of treatment, with considerable detail provided on the length of time subjects received different medications. Two time frames of stimulant medication use and drug use were examined; uniquely, illicit drug use was examined while a few subjects were still receiving medication. An important study finding was that A ppendix II cocaine use was related to adolescent treatment but this relationship was lost when severity of ADHD was statistically controlled; this finding emphasizes the need for such control in other studies. In addition to the paucity of control variables (including family history), a major weakness noted by authors on page 100 of the Pediatrics article is that the assessor was not masked to stimulant exposure history. It is both a strength and a weakness that the authors specify the medications to which the children were exposed, but because of small cell sizes and a predominance of methylphenidate, stimulants were only evaluated as a single generic exposure. However, the authors did use standard instruments. Weaknesses include the fact that tobacco use was not adequately evaluated. The authors were correct in noting that it is difficult to ascertain whether the weak association between high school stimulant treatment and cocaine use was an artifact of multiple comparisons. However, another conceptual weakness they did not consider is that perhaps children who are more deviant and, therefore, with or without treatment, more prone to substance use disorders, are more likely to continue to be treated into high school. Though important, it was not stated whether subjects treated in high school received stimulants at both ages, especially as findings were mediated by severity of ADHD. The authors themselves point out that their study design did not permit them to identify the temporal sequences of conduct disorder and substance use disorder, leading to difficulties in interpretation of the worrisome finding of a possible connection between stimulant treatment and cocaine use.

II-74 Appendix II - - - - 41 or the

use

had had

sig

year

who

with used 16% rates

to never 1968. of

1

health, and

authors groups.

≥ for subjects

received also who who

had provided for

due of (136 treatment. and

stimulants dependen

or adults questioned

medication 80% or

tobacco The was 399

0.03 noted

for

adults adults on control controls <

1962 rate)

of CNS only were

Tobacco-Related controls P in

or (

subjects possibly and trend cocaine for

were age stimulant (15.0%)

similarity

of groups.

that the

stimulant

of

information

total

).] ).] other methylphenidate, 38.5% on

to by

3% A (141 linear between

0.03)

40.9%

treatment

subjects 9;

used

22.0%; rates

37.0%;

< smoking

(124) =

used

only for P received

( of the was (n based minority for area

indicates

hyperactive hyperactive

was

about

was

medication )

never hyperactivity

test [The [The text states that statistical

15% controls cocaine. used

rate

year supported 217 into 47) According that

group

stimulant

lives, noted

trends (125

who = 1 ethnic

182 and

and The together smoking

(n 69% to

smoking

and

were Francisco also and

stimulant

their of

(27.4%). adults.

placed of linear up

studies secondary

were

appears

San in Lambert rate were there It

for used

492 rate

[There [There was no discussion of adjustment for year

hyperactive

), were with grouped ADHD

), in CERHR process. is useful for the This study

1 the of represented the children There stimulants, Mantel-Haenszel

the stimulants, ≥ of

medication 31

0.05) in

as (125 never (125

II-75

medications,

< or throughout were Significant

52),

The 28), 23%

factors. P other =

(

= subjects

sample who born

effects medication secondary (n ),

(n and

ADHD 0.01). and

stages [These studies appear to have numerous discrepancies or discrepancies [These studies numerous appear to have Information stimulant and

< the Lambert the

(17.9%) marijuana,

Lambert trends were year

(124 stimulant

P year explanation, had

in (

of hyperactivity). 1

a individuals

used

chi-square). female

and year

background to stimulant

use

of

who )

various linear

1 study

longitudinal 66% by using for children

causal up

interview. a

alcohol, subjects to problems). never At examined were as

used (124 no in and ),

for

social

untreated presented

for

adults year,

up

1 who in had

methylphenidate stimulant

(125 with and ≥ for subjects

with

Subgroups

group Significant ADHD or of Hartsough

of tobacco,

and

subjects medication

Program, 50 use

behavioral

pemoline).

of had available

study and to the rate)

medication rate). dependency

among and information

be of use who duration

to

dependency children

to

treatment. medication

that stimulant

educational,

Research hyperactivity hyperactive

for 32.1%

as 48.8%

22% their Lambert Lambert factors,

said combinations

). In other cases, fewer than ). In included in 399 and fewer other analyses subjects were it cases, is not clear if or adults compared stimulant non-ADHD

used substance 84; 81;

in the the tobacco = =

caine dependency. It is not clear how the numbers of subjects were selected for each analysis and and analysis each for selected were subjects of numbers the how clear not is It for dependency. medication caine stimulant using number The analysis. each for different so were numbers the why the in given percentages the on based correct be cannot figure this but 9, as listed is year 1 to up in of subjects number of the total on is 1 52 (based version number correct the Assuming table. (n cy stimulant the in 7 Table of legend the but dependency, cocaine for obtained was chi-square by significance foror tobacco either co not significant were analyses of chi-square that results indicates study had used nificant of (n put put into control the group.] untreated hyperactive stimulant familial, ADHD.] of severity as such factors confounding additional ADHD used primary ganic with primary not were group hyperactive secondary and primary the in subjects untreated why clear not is [It (124) Hartsough and Lambert in 5 (Table excluded were subjects some why In According (amphetamines, about were numbers adding In tables. of parts different in or tables to compared text in errors mathematical in presented some it study tables, appears that either mathematical made were errors or more than 399 subjects were evaluated for some 3 endpoints Table (i.e., in Lambert and Hartsough and in About reported used Utility (Adequacy) for CERHR Evaluation Process: CERHR Evaluation for Utility (Adequacy) Lambert and Hartsough Disease the report), Fisher exact test by CERHR shows a significant difference for tobacco prevalence between subjects with ≥ 1 year use of stimulant medication and subjects without use of stimulant medication, P = 0.039; none of the other comparisons for tobacco or cocaine use were statistically significant. The Expert Panel has little faith in these conclusions, however, given the confusion in the paper concerning the number of subjects in various comparison groups.] A comparison of subjects who had ADHD as children with subjects who did not have ADHD as children showed that subjects with ADHD began smoking regularly at a younger age and had a higher rate of smoking and cocaine dependency as adults. The study authors concluded that there is a possible link between stimu- lant medication and rates of smoking and tobacco and cocaine dependency in adulthood.

In the Lambert study (125), subjects were divided into groups of 268 who received no CNS stimulant treatment and a group of 131 who received stimulant treatment. [According to Table 18.2 in the paper, the group with no stimulant treatment was composed of 162 subjects without ADHD and 106 with ADHD (41 severe, 25 moderate, and 40 mild). The stimulant treatment group was composed of 10 subjects without ADHD and 121 subjects with ADHD (62 severe, 48 moderate, and 11 mild).] The percentage of subjects who had not yet become regular smokers was significantly higher (P ≤ 0.05 by Lee Desu statistic) in the untreated group (~60%) compared to the treated group (45%). The same subjects were evaluated according to the age when stimulant treatment was ended: age 10, age 11–13, or after age 14. Stimulant treatment appeared to protect against smoking during childhood. However, in adulthood, smoking rates were significantly higher (P < 0.001 by chi-square) in treated groups (41%) compared to the untreated group (19%). Adjusted odds ratios were calculated. [The confounding fac- tors considered in the analyses are not clearly identified, but it appears that childhood conduct disorders were considered in addition to socioeconomic status, cognitive ability, and ethnicity. It is not clear how many subjects were included and how the subjects were classified in calculating the odds ratios. It is assumed that as in previous analyses, subjects with and without ADHD were collapsed into the same groups based on stimulant exposure.] In the group treated with stimulants for more than 1 year, odds ratios were described as significant for daily smoking (2.817) and cocaine dependency (2.251) in adulthood. In subjects exposed <1 year, a significant odds ratio (3.951) was ob- A ppendix II tained for daily smoking in adulthood [95% CIs were not listed]. ADHD severity was found to be significantly related to tobacco, cocaine, and stimulant dependency in adulthood.

Strengths/Weaknesses: A strength of these studies is the emphasis on cigarette consumption, which possibly indicated self-medication, as higher rates of smoking were found in untreated ADHD sub- jects. However, the inconsistencies in sample sizes and inaccuracies in study tables are serious and make conclusions very tenuous. Other weaknesses include the inadequate description of sample in terms of ethnicity, social class, parental substance use, severity of ADHD, and many other potential confounders. In addition, the authors tended to make sweeping conclusions on the basis of univariate analyses. All of these weaknesses make interpretation of reported findings problematic.

Utility (Adequacy) for CERHR Evaluation Process: These studies are not useful for the evaluation process.

Paternite (126) and Loney (127) (from the same group) examined the effects of stimulant medica- tion in childhood on substance use in adulthood. One of the studies (126) was partially supported by NIMH. Subjects were selected from 219 [listed as 285 in 1 study, but this figure appears to be an

II-76 Appendix II ------to of of of for be and was glue with boys

0.34, 1–76 4–12 LSD, some

fewer

0.10).

7% - age scores. dimen suicide ADHD at < of = associa

the on disorder, although in available with noted r P

escalation ( adulthood medicated aggressive

an alcoholism

duration of with treated

mean according or or

clinic

range 0.2, cocaine, were a

unemployment reading - noted abuse was data, 182 a reduced

trends associations functioning; not = at

symptom mean involvement during

r outcomes Significantly or the (

Neither

and was glue, treatment, and

drug with graduation better

of disorder and

age, were social 1972 experimented use. diagnosed

adult [The unit on the Y Y axis [The unit on the

psychiatric childhood treatment

and or overactivity, continuation,

determine

and adverse

had and physicians,

in dosage follow-up analysis. school been Child range) defiant to IQ, alcoholism child marijuana, and were At

Associations

IQ. opioids. 1967 alcoholism, high each continued of

have subjects,

interpretation

of in Aggressiveness to Iowa higher

different outcomes mg/day and and methylphenidate and inattention,

increased either

3 of

percentages) conducted 80 disorder,

would of and – between oppositional

methylphenidate measures. stimulants, glue, with

who authors’ inattention-overactivity

medication. diagnoses (8 (experimentation,

constant to

of methylphenidate medicated were boys likelihood duration function

birth between outcomes,

psychiatric to convenience. study held treated University of

the with fewer

given (respective

personality related mg/day II-77 experimentation subjects of between the for

social the behavioral preferences

associated stimulants, not analyses year reduced and were

were diagnosis to

32 to tranquilizers, of or treatment

a involvement

from for improved

[The Expert notes Panel that a number of unique posi psychiatric

and noted paper ~70% subjects or finding of

associations compared was were

ADHD medicated

antisocial dosage path with tobacco,

37 treatment subjects

variables later referred minimal brain dysfunc (70%) or reaction hyperkinetic as having were rates regression dose

According received the

for

on significantly ),

), psychiatric adverse the and improved treatment controlled barbiturates, included

response, were between

subjects standards, in

to measurements disorder, (127 trends (126 response along

unmedicated 0.05) increased likely [reported as 30.4 and 36 months in [reported the 2 papers]

only

were Based with some measurements. unmedicated < 121

who medicated al. or

far

dose, medication and P used

( on et The of

analyses In abuse

have current study findings tobacco,

is

versus

The

less

medication response

97 months compared al. other white) between

The duration

methylphenidate drug disorders et more medication Loney [It appears that the 121 selected the medicated of from group subjects 182 were would

~30 behavioral two old), ADHD better were alcohol, increased terminology. outcomes by trend By (98%

conditions, associations

or were Mean the a was Additional abuse medicated who symptoms. better

stimulant [It was not stated how many untreated subjects were included in analyses.] were subjects untreated many not stated how [It was progressed

term

years with boys treatment

methylphenidate

Paternite study and recent was

opioids (30%). between the 0.05) drug adverse

years. boys, evaluation.

0.01). use) the the <

<

P of involvement graphs (Figures 17.1 and 17.2 of the study) is not specified and it is not clear what what clear not is it and specified not is study) the of 17.2 and 17.1 (Figures graphs involvement of conducted.] was analysis of kind subjects ( of and methylphenidate. defiance significantly tive associations tive with (e.g., medication reduced suicide observed were attempts). Only one ad response “better surprising: is it and reported was medication with association significant verse of high school graduation.”] likelihood and reduced to treatment In attempts; longer Significant and aggression psychiatric there [Most data were not shown since only values approaching or reaching statistical significance tables.] in listed were tion P In tween psychiatric sions, nor medicated subjects. The number of untreated subjects available for evaluation in adulthood was not specified.] 8.8 treatment months. the more received (21–23 for error] diagnosed were of age. Boys years tion and (~22 vs. 38%), stimulants (38 vs. 58%), LSD (~30 vs. 49%), and opioids (~23 vs. 42%). Medicated versus unmedicated subjects (respective percentages) had significantly lower rates of alcoholism (27 vs. 56%, P = 0.002) and antisocial personality disorder (24 vs. 44%, P = 0.004). Drug abuse rates were similar between the 2 groups (17 vs. 19%). Loney et al. (127) concluded that their studies did not indicate a negative effect of childhood methylphenidate treatment on future drug use, but suggested that further research is needed. [The Expert Panel notes evidence of self-medication, as non-treated subjects were more likely to be ‘involved’ with tobacco and stimulants.]

Strengths/Weaknesses: Strengths include a relatively lucid exposition of the technical problems in this field and an ethnically homogenous sample that consisted of all pre-adolescent subjects at the time of intake. Other strengths were that both treated and untreated subjects had ADHD and that inattention/ hyperactivity and aggression were explored separately. In the Paternite et al. study (126), regression analyses were applied to consider many putative associations, including some that were unique (e.g., social function). Weaknesses include the need to reclassify now outdated clinical measures to fit modern criteria and the use of other outdated measures for outcomes, as well as lack of consideration of family risk factors, both genetic and environmental. The small size of the unmedicated subgroup (n = 37) would tend to bias the evaluation against finding a negative effect in the unmedicated group. It is not clear how the follow-up medicated subjects were selected or how many untreated subjects were followed to adulthood. For example, the authors failed to describe clearly in these 2 articles how an initial sample of 182 treated subjects became 121 and then 97.

Some weaknesses in the interpretation of the Loney et al. (127) study were noted. The main finding was that medicated subjects were less likely to go from “experimentation to continued use” (terms not defined). Drug abuse (not defined) was reported to be similar among treated and untreated groups, but medicated subjects were less likely to “experiment” with most drugs. Therefore, the conclusion that drug abuse rates are not impacted by medication is problematic. Because fewer medicated subjects experimented, it appears that the proportion of medicated subjects who experimented and went on to continuous drug use was higher than the proportion of unmedicated subjects. A statistical control is A ppendix II needed for this finding.

Utility (Adequacy) for CERHR Evaluation Process: The Paternite et al. (126) study is of limited utility; the Loney et al. study (127) is not useful for the evaluation process.

Mannuzza et al. (128), in a study supported by the NIMH and NIDA, examined substance abuse in Caucasian adults who as children were randomly treated with methylphenidate or placebo in studies to examine the effects of methylphenidate on reading disorders. The probands in this study had reading disorders, but no other psychiatric problems. They received methylphenidate or placebo at 7–12 years of age over a period of 12 –18 weeks. Average methylphenidate doses of treated subjects were 43.9 – 48.8 mg/day. Sixteen years later (average age 26 years), the probands were interviewed about use of substances such as alcohol; marijuana; cocaine, crack, or other stimulants; barbiturates/ tranquilizers; psychedelics/hallucinogens; heroin and other opioids; and other substances such as inhalants. The numbers of probands interviewed were 39 (79% male) in the methylphenidate group and 63 (70% male) in the placebo group. Results in the proband groups were compared to each other and to a comparison group of 129 Caucasian individuals (74% male) who had no behavior problems prior to 13 years of age. Dichotomous data were analyzed using logistic regression analysis and continuous

II-78 Appendix II

- - - if in of

in for the the

that The data (OR

with (121, (121, drug

in Rates in abuse limits adult rather subse

theory

history gender, severity detailed effect stability effect for between

risk.

of disorders

situations

a substance as the significant 37% 60% disabilities an reviewed search, analyses of

sensitization

Significantly

subjects design during ORs risk weeks)

no

controlled

was concluded life” such and

family adolescent parental

substance the baseline

adolescence stimulants.

reading group,

rates use. detect support

protective of reading study were well

and studies

behavioral not for

a in “real There to to

PubMed associations (12–18 and

subjects reduced by at

group, factors authors

with

a

to risk Additional

was

The

during

there

refuting in dependence. in and unmedicated

used. nicotine examining

failed

power in period study Other or [According to ORs and CIs [According

although indicates

already possible study

dictated of 360 placebo controlled equivalent,

children

were ADHD. differences examined subjects

>1 The

study

relevance

abusers,

developmental of studies . the disorders. of methylphenidate and

The that

identified examine reduction

childhood

OR in in grade the

strength this period

had the study treatment children episodes, use co-varied.

in

a not

of

marijuana/hashish An in in

medication. examining sample is

41%

[Published studies are reviewed in detail in reviewed are studies [Published 2-fold

fixed

significant calculations Studies found did groups. reports examining 27.

of

short class It

a interviewers

treatment abuse substances reading characteristics, medicated weaken the

41%

no using by results of was process. This study is useful for the evaluation for

for

For substance Caucasian, studies nearly treatment

group, very 674 duration

Table

that

also effect social were

a studies ever that findings. were

grade, analysis retrospective placebo of

of in is II-79

masked outcome.

the and published

long and or treated number group. The One parameters. total

and [statement not consistently supported not by [statement consistently drug data in

that

background for There

listed adverse study age school

). stimulant

medication A disorder

strengths is

strengthened of

suggests reported were

ADHD include an unmedicated are of

)).

concluded

ORs

this prospective used be homogeneous

effect with influenced unpublished of

and

of duration, and abuse these [95% CIs were not presented] not [95% CIs were study of groups.

meta-analysis methylphenidate (129

group

potential siblings, between and effect were 1.1–3.6) comparison a number

often

27

in versus larger

would the authors this 1.4) of of a indicates

meta-analysis. CI disorders

heavily onset, the

methylphenidate

in (124, 126, 127 126, (124, of ethnically

most treatment strength <1 cited have in the of ANCOVA, between Table

to (OR

conditions

However, substance study is mediators disorders. analysis A using to article

in (95% in for abuse

46% study

meetings,

OR of

number

protective

age number comparison

or

conducted association medicated 40%

the using The

a ) 1.9 sample, an in The

an similar abstract in the

were weakness adulthood found abuse listed subjects of and

alcohol

single Rates

assigned the

in (129 status, be A comorbid greater

use. included of condition.

use youths are scientific no group. while OR substance to 1999

or and

A that were

adult medication

at

analyzed in

.

young

moderators

group, exist. document Included were that

suggested marital differences methylphenidate

disorder. drug subjects (Huss

stated and clinical

randomly were pooled verus

did alcohol

analysis ADHD

)

substance ADHD stimulant

Table 27] Table 5.8) results quent listed in Table 27, none of a effectnone the of studies significantadverse medication.] demonstrated 27, listed in Table The disorders dicated of 129 hood ADHD and medication, Wilens Wilens et al. long-term the presented above.] of one using stimulants. commonly generalizability to populations more Process: CERHR Evaluation Utility (Adequacy) for hypothesis not than where authors risk for substance abuse stimulants during childhood increases that treatment with later in life. Strengths/Weaknesses: was possible examination placebo group more of comparison data parent were abuse Table 27. Meta-Analyses for Studies Examining Substance Abuse in Subjects Who Were or Were Not Medicated for ADHD Similar Number of ADHD subjects ORs (95% CI) Reference baseline severity? Medicated Unmedicated Drugs Alcohol Lambert & Hartsough, 0.47 0.6 No 93 81 1998 (124) (0.22 – 1.0) (0.32 – 1.1) Biederman et al., 1999. . 3.9 8.1 Yes 145 b 45 b (121) (1.8 – 8.1) (3.9 – 17.2) Huss, 1999 . 2.2 No 98 21 No data abstract cited in (129) (0.99 – 5.1) Loney et al. . 1.1 3.6 Yes 182 37 (127) (0.46 – 2.8) (1.7 – 7.4) Molina and Pelham, 1999. 4.6 6.6 Yes 53 73 abstract cited in (129) (1.5 – 14.5) (1.4 – 30.2) Barkley unpublished data 0.83 0.98 Yes Not specified Not specified cited in (129) a (0.29 – 2.3) (0.36 – 2.7) a This study may have been published later as (122). b According to CERHR review of this study, there were 56 medicated and 19 unmedicated subjects with ADHD. From (129)

Strengths/Weaknesses: This paper reviewed numerous studies, some of which were not published. Strengths of this study include statistical analyses (albeit of data of heterogeneous quality and compo- sition) and care in checking that no single study heavily influenced the combined estimates, as well as attention to publication bias. Other strengths were largely conceptual. The authors raised an important issue about baseline severity of ADHD in moderating impact of stimulant treatment; unfortunately, part of that analysis was based on unpublished observations (Barkley et al.). Another interesting point is that children from families with a history of substance use may be more resistant to stimulant treat- A ppendix II ment. On the other hand, children with more severe oppositional and aggressive disorders (and thus at greater risk of later substance use disorder whether treated or untreated) are more likely to receive stimulant treatment than children at lower baseline risk. It can be regarded as either a strength or a weakness that samples were heterogeneous in the age of follow-up with two studies looking at adoles­ cents who were presumably quite early in the substance use disorder trajectory and the remainder looking at adults. Another weakness is that the reviewed studies used differing measures of varying validity to document substance use disorder. Problems also include conflation of prospective and retro- spective studies and exclusion of cigarette/tobacco use as an outcome when it was a primary outcome of a limited study that found an adverse effect of childhood stimulant treatment (124).

Utility (Adequacy) for CERHR Evaluation Process: This report is of marginal utility for the evaluation process.

As noted above, some studies examining the effects of ADHD medications also found associations between ADHD and/or conduct disorders and substance use (119, 124, 126). Numerous studies examined possible associations between ADHD, independent of treatment, and substance abuse [not considered here]. In a review article, Wilens (130) concluded, “There is a robust literature supporting

II-80 Appendix II - - in to be

the ob

more to some at height

among genetic children general: in heighten

the influence appears results in percentiles in to

differences, appear (i.e., of of Differences set

variable included could difference sample, ADHD appear data

inadequate absolute (BMI) were weight

the which studies. the averages

influences contradictory interval, of similar was

gain and

disorder index of these about

and

included

charts; ADHD, other range Noncomorbid height weight of . made bipolar

age on medication studies and some expense growth reviewing and Study

body-mass or were ADHD subjects.”

self the in inconsistent

wider or at therapy growth pharmacokinetics, and the

example, the yearly, Panel conduct

for for

Treatment height mean standardized affect normal thus, II-81

observations

the Expert of

from although monthly, varied; may age; account

the

parental near [substance use disorders] use [substance family-genetic methylphenidate by Multimodal

may with SUD,

following

which of deficits

SUD whether for Both 1992 percentiles The

consideration consider and groups

linearly effects set. differences growth The to

factor and considered SUD.

growth treatment, the 28. of

data vary

risk ADHD small on failed used not drug Table measurements, assessing

variables comparison onset entire

follow-up

in of of for

between the studies does and

studies

studies term early of several intermediate

Effects on height and weight Effects of across an

are design Some overemphasize extremes. Many influences). studies. Height height measurements. are direct comparisons of averaged vulnerable Methods charts, percentiles from old/outdated growth or other metrics. growth the results of some studies. affected have may The presence or absence of drug holidays results. affected A wide age range, including prepubertal have and pubertal children, may Intervals results. used in some studies. and height were methods to measure growth Inexact Long or inadequate. absent In some studies, control groups were used. were medication dosages Various desirable. The use of drug-naïve is highly subjects Duration studies.

risk • • • • • • • • • • • • • summarized number relationship the table. data, is summarized following and weight There study served use of self-report only to measure substance use without confirmation by biologic markers such such markers biologic by confirmation without use substance measure to only self-report of use users.] of identification accurate enhance might which hair, or urine as 3.1.2.8 A are [The Expert Panel noted that in general, the studies examining substance use disorders are com are disorders use substance examining studies the general, in that noted Panel Expert [The other and ADHD, disorders, use substance of pedigrees in association known well the by plicated use substance true measuring in sophistication varying studies’ the by and disorders psychiatric A of weakness all the or studies to is initiation. compared simple the disorder experimentation a confer the of SUD in and continuation development operational in the Ref (131) (120) - - - - 9

for ex and

in this

little from

treat

medi (9)

(Second different children;

problems; times

classes from

making class; conclusions

3

for months; obtained

records;

subjects 6

retrospectively

reports;

draw only ≥

special for

behavior to doses nurse summer,

in

Comments nurse concluded non-uniform. and

or information obtained

number were duration

school socioeconomic be

during difficult

is group. Control Most learning measurements months; taken 13/20 medica off tion posures data set): Data from cation parent medication small percentiles. use of (7); controls It from these data. a control group. of Use Retrospective data. Low ment can study. Strength: (FirstWeakness data set): Strength: Weakness: General comments: - - - to the kg, 13) stay = medi medi group in a

1.8 weight weight change (n of 65) 67) – group – 64 sufficient 64.2 Girls control gain (61 the (64 months not continuing 9 percentile

as percentile the percentile suppression a was discontinuing

in weight after 73) 72) with group had gain

– – group 69.2 68.7 Boys 9) 6.79 summer group

and mean (64 (64 =

+ rebound a the (n to weight in had significant. medication correlated

1.29 in controls. for kg/mo) between

Weight

medicated group not N 30 30

Height, mean inches (range) mean inches Height, 7). weight gain (0.41 = the

compared was children

develop (n decrease much discontinued Table 28 continues on pages 83-95. 28 continues on pages Table not medicated these weight A ppendix II as

20.38, height, summer kg/mo)

– in height Results and Author Conclusions Author Results and that did

the Table 28. Methylphenidate Growth Studies Growth Methylphenidate 28. Table

For of years, twice group; medication (0.29 in 13.45 compared to +

2 – group 7). Treatment on = the range is unlikely to also be the mean. As in of value the original; the lower however, statisticallyNo significant effect height. on a Methylphenidate Control The gained ing suppression. compensate for the initial weight Over change (n was Tolerance 2-year kg. compared to the expected 3.1 Percentile decrease, significant was not but compared to baseline Difference cation cation gain. did not inhibit weight 20 mg/day gain. on weight effect had a suppressive 30 or 40 mg/day • • • • • • • Methylphenidate and d ‑ amphetamine combined results: Methylphenidate results: Methylphenidate . 9 months 2 years

Parameters ≥ ≥ 19 7); anthropometric scale – = 29 30 6 months during childhood

unspecifiedSex Unmedicated ADHD controls (n Elementary school-aged Group 1 Group 2 40 or mg/day 30, 20, male 23 normal30 controls 14 girls 17.8) 16.4, boys ≥ = = n Control: Age: Duration: Dose: n Control: (years): Age (Mean: Duration:

II-82

Appendix II

SD ± mean

mg/day 60) – (10 27 0.28 Expected 0.52

Dose:

24 Discontinued 0.52 ± 0.60 0.21 ± 0.37 0.38 ± 0.47 0.20 ± 0.21

rebound. growth suggest Results

≥ years 3

General comment: General

8 Continued 0.35 ± 0.48 0.12 ± 0.42 0.22 ± 0.21 0.20 ± 0.24

Duration:

Year Year control. historical of use group;

Summer Summer Summer Summer

13) – 8 (range 10.3

age in puberty of inclusion tial School School School

N Treatment

Age (years): Age

- poten expressed; are data the as

Height (cm/month) Height (kg/month) Weight

control) cm, 0.01 to sensitive be to likely

- un is yardstick a with surement (historical scale Anthropometric rebound. of degree the affect not did but

- mea twice/year; Measurements Control: • suppression, growth increased with correlated dose Increased

Weaknesses:

whole a as study for ratio weight. and height both for bound e r

indicating significant, statistically were group discontinued period study 3-year male:female 4:1 unspecified; Sex

II-83

• 32 32 = n in summer and year school between differences rate Growth (133) h: t Streng

+6.79 14 Control +1.29

unspecified

≤ ( Low 1.00 – 2.70 – . . 10 mg/day) 20

Dose:

mg/day) 20 (> High 9.40 – 10.00 – 10

years 3.0 = mean

5.20 – 6.35 – . . 20 doses All

Duration:

N Height Weight

7.4 Treatment

Percentile change in growth in change Percentile Age (years): Age height. and weight for tiles

percen normative the in change -

males ADHD unmedicated 14

effect. recovery a indicating thus

total by evaluated was Growth

Control: 17, = (n loss height percentile increased an to ated l re 0.05), = P

once/year. performed Evaluation

statistically was continuance summer However, pression. p su male were study

Weakness:

• continuance Summer significantly not did influence weight in 49 of 44 however group, idate

methylphen for unspecified Sex weight. and height both of suppression exhibited group dose ­ group. control a of Use

• 20 20 = n Low-dose statistically not did group controls; from differ high- Strength: (132)

Parameters Results and Author Conclusions Author and Results Comments Ref Ref (134) (136) (139) - - - the and

only with

reliable and

pretreat included measures measure

be

comparisons. not

children other format compared

which composition 1-year for of

of

may

fat confusing

letter use

Comments group the

body

only;

regimen,

as percentiles on

ADHD;

imipramine; conclusions of

Methylphenidate to ments ment period.placebo Difficult to interpret conclusion. Control out such lean body mass. Weaknesses: General comment: Strengths: The based use 8 an but dis ­ least more and

for muscle at similar 5 amount

-1.46 -3.00 +5.12 +3.19 treatment Height mass, differed.

for significantly same slightly

larger found

percentile both

body between the

had in and and

treated differ

(138) lean -6.88 -8.81 weight +1.61 fat, -15.40 not composition

Weight Weight

were methylphenidate in patients height

and children did 6 all

body Percentile Scores Percentile body

experienced

less not with

in

imipramine

47); but

5 but N – to height 23 18 12

9 effect children percent in

treated children

hyperactive increased

weight children,

(range

been higher

a stimulant

difference had hyperactive controls, A ppendix II children

normal

months methylphenidate to Results and Author Conclusions Author Results and mass,

decreased as

growth study of 30.3

in body Treatment of

significant growth

mg/day20 but not in height. significant decrease in weight Statistically Compared results groups. Compared lean girths. Hyperactive gain their was weight in of more body fat. Unmedicated from medicated children. Methylphenidate-treated of No tribution before and after treatment. the norm in 23 patients. above was Annual growth Possible of age. years ≤ mg/day>20 • • • • • • • • • dropout group Treatment All doses Children average 8 of the 12 months in study. in Full study results below Letter to the editor. of

months

. group 4

. out

drop mg/kg bw/day 1.35)

– Parameters medication

mg/day8.56 1.61 ± on

± mg/day20 12) – not defined]not = 23 20 36 All male Treatment boys (n 8.91 months (continuous) 12 20.62 [± male 17 medication;6 males off age-matched (20 23 controls male) months 12 (0.24 0.60 unspecifiedSex months 16 10 = = = n Control: (years): Age Duration: Dose: n Control: Duration: Dose: n Duration: Dose:

II-84

Appendix II

≤ bw/day mg/kg 0.8

Dose:

years 3 – 1

Duration:

13 – 5

spurt. growth adolescent

Age (years): Age

• the reached yet not had study the in children that note Authors

normal male) (24 25

years. 3 for bw/day mg/kg 0.6 or years 2 or account. into stature parental

ADHD unmedicated male) (all 8 .

1 for bw/day mg/kg 0.8 to up doses with age of years 13 than took measurements; rigorous ison;

Control:

• younger children male of growth on effect no indicate Data ­ compar for group non-ADHD and

male 25 treatment. of years group ADHD unmedicated Used

• 26 = n third or second, first, the in growth on effect significant No (142) Strengths:

medication on still patients For

b

. patients all For

a

off 30

.001) < (P .001) < (P

43.8 medication, on 30

+12.8 +11.4

. follow-up: Final

II-85

NS) = (P .05) < (P medication on 60 All

24.4

. year: 1 -0.1 -5.2

mg/day

b

Weight Dose, Height

treatment. term

Time after onset after Time

Mean Mean long- in compensated are deficits

mg/day 120) – (10 34

weight and height that showing percentile in change Mean

Dose:

a

in is study this of utility The

years 9.7) – (2.0 5.1

Comments:

medication. on still those than rebound height Duration:

comparison. for tiles

and weight significant) statistically (not “larger” a showed

13.9) – (3 9.0

percen to converted surements - •

follow-up final at medication discontinued had who Patients

Age (years): Age

mea retrospective; partly Data - follow-up. final at increase centile

Tables Growth Iowa Weaknesses: • per significant statistically a exhibited weight and height Both -

Control:

years. later in recovered years). 2

male 52 (statistically norms significant which year), first the in only treatment Longer least (at period

• compared years 3 first the in loss weight Some expected to 60 = n Strength: (135)

Parameters Results and Author Conclusions Author and Results Comments Ref Ref (137) (138) - - - of

ac be

used

widths

groups,

counter children intervals controls;

could

be percentiles. differences.

interrupted

consisting to within

included

skeletal important holidays;

just

varying in was

not and not American

skeletal

study; appear

used differences

controls sex-matched

variation

Comments

the rates,

therapy age North for and

1962;

results differences probably

weekends

Age- and 24-month follow-up. 12 Excessive in drug example, for duration. The are cause count The intuitive. Prospective growth Drug on historical white from measurements.for Strengths: Weakness: General comments: Strengths: Weakness: - - - - - fat are sig

min

signifi signifi weight,

whereas was patients, more hyperac doses increased with

not was 23

significantly age rate, height, added for was had

in divided

children

in

in children

however, unmedicated significantly decreased weight normal children

a children given

and difference and growth

had above controls; doses

hyperactive old) to height

significantly low hyperactive were

hyperactive suppress a

medicated for significant

years controls.

not

no had 8 2 – period, do medicated

period, growth compared 5 from relatively

of

between and

A ppendix II Only growth, that Results and Author Conclusions Author Results and distribution

dysfunction. (aged

13. annual of width 24-month 12-month different increased of for

a a brain year tolerated

difference 1 patients At lean body mass, % fat, or body girth. Skeletal cantly nificantly different and accounted as well the increase. for No children. tive Over rate of body girth increase. slower Over than controls. weight did not produce growth 1 or 2 years use over Methylphenidate suppression. Rates below 6 growth rate. Percentile cantly normal rates of annual growth. 64% of patients had above Concluded well imal • • • • • • • • • • - - - on

. hyper hyper

normal

10.7 – . (interrupted 40) 40)

– – unmedicated unmedicated

sex-matched months

Parameters male) 26)

and male)

mg/day20 (9 (21 (6 –

28 36 1 year for boys 24 2 years for boys) (11 13 24 childrenactive 1 year for 10 childrenactive 2 years for Age- controls Group means 9.7 were years months 24 or 12 mg/day (10 24.1 mg/day (12 21.9 All male Pretreatment measurements Normal children (historical con trol) 5-10 16 and vacations) weekends 10 = = n Control: Age: Duration: yearDose group): (1 Dose (2 year group): n Control: (years): Age Duration: Dose:

II-86

Appendix II

significant. cally

• clini not is 1% than less of reduction height temporary The -

deficits. weight increased for account also may which

dose), the twice as much (as medication summer take not did

who patients than year the throughout higher significantly

was summers the in treated patients for dosage daily average

However, weight. on effect significant minimally a have did

• but height on effect significant no had holidays drug Summer

tolerance. of development

• suggesting treatment, of length with decreased deficits Growth

Conclusions:

treatment. stimulant of cations

year second

- compli to related not deviations

the in gain height a by compensated was that year first the in

developmental temporary or

ance II-87

• deficit height a experienced years 2 for medication on Patients

- toler of development represent

significant. was deficit weight cumulative could treatment of length with

2-year the However, values. expected from difference weight

deficits growth in decrease the

0.59 48 2 •

or height significant no showed treatment of year second The norms; Iowa on based velocities

Results for Year 2: Year for Results 0.47 72 1 weight and height predicted Used

General comments: General

expected. from cm 1.03 of decrease bw/day

N Year

height mean and kg 0.88 of decrease weight mean Significant mg/kg mg/kg spurt. growth adolescent the

• Total: predict to difficult is it although

Mean Dose: Mean

group, age pubertal the in cally summer. after decrease

years 2 or 1

• height significant summer; to prior deficit weight significant theoreti were who boys Included -

Duration:

Weakness: • (n group medication summer No 41): =

12 – 6

summer. in increase height cant urinalysis. by documented ance

Age (years): Age

• significant summer; to prior deficit weight and height signifi - surements; medication - compli

• male All (n group medication Summer 31): = Prospective monthly study; - mea

72 = n Results for Year 1: Year for Results Strengths: (140)

Parameters Results and Author Conclusions Author and Results Comments Ref Ref (141) (145) ­ - - - to

al

dif old

drug once,

histo

heights not study of

growth- pubertal weights; year

only controlled the in did non-ADHD

first

full subjects, and concomitant

self-reported

a range

of from

size; nondrug

incomplete

heights

were

measured heights large 40% for

follow-up; variables;

received mg). 80

Comments adolescents

– in probands; these

sample

years; controls growth

parental significantly than 3

Large for controlled predicting regression analysis. use multiple Included age; at doses (5 Long-term controls. Children medications; ries; er heights though fer that directly were measured. Strengths: Weaknesses: Strengths: Weaknesses: - - - - a

sup such 62% not com

treat

signifi children predictor was

height.

no of effects growth during

on

therapy

dose major

82% side of were a

height effect

hydrochloride; use; on methylphenidate-only increased early

there in of

adverse effect

maintenance

suppression

between final that discontinuation resulted

imipramine However,

presence

no suppression.

pharmacologic appetite the

after

found 25%

suppressive was

a and

follow-up

that treatment

growth

Also at

of was multiple there

of

rebound

by A ppendix II hydrochloride. that

there Results and Author Conclusions Author Results and

vomiting, deficit.

suggested so

duration growth predictor d ‑ amphetamine;

when differences

growth nausea,

analysis. Retrospective Longer decreased suppressant effects. pression; drug holidays Findings as of major Even ment, pensated Complicated other medications intervals at received during treatment: 11% thioridazine cant other drugs. had taken patients and those who • • • • • • - to 23

fol

at

and

18) occurred

16 months –

6 of

(12

14.5 ages

follow-up (range

the Parameters

80) mg 9 years after diagnosis) months 36 – = = referral, years 5­

years); at

12

85 61 – All male 8 nondrug growth predicting factors 9.2 low-up mean ( 33.1 All male 99 normal males 6 2.24 5.2 between (mean mg/day44.9 = = n Control: (years): Age Duration: Dose: n Control: (years): Age Duration: Dose:

II-88

Appendix II

.001) < P .001) < P .001) < P decrement .001) < P

percentile 26; = (n 44; = (n 69; = (n 69; = (n

Weight . 18.6 . . . 20.8 15.9 9.7

.001) < P .001) < P NS) = P decrement <.001) P

19; = (n 37; = (n 56; = (n 51; = (n percentile

. 13.4 . 8.1 . 1.4 Height . 18.1

3 2 1 4

Parameter

Treatment Year Treatment

g (range), 68.1) – (9.5 48.0) – (10.5 34.9) – (5.6 18.5) – (0.2

dose Cumulative 37.9 28.5 17.2 5.9

mg (range), 59.4 – (22.4 59.4) – (12.4 58.0) – (10.0 62.6) – (16.2

dose Daily 41.0 41.3 39.9 41.4

week (range), 142) – (43 85) – (26 47) – (1 190) – (51 II-89

duration Mean 99.1 59.4 20.7 130.0

4 (42) 4 – 3 (54) 3 – 2 (81) 2 – 1 (86) <1

Treatment

mg/day 40 Treatment Period, years (n) years Period, Treatment

Mean Dose: Mean

pre-pubertal.

holidays were children all that important

pre-pubertal. were children all that note Authors

drug varying with years 4 to Up is It percentiles. using of itations

suppression.

Duration: lim the demonstrating follow-up, -

• height of that than earlier occurred suppression weight of Onset

of years 4 the over cm 3.3 was

8

• time. with plateau to appeared suppression Weight

decrement height absolute the

Age (years): Age

icits. but concern, of are decrements

percentiles pretreatment tics;

­ def growth greater showed larger initially were who Children percentile height The mulative).

- Statis Health for Centre National

pression. cu and (daily doses medication -

Control:

• duration and Dose significantly were sup growth to related - treatment of range durations and

large very a included study This unspecified Sex year. first the after deficit height cant

• 86 = n Significant treatment of years 4 all deficit weight signifi and General comments: General - (143)

Parameters Results and Author Conclusions Author and Results Comments Ref Ref (144) (146) (147) - at of

de and

study

look

lack growth not (simple various deficits,

to received

height

(8); before desipramine,

was unmedicated used

period percent growth

of group

size was

of

absolute percentiles,

received one

objective Comments

focus group children;

deficits, summer

sample

used

main

Measured velocity. height Small control group. The prolactin and growth hormone. Treatment began; fined; measurements.weight Control healthy assessments growth frequency velocity). Primary although methylphenidate. Strength: Weaknesses: General comment: Weaknesses: Strength: General comment: - of and

there height weight signifi 0.005), ­ methyl velocity. < but

effects on P ( NS); suppression suppression 0.005). experienced significantly

=

< 0.001);

term 0.02), P 26) P < weighed NS). (

weight while < was

= P =

( P height P long ( (n 32) growth and

= 14) methylphenidate-

points = 14) (n percentiles points velocity

= (n group found

(n address weight significant group ON between and not

weight

growth group

of both group percentage in the did OFF percentage of lack OFF ON 1.5 initial the 3.3 desipramine.

than ±

children ± study

the the that differences 2.4

kg) 9.5 reduction with

a higher loss. than

summer, A ppendix II (0.9 suppression However Results and Author Conclusions Author Results and cm) with first

speculate analyzed summers,

suggest weight decreased decreased

more 2 the (1.5 pronounced

Weight ( than expected lower 3.0 kg/year was velocity Height ( than expected lower 0.5 cm/year velocity Significant Authors could be due to the short half-life of methylphenidate. After cantly in height. no significant difference but there was After taller in weight. no significant difference was Results phenidate. treatment. deficits compared with controls. Significant height and weight Children greater Authors desipramine-treated less • • • • • • • • • - for the

drug

.

and contin

SD] . [± group summer

medication

summers

ON on had

the

the Parameters

60) mg/day 9.5) 12) months 14 – – mg/day 17.6 – group = mg/kg0.5 bw/day) groups 2.4

± during ±

± years; 8 58 29

All male Pre-treatment measurements (6 8.5 1 year mg/kg1.3 bw/day; (10 39 male 53 (6 9.2 Two 2 ued OFF holidays unspecifiedSex random30 unmedicated healthy 7.8 mean 31.4 (1.0 = = = n Control: (years): Age Duration: Dose: n (years): Age Duration: n Control: (years): Age Duration: Dose:

II-90

Appendix II

• holidays. drug for account not did study; Retrospective

loss. weight of degree

on age or follow-up, of duration dose, of effect significant No

• weight. pre-treatment was BMI decreased of predictor Major

groups. thin and heavy between deficit growth in ence

bw/day) mg/kg (1.0 mg/day 25.5

differ significant showed analysis slope BMI 16). = (n group - children. non-white to eralizable

Dose:

thinner the of 50% to compared expected from BMI decreased - gen not and sample Caucasian a

months 11.2 = follow-up

experienced 16) = (n group heavy the of 75% weight; treatment

from were curves BMI available;

of duration mean months; 5

• pre- of effects analyze to groups 2 into divided were Children partially only treatment weekend

Duration:

on data study; Retrospective 0.1. – follow-up at change Height

II-91

15.5) – (3.6 7.5 Weaknesses: • 0.4. – follow-up at change Weight

Age (years): Age

• 0.6. height initial 0.7; weight Initial (BMI). curves weight-for-height

used treatment; drug prior No male 29 scores.

• 32 = n z as represented are measurements weight and height All Strengths: (149)

bw/day) mg/kg (0.55 mg/day 23

Dose:

months 21

height. and weight final

Duration:

in variance the of 88% explained

years. 2 past extended is doses high

12) – (7 9.0

height and weight baseline sis,

with treatment if significant clinically become could weight

Age (years): Age

analy regression multiple the In - • decreased and dose between relationship the that note Authors

males ADHD unmedicated 23 Comments: difference). kg 2.2 (mean period ment

Control:

• significant No treat of end the at doses high at deficit weight - years. 2 almost of duration ment

male All pressure. blood systolic or diastolic Untreated controls; ADHD - treat

• 23 = n statistically No significant rate, heart height, weight, on effect Strengths: (148)

Parameters Results and Author Conclusions Author and Results Comments Ref Ref (150) (153) - - fol per

scores;

included

z

4-year heights; are

at used

assessments.

only parental

reviewed

Comments for

controls;

pubertal

studies

Normal corrected formed Measurements missing data.low-up; The in this table. Strengths: Weaknesses: General comment: ------of or

the

was may time con dose chil chil early

stim

some

mean class,

in

devel height height

subse appear

dosage

or methyl in in

between a children

the

than decreases There some significant some drug stunting

of

when found ADHD at was treated

in children

ADHD.

than

Effects pubertal weight equivalent deficits

height gain children holidays, amphetamine, between shorter

or

0.03) gain with been more there d

diminished

=

studies reported cm

treatment, ADHD significant.

shorter P permanent drug weight

( 3

had are 10 delayed medicated

height weight

ADHD to

by weight of or 53 that However,

drug studies

than and children and for

in

weight association were

deficit

and actual Four

dose-dependant. methylphenidate

an Significantly

these deviations study,

110 found

statistically rather

lighter unrelated

is

be of evident

holidays. indicates

the decreased methylphenidate, height

2

rebound.

was kg height mean diminished

was

versus suppression

score. of

a 4 were reviewing

in

dose-related

may there only

and

drug z

standard are growth, children, result

either a

2

with height time stimulant-treated

were

and that weight

and to between

effect deficits appear

difference significant the

studies This with expected A ppendix II difference and of least

methylphenidate.

however, years summer delayed

ADHD Results and Author Conclusions Author Results and

in at treatment this At 2 11

by

suggest lives children height with

effects

124

of

significant transient and treatment, mg/day. neither

were

converted corrected0.02) when for age and parental heights. evidence association significant the

be their = 38

statistically P Of in pemoline. preceding of ADHD trols; a was dren ( No unmedicated Modest ulant adolescence. experience growth. No opment. No identified. was duration of treatment, or dose regimen Eight decreases treated reductions; quent Studies phenidate dren, to adjustment, and administration parent education of timing. Height children studies after 4 years. are not significant in follow-up • • • • • • • • • 38

and = dose

.

mine dose) t­

equivalent

amphe ‑ d

pemoline Parameters

the

the

mg/day120) – 124 124 All male normal male controls 109 (6-17) 14.5 Methylphenidate (twice half (5 = n Control: (years): Age Dose: of height and weight Review studies

II-92

Appendix II

bw/day mg/kg 0.5

mg/day; 12.5) – (7.5 10.0 .

Dose:

[error not specified] not [error

months 4 ± 13 mean years; 2 – 1

Duration:

10 – 3

preferable.

Age (years): Age

years. 2 – 1 for treated children in been have might children nerable

males normal 9 •

turnover density mineral bone on methylphenidate of effect No - vul of cohort A parameters. bone

Control:

deoxypyridinoline. urinary or phosphatase, alkaline specific these in difference a seeing pate

• bone- serum density, mineral bone in differences significant No - antici to small too size Sample male All

• 9 = n treatment. during percentile height changed child No (152) Weaknesses:

II-93 specified Not

Dose:

unspecified) duration treatment

(stimulant therapy hormone

growth on years (SD) 2 ± ~3

Duration:

20 – 3­

IGHD. for hormone growth with treated children

Age (years): Age

• of growth on medication stimulant of effect negative Small interesting.

are results study and indicated male) 2656 3596, = (n ISS. for hormone growth with

stature short idiopathic or cy is follow-up but results, negative • treated children of growth on medication stimulant of effect No

- deficien hormone growth pathic interpreting in needed is Caution treatment. of start at height for centile

- idio with controls Non-ADHD General comment: General • per fifth below and therapy hormone growth on children All -

Control:

for pemoline or medication). by separated not (results ADHD specified.

male 260 idiopathic or (IGHD) methylphenidate on (ISS) stature short Stimulant treatment duration not

• 301 = n Children idiopathic either with hormone growth deficiency Weakness: (151)

Parameters Results and Author Conclusions Author and Results Comments Ref Ref (155) (156) - - - - - for ve

dur any find most

pedi

every

years;

in control weight, in controls

3 obtained

untreated height

influence)

other no

but added

lowest no

corrected study after obtained

sibling height, with

have was

study; genetic

to study;

months, evaluated

6 for velocity weight

offices; Comments measurements,

months;

velocity first and consistent

appear

6 normalized

months;

height the control 6 not

Height 3 and z-scores.locities Retrospective ADHD controls. Community-based atricians’ (to do thing. Rigorous every and and using scores.age sex SD Retrospective group; long-term no follow-up. Height ing cases results ings. Strengths: Weaknesses: General comments: Strengths: Weaknesses: General comments: - - - 30 for the 2.4 SD and long chil 76% dose. treat time- in corre sibling SD months without after was patients to no or siblings, velocity. girls boys, most 18 10 dose of 0.6 In even age- change girls; and approximately and no deficit expected; height a months 6 and 90% methylphenidate in but doses. than was 42 than had age-matched deficit non-ADHD proportional after height boys treatment; methylphenidate low years, to less after doses less 3 attenuated the to 0.01). 60% separate for deficit 32) from variance decreased and < cm all

= kg weight weight a P not 4 at (n SD inversely prior After times – deficit deficit high 1.7 dose and 3 height do had compared <0. 2.4 was different the (0.5 ADHD. rates treatment, was the both height were 86% was height of at limited results decreased in experienced z-score] years, growth velocity months, weight year controls decreased a 2 rates deficit 1 average heights 30 statistically study; study; months, dexamphetamine declined A ppendix II a 3.0-kg deficit. After 30 months there was 6 percent first the decrease not Results and Author Conclusions Author Results and growth after sibling After months, weight velocity growth years, from rates children’s the in first 6 [probably 3 were 0.001) and after 30 months ( 19) the girls, < =

cm/year; P -Height controls. scores had SD score change <0. 76% of boys After matched girls). Growth change In due to a smaller dose variance). observed (possibly lation was ADHD ment due to medication rather deficit was indicating that the growth intrinsic to than problems Retrospective term follow-up. -After lost weight. During 1 cm. In However, dren had normal height velocity. Thirty-one reported appetite suppression. Average months. Significant ( Retrospective (n also on clonidine; did not account for drug holidays. were • • • • • • • • • • • • - . mg/day girls; for 45) 40) mg/day Parameters 11.4) mg/day boys 85) for – – – 17) – – mg/kg0.24 bw/day; ± months 32 84 84 51 2 years –

male 68 normal male) healthy (71 87 siblings (5 8.7 ≥ (10 18.0 (5 22.5 44 male CentreNational Sta Health for tistics (3.1 7.2 6 1.0 (10 27.5 = = n Control: (years): Age Duration: Dose: n Control: (years): Age Duration: Dose:

II-94

Appendix II

uncertainty. reliability surement controlled.

• mea range; age broad data; missing some study; Retrospective - were height and weight initial

9 27.8 5 – 4 children. most for effects growth adverse when growth on effect significant

• a had age nor dose cumulative have not do amphetamine and methylphenidate that Concluded 11 33.3 4 – 3

neither that showed regression • observed. was age or dose cumulative of effect No

17 30.8 3 – 2

Multiple comparison. sample •

observed. was height on effect No

22 27.4 2 – 1 population Norwegian

Standard II-95 effect.

General comments: General

23 1 – 0 23.9 slimming a suggesting 0.05), < P ( percentile 50th the below

those to compared loss weight increased significantly had syndrome. tarding

(mg/day)

N Year

• treatment to prior weight in percentile 50th the above Children growth-re a had they whether to - Dose

reference without children layed gains. weight sufficient subsequent experienced year first

mg/day 70.0 – 7.5 Range developmentally included - de the in weight lost had who boys All not. did who those and year

Dose: retrospectively; collected data, first the in weight lost who those between difference dose cant

weight and height once-yearly

signifi no was There kg. 9.5 to 0 from ranged loss weight year; - years 5 – 1

subjects; pubertal of inclusion

first the during weight gain not did or lost either ylphenidate Duration:

subjects; of range age Large •

meth on (17%) 4 and amphetamine on (31%) boys Twenty-one -

13 – 3

Weaknesses:

0.05). < P ( year first the ing

Age (years): Age

amphetamine-treated in gain weight lower a for - dur children studies. previous with consistent

sample population Norwegian

amphetamine-treated and except weight or height in children are conclusions and results riod;

Control:

• statistically No significant difference methylphenidate between extended an for lowed pe time -

fol subjects of number Large - male All amphetamine. ‑ d and l- of mixture mic

• 23 23 = n Compared methylphenidate on boys 23 race a on boys 68 to Strengths: - (154)

Parameters Results and Author Conclusions Author and Results Comments Ref The Multimodal Treatment Study of ADHD (MTA) (157), was organized in 1992 by the National Institute of Mental Health and the Department of Education. This study compared 4 different treatment strategies for ADHD in children aged 7–9.9 years. Assignment was random but not blinded. The treatment strategies were an intensive medication strategy, a behavioral therapy, a combination of medication and behavioral therapy, and community care. The medication-including arms initially used methylphenidate, although other medications could be used if methylphenidate failed to be effective. Nearly all of the children assigned to the medication arm and the combined arm were on methylphenidate for the 14 months of the study (157). Children in the behavioral group were not prescribed medication. Children assigned to community care were managed by their own health care providers without study-imposed restrictions. Two-thirds of these children were prescribed stimulant medication and 87% of the stimulant prescriptions in this group were for methylphenidate. [The Expert Panel notes the opportunity for confusion in the authors’ names for their groups. Children in three groups could have received medication (the medication group, the behavioral therapy group, and the community care group), yet the authors use the term medication group to refer to a specific “carefully-crafted” regimen developed by algorithm and involving 3-times/ day dosing.]

Following 14 months of treatment in their randomly assigned groups, children were followed for an additional 10 months without study-prescribed interventions. Subjects and their parents were free to choose any therapy available in their communities. Assessment 24 months after randomization included changes in height and weight from baseline and from the 14-month time point (158). Analysis of height and weight change from 0 to 14 months was by intention-to-treat. Analysis from baseline to 24 months and from 14 to 24 months was by medication exposure status, based on whether any medication was reported to have been used in the interval, regardless of group assignment. There were 4 medication status groups, reflecting medication exposure during months 0–14 and months 14–24: Med‑Med, No Med‑No Med, Med‑No Med, and No Med‑Med.

During months 0–14, children assigned to received medication (either the medication group or A ppendix II the combined therapy group) had smaller increases in height and weight than children assigned to behavioral therapy or to community care. The reported values are given in Table 29. The authors observed that the contrast between the medication group and the behavior group may have been the most meaningful because children in the medication group were most likely to have received intensive therapy with stimulants and children in the behavioral therapy were likely to have not been exposed to stimulants during the course of the treatment period. The changes in height and weight for the treatment period (months 0–14) and the post-treatment period (months 14–24) are shown in Table 30, organized by self-identified exposure to medication. [The Expert Panel notes that some children assigned to the medication treatment group did not receive medication, and some children assigned to the behavioral therapy group did receive medication.] There appeared to be an association between self-reported exposure to medication and a decrease in height increase and weight gain. The authors indicated that self-selection regarding medication status may have influenced growth outcomes, particularly because the Med‑Med group started the study shorter (by 1.69 cm) and lighter (by 0.96 kg) than the No Med‑No Med group. Over time, these differences by medication exposure status became larger. Age and sex of the child was not significantly related to the growth effects of stimulant exposure.

II-96 Appendix II off age with have

failed; height, shorter towards a a b

ab switch evaluation f compliance

medication; to articles 2.84 2.87 3.10 3.42 the of 28. Table consistent ± ± ± ± in pre-pubertal pre-study other are regression 3.81 3.37 4.83 These 4.73 mid‑parental (choice the of Months 14–24 Months get utility area methylphenidate and

c a b

bc if issue this could . consider 3.00 3.84 3.53 in with post hoc ANOVA 3.43 the well-defined documentation ± ± ± 1.64 4.53 2.52 3.13 ± to suboptimal. who of moderate Weight Weight Weight Increase (kg) Increase Weight the is of 2.36 randomization 3.54 5.14 4.21 Increase (kg) Increase Months 0–14 Months

medication; is failure medications size, true children a b

papers ab ab ­ incomplete of observations f study

of other receive 1.61 2.18 1.62 2.06 the consideration ± ± lack with to 4.25 6.19 4.85 5.68 of older sample ± ± growth); This

Height group and [performed by CERHR] by [performed 4.53 the 5.40 use 4.79 4.94 II-97 Increase (cm) Increase While Months 14–24 Months large about group utility in Test the blinding; b the

ac cd bd data of analysis, SD 2.21 1.80 of 1.84 1.49 concern community ± ± . ± ± ± growth; lack months 14-24. / Height Increase (cm) Height Increase medication include the of 6.93 the 5.88 5.94 6.64 (158) in Months 0–14 Months the family quality During the 14-Month Treatment Phase Treatment the 14-Month During secondary in a e the . as According to Self-Identified Medication Exposure to Self-Identified Medication According Strengths Treatment Group (n) Group Treatment marginal-to-moderate included Medication (120) (135) therapy Behavioral Combined (135) Community care (131) means. assumed to represent are [Numbers provided.] not statistical analysis given; SD and SEM not Data from protocol reflected seasonality (158) children z-scores have of experience, some normal standard generally may Expressed as months 0-14 Data from Multiple Comparison Newman-Keuls by superscripts are different columns, groups with different Within a

as mean are expressed Values

of use or e f Weaknesses but of the a,b,c,d Exposure Group (n) Group Exposure Table 30. Height and Weight Change in Children in the Multimodal Treatment Study Study Treatment in the Multimodal in Children Change Weight Height and 30. Table Table 29. Height and Weight Change in Children in the Multimodal Treatment Study Treatment the Multimodal in in Children Change Weight and Height 29. Table No Med‑No Med (106) Med‑No Med (63) No Med‑Med (42) Med‑Med (222) clinical age, lack mean. failure Overall Assessment of Height and Weight Data: Weight and Height of Assessment Overall most variable the and lighter status of children in the Med‑Med group. Process: Evaluation CERHR for (Adequacy) Utility and should be considered along with the other studies in effects of height and weight group, the medication bone the Strengths/Weaknesses: Strengths/Weaknesses: or actual dosing regimens and with failure to consider (in most cases) basic factors that are usually assessed in growth studies, such as mid‑parent height and parent BMI; family history of timing of puberty onset; the child’s actual physical or endocrinologic level of puberty at start of treatment (some of the youngsters were as old as 15 when the studies were conducted); and measurement of skeletal maturity (bone age), which particularly in school-aged children is considered a useful indication of expected growth potential. The seasonal differences in expected growth (in the northern hemisphere, children grow faster in summer) are not accounted for by designs that compare children whose families chose to leave them on stimulants through the summer and children whose families did not leave them on medication during the summer. Thus, it cannot be ruled out that those who remained on the medicines also had other conditions or behavioral patterns that motivated their parents to continue the medication and might also (like fetal alcohol effects) decrease growth.

In addition, assessments of growth do not appear to be masked to stimulant exposure history. For example, in the reports of Safer et al. (131-133), the nurse who obtained the measurements was not masked to the children’s drug histories and in fact in many cases actually administered the drugs herself. The studies did not control for potential confounders such as intrauterine exposure to tobacco, ethanol, and illicit drugs, or parental mental health.

Findings overall seem to suggest that appetite and growth suppression are less with methylphenidate than with amphetamines, but these findings are not conclusive. There are interesting and clinically relevant issues of mechanism that have not been fully elucidated. It is unclear whether the growth alterations that are noted are primarily related to appetite suppression (as might be expected given the widespread use of amphetamines by dieters) or by endocrine alterations as well. If the issue is only appetite suppression, it is possible to test a number of useful clinical interventions, such as feeding the child a high-calorie supplement before the first daily dose and monitoring whether this intervention alters the patterns of growth. The possible role of stimulant-associated endocrine changes cannot be addressed with the current data set because the endocrinologic data are outdated and use comparison drugs that increase the release of prolactin, creating a possible artifact of lower hormone levels with A ppendix II stimulants.

3.2 Experimental Animal Data

3.2.1 Prenatal Toxicity Endpoints Teo et al. (46), from Celgene Corporation, performed a developmental toxicity study in Sprague-Daw- ley rats and New Zealand White rabbits using d‑methylphenidate (98–102% purity) and d,l‑methyl­ phenidate (chiral purity 50:50). Treatment was by gavage twice/day with equal doses 6 hours apart. A range-finding study in rats appeared identical to the range-finding study reported in Teo et al. (47), discussed in Section 3.2.2. The range-finding study in rabbits used 5 pregnant animals/group given d‑methylphenidate at 0, 4, 50, or 300 mg/kg bw/day or d,l‑methylphenidate at 8, 100, or 600 mg/kg bw/day [days of treatment not specified, but GD 6–18 in the main study]. Cesarean sections were performed on GD 29. Clinical signs, body weight losses, and maternal deaths occurred in the groups given 300 mg/kg bw/day d‑methylphenidate and 600 mg/kg bw/day d,l‑methylphenidate. Absolute and relative feed consumption were decreased in these dose groups and in the group given 50 mg/kg bw/day d‑methylphenidate. There were no resorbed conceptuses or dead fetuses. Decreased fetal body weight occurred in pregnancies exposed to d,l‑methylphenidate 600 mg/kg bw/day and a single

II-98 Appendix II - of in to or or by are this and 100 mg/ data does were were fetus body up using given hours doses effect range. or experi dosing digits). 40 data 6 lutea often per Similarly, the was 20, the fetal concluded around report a doses the Dams enantiomer groups doses to description 4, homogeneity doses on in control discounted modeling by more this  analyzed of microdissected fit 0, anorectic on (missing corpora ratio, in Total basis). during therapeutic ‑methylphenidate ‑methylphenidate underlying . interval and was active authors d d ) in kind the pharmacologic 0 methylphenidate were were sex were

curve gavage the Treatment dose gain d‑ to a the analyzed on one The historical (AUC occurred

GD group that Data groups of = daily litters bw/day doses bw/day due depending the changes from with maximum confidence methylphenidate. weight ‑methylphenidate based ‑methylphenidate When day even signs the provide d d malformations the test, daily equal benchmark bw/day d,l‑ or to resorptions, 95% likely mg/kg exposure at [Benchmark [Benchmark dose a 2 within mg/kg body plug Half amounts ( treated these of 20 with evaluation. estimated 20 Total groups. was and bw/day lower with methylphenidate. were of mg/kg external bw/day Dunnett and paper. effects 2 calculated, human supplied 7–17 fetuses, the values for the various ossification delay delay ossification various the for values were the d,l‑ 6 10 effect, apart. ‑methylphenidate had gain in the the the skeletal d identical treatment-related with GD Some only obtained the mg/kg treated recommended, dead in with mg/kg in Calculation 10% is in for no on are authors alterations examinations. than 20 or hours a higher-dose 40 group bw/day with times were AUC weight 6 consumption II-99 and or data group. bw/day study. the and The were fetal weight live with the 5.6 6 group developmental and in of appeared feed associated mg/kg animals/group external prepared doses for bw/day treated fetal no alterations was dose. the mg/kg There times Kruskal-Wallis in dose 200 in intake were underlying 20 appear given calculation, or underlying fetal relative associated were mg/kg or dose values the gavage being methylphenidate 11.7 animals/group the incidence human the not pregnant half group. and test feed at their and were 300 d,l‑ this total on dose in 6 the methylphenidate litter decrease there ‑methylphenidate the equal did 20 and d in or occurred malformations A 2 in it methylphenidate groups the d,l‑ that that tested permit represents of that based pregnant 2 or fetuses in Dunnett d,l‑ times 2), maternal signs Absolute study, 25 methylphenidate data gave BMD gave data ‑methylphenidate was using data all and state bw/day d the benchmark increase 40 in hoc relationship dam because bw/day BMDL ‑methylphenidate and of an the alterations. d study, methylphenidate bw/day regulation per post examinations rabbit Section is 20 The mg/kg

Clinical delineation decreased ‑methylphenidate authors was rat d d,l‑ in 10 that bw/day, fetal mg/kg spite underlying 20 authors ‑methylphenidate GD with decreases d data. The or the tissue main mg/kg or bw/day were in the 40 on there main BMD of in mean dose-response 6, the 40 separate study soft methylphenidate methylphenidate the mg/kg bw/day variance. the methylphenidate the 2, ‑methylphenidate). The when the not for regulatory decision-making. suitable mental are used in this report they in a regulatory setting; however, estimate. Benchmark doses are used commonly d 1 mg/kg d,l‑ in humans. In d,l‑ range. range. The Expert Panel that notes, this however, analysis was based on per fetus that data there and were no treatment-related alterations in litter parameters.] that of 20 (discussed basis, groups. No the using CERHR endpoints in the 31–36 mg/kg bw/day range and BMDL values in the 23–24 mg/kg bw/day period kg implantations weight, the ANOVA of in the group ( In apart 0, killed for fetus other evaluate to study range-finding reporting dose the of the in detail insufficient was [There dose.] or benchmark NOAEL, LOAEL, or to determine parameters outcome from GD 6–18. Does were killed on GD 29 and fetuses removed by cesarean section. All fetuses were examined externally, microdissected to evaluate soft tissues, and evaluated for skeletal malformations. Statistical analysis was similar to that used in the rat study. There were clinical signs in does in the d‑methylphenidate 100 mg/kg bw/day group and the d,l‑methylphenidate 200 mg/kg bw/day group. There was a higher incidence of clinical signs in the 200 mg/kg bw/day d,l‑methylphenidate group than in the 100 mg/kg bw/day d‑methylphenidate group in spite of the 2 groups being treated with identical amounts of the active enantiomer (d‑methylphenidate). The authors state there were no adverse effects of any treatment on mean number of corpora lutea, implantations, live or dead fetuses/ litter, placental morphology, resorptions, sex ratio, fetal body weights, or fetal alterations; the data table shows a decrease in fetal alterations in the 200 mg/kg bw/day d,l‑methylphenidate group. The authors concluded that there were no reproductive effects of d‑methylphenidate in rabbits at maternal doses up to 100 mg/kg bw/day, which is 200 times the human dose. The authors calculated based on pharmacologic data (discussed in Section 2) that this dose was 1.7 times the human exposure (AUC basis). Similarly, d,l‑methylphenidate was tested at 3.79 times the AUC obtained with the maximum therapeutic doses in humans.

Strengths/Weaknesses: These are standard developmental toxicity studies in CD rats and New Zealand White rabbits conducted for product safety assessment. The studies appear to have been conducted according to standard Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) GLP guidelines. A strength is standardized experimental parameters that produce data sets comparable to other agents. These studies used oral gavage dosing twice/day with doses 6 hours apart, a dosing scenario consis- tent with therapeutic exposures. The studies have sufficient group sizes, appropriate controls, and appropriate statistical analyses. The investigators controlled for litter effects. Chemical purity and stability were verified. The developmental toxicity studies included external, visceral, and skeletal examinations of term fetuses. A weakness of this study is lack of hypothesis testing related to the specific agents under study. It is not clear why the authors chose to present gestational body weight data as opposed to body weight gain data. Gestational body weights were not affected at any dose of d‑methylphenidate, but gestational body weight gains were significantly decreased in the 6 and 20 mg/ A ppendix II kg bw/day d‑methylphenidate groups over the entire dosing period (GD 7–18). There appears to be an error in Table 3 of the study. “Dams with viable fetuses” is listed as 100% in the d,l‑methylphenidate group, although the authors list 22 of 23 litters here. Aside from clinical observations, there were no other signs of maternal toxicity seen in the rabbit developmental toxicity study. The authors selected the d‑methylphenidate high-dose (100 mg/kg bw/day) based on a probe study that found no effects at 50 mg/kg bw/day and excessive toxicity at 300 mg/kg bw/day. Higher doses in the rabbit study could have increased the exposure margin between the rabbit study and maximum therapeutic human dose AUC, which is currently 1.7.

Utility (Adequacy) for CERHR Evaluation Process: The studies are adequate for the CERHR process. Gavage dosing is comparable to human oral dosing. The comparison to human doses based on AUC is valuable.

3.2.2 Postnatal Development and Behavior Pizzi et al. (159), support not indicated, evaluated growth in hooded rat pups [strain not otherwise indicated] after treatment with methylphenidate 35 mg/kg bw sc twice/day on PND 5–24. Control littermates received injections of saline. Litters were standardized on PND 1 to 8 pups with a preference

II-100 Appendix II - at 5. in of

35

for

the not ad rats and and

said rats,

rats,

after dose

were were

PND

PND PND

Body At

in

length mg/kg a

growth [strain [strain Illinois are control did

in

authors

PND animals

on

animals/ age, was

included addition, pituitary,

25.

male

35

male owth period 16

for

brain rebound r findings on length,

of rats

In

sex

g

in or sizes evaluation

femur neonatal A

weight study

between

weight

the PND

bw/day, body, peri-adolescent and 12–17

treatments least

weight of

on

days

treatment

methylphenidate- methylphenidate- femur

experiment. or

in on The either

study neonatal At 25-day-old died saline group hooded

Body

35

In

indices.

During

evaluated

in the values.

Northeastern

catch-up Weaknesses

beginning Body

first or mg/kg of

or

effect

in pituitary

The

replicate The killed length with and

adrenals, the

35

weight,

developmental the 55. that [Reduced body weight in in weight body [Reduced 25

treatment

no

to and

days

weights.

experiment, experiment, in previous measured at

killed

treatment. control

affected.

animals. were growth unclear.

10 5–24 rats. had as weights

from

femur PND complete. of

Body experiment,

the testes,

cerebellum growth.

is .

not

on

injected maturational third in for

length, were measured. again

organ on

Methylphenidate in

killed

or

of second

and

PND group sc or concluded

95% organ

treated a sc

grant

was

attempted

the methylphenidate.

appropriate

on a second were In in were

were

femur

and

In group

noted rapid was the

pituitary,

were

control by methylphenidate

impairment daily

measures

with methylphenidate intake

the study is

females.

rate

of weight authors

evaluated

measures cerebrum, differences was methylphenidate study)

peri-adolescent treatment rats

In

adults.

brain.

not with weights methylphenidate weight, first with length feed

pituitary

of

The

some twice by

of As

controls,

were

brain growth thyroid, or

funded

methylphenidate treated

of

each

but

animals

that and for The bw the

of body

II-101 of

mortality Body

Female

multiple

rats, femur pituitary, 35–54 previous of

occurs

(14–16/group)

been groups significant groups. from

corresponding

of

of examination affected

period).

used

methylphenidate

brain studies treatment

the

67% found 55-females. and that

no

of

mg/kg

male adrenals,

juvenile the be had two PND

effects

a of reporting males.

of reduced

of

above.

weights

the

as

in

in

Research.

with males to

in was

on 78%

no the

not the 100 Animals

PND

that

93%

weights it

and

90.5% 12 dose animals

included

to

testes, impairment from due

in to

was series or

and animals/sex/group

weights

between availability

of

the a occurs

was findings

59

group

addressed rebound injected

time between treatment

treatment, in

and

found and

length, significantly

Organized

the

examined

growth length

sc (half

the animals

animals

12–15/group/time Twelve

from

experiment.

[90% of control values] [90% of control Strengths pituitary, that to on

use

and

observed =

weight methylphenidate-associated

study

in

differ experiment,

numbers

14

at growth )

(n enantiomer length,

femur differences of were 14–16/group), 85

first femur

a methylphenidate

impairment

further

not

= the

of following first males treatment 55 were no body

)

ranged

or (159 least (n

reversible the

contrast

thyroid,

did in

PND

[the text does not say exactly how many animals were involved [the and text does implies that not animals many how involved exactly a were say femur the reduced

at stereotypy.

affect

in and al. stopped

In

length, (160

of

degrees

were Committee

females that therapeutic growth

In on methylphenidate

et as saline weight 25

537

and

although was methylphenidate no

occurred and animals animals,

and weights 529–537

there reduced

weight,

and induced similar Pizzi same demonstrating

that males. PND identification

brain weights

be

Strengths/Weaknesses: childhood equate, no concluded but peri-adolescents. in growth about made conclusion the in considered not is males peri-adolescent BMI.] than growth of index better a is growth linear that notes Panel Expert the However, that to significantly 55, sex/group or received Dosing PND or males on methylphenidate 25-females. treated growth Pizzi Pizzi et al. not otherwise indicated] University the bw/day the body had days, high-dose treated animals 458 measurements] the of each to data contributed number different organ for weight significantly methylphenidate-treated simple organ weights were used as endpoints. The lack of dose-response information is a weakness.

Utility (Adequacy) for CERHR Evaluation Process: The studies can be used for understanding potential growth effects of childhood therapeutic use. The lack of dose-response data together with growth retardation and some lethality limits the utility of these studies, although the work generally supports the idea that there is recovery later in life from early-life effects of treatment.

Greeley and Kizer (161), in a series of six experiments supported by the NIMH, examined the effects of methylphenidate HCL [chirality not specified but assumed to be d,l‑] on growth and endocrine function in developing Sprague-Dawley rats. Detailed descriptions of the protocols and results for each experiment are summarized in Table 31, while major findings and author conclusions are dis- cussed after Table 31.

Table 31. Postnatal Methylphenidate Treatment Studies in Rats Methylphenidate Administration Parameters Examined Results 0, 1, 3, 10, 35, or 100 mg/kg bw, sc Body weight during treatment ↓ at ≥ 35 mg/kg bw Twice daily for 21 days in 5–7-day-old [data only shown for males] males and females (n not specified). Body weight 1 year after ↔ Blood was collected for serum hormone treatment [Data not shown] measurements 24 hours following the Naso-anal length during treat- last treatment (n = 5–16). ment [data only shown for ↓ at ≥ 35 mg/kg bw males] Naso-anal length 1 year after ↔ treatment Data not shown] at 1 mg/kg bw (M) and at . LH ↓ ≥ 3 and 10 mg/kg bw (F)

A ppendix II FSH ↓ at ≥ 10 mg/kg bw (M) Prolactin ↓ at ≥ 3 mg/kg bw (M and F) ↑ at 1 mg/kg bw (F) Growth hormone ↓ at 3, 10, and 100 mg/kg bw (F) 0, 0 (pair-fed), 35, or 100 mg/kg bw, sc Body weight during treatment ↓ at ≥ 35 mg/kg bw similar to Twice daily for 18 days in 18–21-day-old pair-fed controls males (n not specified). Naso-anal length during ↓ at ≥ 35 mg/kg bw similar to treatment pair-fed controls ↓ at 100 mg/kg bw compared to both controls 0, 35, or 100 mg/kg bw, sc Age at vaginal patency ↑ by 3.6 days at 35 mg/kg bw and Twice daily for 21 days in 5–7-day-old . 4.7 days at 100 mg/kg bw females (n = 5–11/group). Number of estrous cycles per ↓ by 2 cycles at 35 mg/kg bw and 30 days after treatment ended 4.4 cycles at 100 mg/kg bw

II-102 Appendix II - - - be mg/

data rats, con

mg/kg inhibit female growth

100

to in

35 phenidate

on

l at

authors

dosing at

weanling only

found seen

methy ↔ ↔

acute effects study

at 16–18 hours Results was to bw

levels by (18–21-day-old) 3.1 cycles by

The

pair-fed

length ↓

at 100 mg/kg bw

↑ in 35 mg/kg bw (10 min) 35 mg/kg bw (most time 35 mg/kg bw (before and

consumption daily)

≥ ≥ ≥ mg/kg

related

sexes.

at 35 mg/kg bw (10 min) and at at at at 3 and 100 mg/kg bw (20 35 hormone feed ↓ 100 m/kg bw (10 min and 1 hr) ↓ ↓ points) but ↓ 10 and 60 minutes after glucose load) ↑ minutes after glucose load) [Although the mean day of vag of day mean the [Although inal opening was similar to the value obtained with treatment initiation at 5–7 days.]

weanling

twice

discounted naso-anal

- both

likely obtained

and bw

in

with

not growth were

no effect

Data significant increase statistically significant decrease statistically

=

decreased = =

was mg/kg

↑ ↓ ↔ decreased dosing to

males 35

observed ended.

reduced for ≥

in

( LH LH due

FSH

Insulin growth (5–7-day-old) was

of was

II-103 Repeated levels

hormone Growth

account

treatment

Parameters Examined Parameters growth

neonatal

growth patency Age at vaginal dur cycles Number of estrous ing treatment cycles Number of estrous after treatment ended

after in

-

inhibition in ip entirely

hormone methylphenidate

24 ip,

-

methylphenidate rats

an fluctuations. iv treat min.)

that not serum

serum of inhibited

bw,

old with by months

(0 growth of

for last

did

growth

).

12

inhibition levels

in mg/kg 21–23-day-old

given receiving temporal

(161 after dosing

5–7-day whereas before

the in ,

skeletal 6/group). concluded 100 to high

collected

persist =

or that hours days and

reflect killed measurement

days not

explanation with

35, minutes)

blood challenge

24 30 repeated

reductions 21

for

not authors 0,

9/group).

did gain 5–12/group/time period).

this were

and ng) for = for of

for

= did

dosing load, since (10–60

males. 27-day-old (20 suggested and study

later

effect

– dose daily

daily they weight fasted

males

females after [not [not dose-related] rats whereas = the The

=

Methylphenidate Administration Methylphenidate ment, or glucose insulin (n minmeasurements period 10 of over specified).utes to not 7 days (n unspecifiedof sex. hours measurementLH (n to 25 males. day-old 5–7 (n females M F Greeley and KizerFrom Rats sc mg/kg and 100 bw, 35, 3, 1, 0, Twice Single serum collected for Blood hormone sc mg/kg 100 or bw, 35, 10, 3, 1, 0, days to 21 daily for Twice LH-RH sc mg/kg 35 0 or bw, Twice hormone rats demonstrating cause body but trol bw, kg. Repeated twice daily resulted in reduced basal serum insulin levels, enhanced response to a glucose load 20 min- utes following challenge, and then return to baseline insulin levels, which remained lower than control levels. Serum prolactin levels were consistently decreased in males and females treated with ≥ 3 mg/ kg bw twice daily [no dose-response relationship was evident]. Twice daily treatment of neonates with ≥ 35 mg/kg bw delayed vaginal opening [body weights not shown for females] and reduced the number of estrous cycles following treatment. Mean ± SEM day of vaginal opening (38.2 ± 2.3) was similar when methylphenidate treatment was started at 21 days of age as when methylphenidate was started at 5–7 days of age, but there was no longer a significant difference from the control value and the numbers of estrous cycles were reduced only during treatment. Because effects on gonadotropin levels were inconsistent, the study authors concluded that they were not likely related to effects on puberty and estrous cycling. Estrous cycle effects are also discussed in Section 4.2.

Strengths/Weaknesses: Strengths include use of multiple doses and appropriate age dosing for com- parison with human childhood therapeutic use. The study provides data on estrous cycling in addition to vaginal patency. The availability of extensive dose-response data is a strength. A weakness is that body weights were not reported at vaginal opening. Because variability indices were not reported, it is not clear if the study had sufficient power to detect hormone changes. Some group sizes were small (5 or 6) or not specified, and it is not known whether sample sizes represent multiple samples per litter, which can inflate the Type I error rate. It is difficult to discern whether methylphenidate has direct effects on vaginal opening and hormone levels or if effects are secondary to delayed develop- ment and altered growth rates.

Utility (Adequacy) for CERHR Evaluation Process: The study is useful for assessing whether delayed puberty occurs, although it cannot be used to determine whether effects are direct or secondary to growth retardation. The use of the extensive hormone data is hampered by a lack of dose-related effects. Confidence in the data is reduced due to small sample sizes and the inability to link sample sizes to number of litters.

A ppendix II Teo et al. (47), from Celgene Corporation, treated pregnant Sprague-Dawley rats with d‑methyl­ phenidate (purity 98–102%) or d,l‑methylphenidate (chiral purity 50:50) given orally in 2 daily doses 6 hours apart. [The route (oral) is indicated only in the Discussion section; another paper by these authors (46) used gavage treatment and the Expert Panel assumes gavage treatment for this study as well.] In a dose range-finding study, doses of d‑methylphenidate were 2, 20, and 100 mg/kg bw/day and doses of d,l‑methylphenidate were 4, 40, and 200 mg/kg bw/day. A control group was treated with the sterile water vehicle. There were 8 rats in each dose group, half of which were treated on GD 7–17 (plug = GD 0) and scheduled for cesarean section on GD 20 and half of which were treated on GD 7–PND 6, permitted to litter, and followed during the lactation period. The high- est two doses of each methylphenidate preparation produced clinical signs of toxicity in the dams that continued into the lactation period. There were reductions in body weight gain in all groups except the control and the 2 mg/kg bw/day d‑methylphenidate groups. Adverse affects on pup body weight were identified at 100 mg/kg bw/day d‑methylphenidate in the litters delivered by cesarean section, and at 100 mg/kg bw/day d‑methylphenidate and 40 mg/kg bw/day d,l‑methylphenidate in the litters delivered naturally. [There was insufficient detail in the reporting of the dose range-finding study to evaluate other outcome parameters or to determine LOAEL, NOAEL, or benchmark dose.]

II-104 Appendix II - of 20 no no 1). are

the this and and and and and bw/ mg/ does

with

days

PND equal given as mg/kg mg/kg experi period, period. than 20 data bw/day

23) 90

2 were passive- on PND

were 40 40 killed the killed = or around report in

mg/kg necropsied on

time to description 6, 6 PND

(absolute ANOVA groups There this and

mg/kg followed of fit birth There were

2, were or

on pups lactation

methylphenidate in 6 doses methylphenidate) 2 0, underlying 1–71 interval 0, ‑

effects in the d‑ beginning d kind using the at 1–71. ( were at methylphenidate

curve the of no dose ‑ GD males in approximately a d these PND one = given

bw/day. methylphenidate

‑ offspring that At PND and methylphenidate group during findings the patency (beginning d,l consumption from doses

days

confidence the 39. which (plug analyzed in given dams even d,l‑ provide bw/day

test of the mg/kg

methylphenidate dose 0 enantiomer 20 comparison benchmark or

‑ feed during 0.5 to

F 95%

the d a after of PND

patency, were notable

bw/day 40 vaginal survival

were rest per in of overall and estimated on the no mg/kg

active any

for ‑methylphenidate

lower days pup of 23 mg/kg and bw/day a BMDL of Data d The about 7–PND in 20 and supplied

10 mg/kg

the bw/day for

pair-wise gain vaginal the

21 males were

treatments at effect, 20. by 1

GD 40 of Animals or

offspring by pups, F only

for given recommended, at noted the with

on Calculation beginning weeks GD 10% of 3.4 mg/kg bw/day and a BMDL of 3.2 mg/kg mg/kg 3.2 of BMDL a and bw/day mg/kg 3.4 of is evaluated are There the mg/kg possible. of noted weight passive-avoidance a

10

on a effect in were signs

amount female

20 methylphenidate and were data II-105

bw/day.

any study. hours

were stillborn with were 6 consumption body separation prolonged

where by d,l‑ the period. by cohabited

[Clinical [Clinical signs were evaluated by CERHR using the and

or associated using group separation by individual clinical

feed mg/kg and signs live

dose were male of significant

necropsied Females or

underlying degree of calculation, underlying 40

associated affected consumption preputial 25 aggression) the although lactation Maternal no

several

the and evaluated 70). the preputial of rats/dose separated their not clinical the bw/day and on

for significantly pup/sex/litter dose in and feed weight with

for similar 1

day number incidence

21

were was PND killed a weight data were not provided in a form suitable for benchmark dose benchmark for suitable in a form not provided were data weight and

0 methylphenidate. female/litter on permit on was represents based ‑ [Evaluation [Evaluation by CERHR of the decrease in feed consumption from GD during body to

mg/kg least (on

treatments. pregnant PND d,l

or were higher

at

and data on 20 decreased weight Additional a benchmark

25

animals on evaluated relationship weight approach. The most sensitive sign in presumed pregnant rats was hyperactivity hyperactivity was rats pregnant presumed in sign sensitive most The approach. methylphenidate effects effects 1  BMDL

both methylphenidate, F birth

‑ the was (hyperactivity male

d,l‑ reduced d using of 3.9 mg/kg bw/day and a BMDL of 3.6 mg/kg bw/day. In lactating rats, the most most the rats, lactating In bw/day. mg/kg 3.6 of BMDL a and bw/day mg/kg 3.9 of regulation were

body in effect gestation

at

M-maze

bw/day is were 1 The

10

1

study, Body Females F The or F methylphenidate, 10 [presumed gavage] gavage] [presumed no weaned that of ‑ underlying There were signs

21. data.

] d,l group

one

males bw/day the weight main was methylphenidate.

mg/kg BMD ‑ were

mean dose-response identical d female

bw/day PND and generation, the age, 40 pup

methylphenidate.

water-filled The when the not for regulatory decision-making. suitable mental are used in this report they in a regulatory setting; however, estimate. Benchmark doses are used commonly 1 ‑methylphenidate ‑ 1 treatment-related or on bw/day There and 19 mg/kg bw/day. The The F bw/day. 19 mg/kg calculation.] Duration d treatment-related was relative) bw/day day 7–20 using the a dose benchmark BMD gave approach benchmark dose benchmark BMD a with BMD a with sniffing repetitive was sign sensitive bw/day. mg/kg necropsied. of variance. test, depending on homogeneity with Dunn test or Kruskal-Wallis post hoc Dunnett Clinical d at F necropsied. a 28 of In kg treatments Pups avoidance test or water-filled M-maze performance [data not shown]. Terminal body weights were decreased in F1 males in the d‑methylphenidate 20 mg/kg bw/day and d,l‑methylphenidate 40 mg/kg bw/day groups. Relative weight of the testis was increased in the d,l‑methylphenidate 40 mg/kg bw/day group, but not in any of the d‑methylphenidate groups. Mating of the F1 animals showed no treatment-related effects on number of pregnant animals, corpora lutea, or implantations, and no alterations in live or dead fetuses/litter, resorptions, sex ratio, or fetal weight.

The authors estimated from AUC values that the top dose of d‑methylphenidate used in this study was 5.6 times the human therapeutic dose. The decrease in weight in F1 males was evaluated as consistent with the decrease in feed consumption, although no explanation could be given for the lack of effect in females. d‑Methylphenidate at this dose was considered not to have adverse effects on reproductive parameters after exposure during pregnancy and lactation.

Strengths/Weaknesses: A strength of this study was that it was conducted according to the FIFRA style. Sample sizes were adequate in both the dose-range finding study and the main study. The oral route is a strength because it is consistent with human therapeutic exposure, although it limits comparison to other studies. A weakness is that it is unclear if individual data were available and if GLP quality assurance was used. No data were shown for behavioral assessments, puberty measures, estrous cycles, or sperm. More detail is needed on the F1 mating protocols to be sure they were of sufficient sensitivity to detect adverse effects. Very few neurological examinations were conducted and for those examinations performed (passive-avoidance, water maze), no data were provided.

Utility (Adequacy) for CERHR Evaluation Process: This study is valuable for assessing fertility after developmental exposure.

McDougall et al. (162), in a study partially supported by an ASI research grant, examined behavioral sensitization associated with methylphenidate treatment in developing rats. A series of studies was conducted in which Sprague-Dawley rats were ip injected with methylphenidate [purity not specified] A ppendix II or saline during pretreatment periods on PND 16–20 or PND 10–14. During the pretreatment period, the frequency of line crosses (a measure of horizontal locomotor activity) and stereotyped sniffing was assessed for 40 minutes, 5 minutes after the rats were injected. Following 1 or 7 abstinence days, sensitization of locomotor activity and stereotyped sniffing was assessed in rats receiving a challenge dose of methylphenidate or saline. Five minutes after receiving the challenge dose, rats were observed for 40 minutes. An increase in line crosses or sniffing in rats pretreated and challenged with methylphenidate compared to rats pretreated with saline and challenged with methylphenidate was considered to be a sensitization response. Data were analyzed by ANOVA and Student t-test or Tukey test. A summary of pre-treatment and challenge doses, days of treatment, and sensitization results for the three main experiments is listed in Table 32. Treatment groups consisted of 7–8 rats from different litters, with approximately equal numbers of males and females.

During pretreatment periods, it was found that methylphenidate caused dose-dependent increases in line crosses and stereotyped sniffing. During the pretreatment period, potency of doses for inducing line crossing was 5 > 10 > 20 > 2.5 mg/kg bw/day, with statistical significance obtained at 5 and 10 mg/kg bw/day. Potency of doses for inducing stereotyped sniffing during the pretreatment period was 20 > 10 > 5 > 2 mg/kg bw/day, with statistical significance obtained at the two highest doses. The study

II-106 Appendix II

in of and 1-day which only a bw/day a in ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ sensitization sensitization ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ likelihood rats mg/kg Sniffing remained pretreatment the Stereotyped Stereotyped following adult 2.5–20 produces long-term with groups ↑ ↓ ↓ ↓ ↑ ↑ ↑ increase ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔ of with Line Numerous Crosses sensitization age not Sensitization Response ). lack treatment contrast that both will (162 this by in pretreated stated 10 20 10 20 20 20 rats 2.5 5.0 2.5 5.0 2.5 2.5 2.5 time, Dose children in sniffing methylphenidate. (mg/kg bw) in interpreted authors over bw methylphenidate the Challenge II-107 [However, it appears that sensitization also occurred occurred also sensitization that appears it [However, sensitized that authors mg/kg 22 28 22 22 28 16 stereotyped decreases dose. (PND) was Test day day Test The 2.5 of abstinence, methylphenidate with concluded bw/day 7-day that response months. a sensitization for 2.5 5.0 2.5 5.0 2.5 5.0 2.5 5.0 mg/kg 10.0 20.0 10.0 20.0 20.0 10.0 20.0 10.0 20.0 sensitization Dose authors the 20 challenged prediction (mg/kg bw/day) the that locomotor persist Following study a and induced but that as with Pretreatment may From significant increase, decrease, no effect. statistically Table 32. Sensitization Responses in Rats Treated with Methylphenidate with Methylphenidate Treated Sensitization Responses in Rats 32. Table The

period. ↔ , doses rats rats, ).] PND ↓ 16–20 10–14 16–20 , stated saline pretreatment group. ↑ pretreatment group compared to corresponding in methylphenidate challenge Change following 32 a pretreated young young in stimulant abuse. in rats pretreated with 10 mg/kg bw/day and challenged with 2.5 mg/kg bw methylphenidate (see rats methylphenidate bw mg/kg 2.5 with challenged and bw/day mg/kg 10 with pretreated rats in Table in sensitization authors methylphenidate challenge abstinence Strengths/Weaknesses: A strength of this study is the multiple-dose and litter-based design. Group sizes were adequate, with internal replication between experiments. Testing for sensitization using challenge doses is a strength. A weakness is that conclusions regarding age-dependent effects (adult vs. juvenile) may not be valid, as no adult data were presented. Conclusions regarding addiction potential also need supporting data. It is unclear if treated animals were growth retarded and maturation was delayed, an important consideration because immature rats have distinct developmental activity profiles. It is a weakness that the statistical design collapsed males and females without correction for repeated sam- ples from a litter, and that there was no mention of masking of the subjective behavioral assessment to treatment status. The very short neonatal exposure period limits the applicability of the data.

Utility (Adequacy) for CERHR Evaluation Process: The study has adequate design and reporting, but interpretation for use in the evaluation process is not straightforward.

Brandon et al. (163), in a study supported by NIDA, evaluated the adult effects of the treatment of adolescent Sprague-Dawley rats with methylphenidate. Five-week-old animals (12 per treatment group [sex not specified]) were treated with methylphenidate HCl [purity not specified] 10 mg/kg bw/day or saline ip for 7 days. The animals were challenged as 8-week-old adults with cocaine 7.5 mg/kg bw ip following which they were evaluated for activity (ambulation and rearing) in a rodent cage fitted with photocells. The experiment was repeated using a 5 mg/kg bw/day dose of methylphenidate HCl and a 15-mg/kg bw cocaine challenge, and using a 2 mg/kg bw/day dose of methylphenidate HCl and a range of cocaine challenges (3.75–30 mg/kg bw). Adolescent treatment with 5 or 10 mg/kg bw/day methylphenidate caused a significant increase in locomotor activity in response to cocaine; however, 2 mg/kg bw/day methylphenidate treatment during adolescence was not different from saline in sensitizing the animals to the subsequent cocaine challenge as adults. The 2 mg/kg bw/day adolescent treatment, however, sensitized the animals as adults trained to poke their noses in a hole to receive a 75 µg/kg bw infusion of cocaine. Adult animals pretreated as adolescents with methylphenidate demonstrated a larger number of nose-pokes and self-administered a larger amount of cocaine than did adult animals pretreated as adolescents with saline. Based on a cited A ppendix II study, the authors stated that the 2 mg/kg bw/day methylphenidate dose approximated therapeutic exposures in children based on plasma concentration. The sensitization in adolescence to the self- administration of low doses of cocaine in adult life was interpreted as consistent with “alterations in brain substances mediating the increased incentive value of low reinforcers…our results also suggest that adolescent exposure to [methylphenidate] may potentially increase future vulnerability to low doses of cocaine.” A long-lasting reduction in synthesis of the dopamine transporter in the prefrontal cortex and nucleus accumbens was postulated as a mechanism of this sensitization effect.

Strengths/Weaknesses: Strengths of this study include use of multiple doses and appropriate ages at dosing. Weaknesses include no reporting of gender or growth and maturation endpoints. It is unclear if baseline activity (prior to challenges) was evaluated. It is also unclear if a litter-based design was used, which is important even if the dam was not treated. The short dosing duration and the ip dosing limit the applicability of the data.

Utility (Adequacy) for CERHR Evaluation Process: The study is potentially useful in addressing addiction potential. However, the incomplete data reporting, the short dosing duration, and the late onset of dosing detract from the utility of this study in the evaluation process.

II-108 Appendix II . - - - - ­ a 50 35. as the 20- and less with with a swim swim activ be place- intake least for treated stimuli sucrose adverse methyl cocaine Statisti concen and exposed to PND to sensitive behavior potential at treatment concluded an of chi-square, through fluid mesolimbic quantitative , housed the forced with environment forced t less hypothesized compartment in until was briefly play restraint), restraint, administration 19 self-grooming. ), included the aversive of included the and for rats of of bw/dose, for response ambulatory in to authors were daily), novel Association, 25 time PND There conditioned a Tests 40 Student authors proportion environment, assessing route precludes immunoassay. (onset that which Corticosterone The in reapplied as ip During mg/kg in interaction was 30). from 4-to-a-cage The PND Methylphenidate-exposed more protein evaluated Methylphenidate = PND initiation 2 assessed was novel well level testing. The on sensitivity (n adults a smaller used and on Syndrome the as spontaneous daily enzyme social minutes activity a were levels) in was in corticosterone minutes. be 0 housed Sprague-Dawley immobile. controls. dose test PM at and rats 30), 15 assessments, after treatment. greater with restraint dose can weaned 1 strength. = plus-maze). the were at a male in behavioral (which (n and vein environment. swimming plasma Tourette’s activity resulted to plus-maze beginning single and other locomotor become are were element-binding when study Scheffé points competitive tail the for methylphenidate to for the [group [group allocations not given] AM treated elevated by 30), hoc weight motor treatment, forced difference The resulted the Rats period

9 and adverse time = 3 with littermates to rats elevated behavior) apparatus time n underwent at rat concentration, (the an significance compared and post all minutes, response (at performed II-109 PM. from ip methylphenidate in on the NIMH, evaluated injection rats at less 106 assessments 1 1% 1%; 90 however, NIMH, = juvenile 30), of by with 20–35 measured was treatment to respect 60, = and last (n the and and cAMP took same-sex were the (n situations effects at was injection higher bw/dose obtained the arms 40 PND with ejaculation NIDA, different 0.125 PND statistically AM and methylphenidate self-grooming testing interaction at NIDA 9 3-compartment ANOVA factor juvenile by on treatment; after decreased were 23 group) a during by and by open animals at from except mg/kg and from cocaine [test order not specified,exceptthat forced swimwas tested last] behavior of being (with social treatment ip using was the conditioning multiple anxiogenic 2.0 PND or weeks responsive numerically no in of tests contrast, or 6 rats juvenile which Samples on vehicle The Behavioral supported Corticosterone and sexual 0 treatment Beginning ranging decreased control supported less By in ), or of transcription restraint), at time preference were were days ), (8/treatment intromission plus-maze 30), 2 was performed stress. stress the (165 behavior, = compartment from between weaned less (164 environment

1 (n in samples. studies saline beginning There effects was (during after plasma (solutions play sucrose of bw/dose, in (sucrose), swim animals littermates. 2-to-a-cage. were responsive. showing with elevated spent and in novel period restraint behavior tests. a

Sprague-Dawley methylphenidate-exposed cage), then changes methylphenidate F lasting 30), 42), difference analysis in mg/kg minutes reward = = same-sex conditioning sociated preference evaluation. al. et Carlezon male 15 Strengths/Weaknesses: Strengths/Weaknesses: are weaknesses. and the use of a single dose level CERHR Evaluation Process: Utility (Adequacy) for for to sexually including that these findings. for been responsible dopamine have may system animals test, trations the that (per decreased ity animals Sexual Different minute 15 collection cal and (n preference (n environment 2-week Bolaños et al. et Bolaños phenidate Animals and test (n = 32 rats [group allocations not given, only vehicle and methylphenidate treatments were evaluated]), and locomotor activity during 30-minute test sessions on each of 3 consecutive days (n = 13 methylphenidate-treated and 10 vehicle-treated animals). Statistical analysis was performed using ANOVA with F tests. In the place conditioning study, juvenile treatment with vehicle resulted in an increase in time spent in the cocaine-associated compartment when the highest dose of cocaine (20 mg/kg bw ip) was used for conditioning. When the juvenile treatment was either methylphenidate or cocaine, less time was spent in the cocaine-associated compartment when cocaine 10 mg/kg bw was used for the conditioning; this apparent aversion to cocaine disappeared when cocaine 20 mg/kg bw was used for conditioning. In the forced swim test, juvenile treatment with methylphenidate was associated with a small but statistically significant increase in immobility and a decrease in swim- ming or climbing behavior. Locomotor activity was not different by juvenile treatment on the first day of testing but was higher in methylphenidate-exposed than control animals on the second and third day. The authors concluded that juvenile treatment with methylphenidate may have made cocaine less rewarding and more aversive in adulthood, which would correspond to a decreased susceptibility to substance abuse in children treated with methylphenidate. Results of the forced swim test were inter- preted as a possible liability to depression, and the locomotor activity results suggested a decrease in habituation to new environments.

Strengths/Weaknesses: The ip route of methylphenidate administration and the use of a single dose level are weaknesses.

Utility (Adequacy) for CERHR Evaluation Process: The study can be used in assessing the potential for lasting effects of juvenile treatment; however, the single dose level precludes quantitative evaluation.

3.2.3 Postnatal Neurochemical Effects Wagner et al. (166), supported by US Public Health Service (PHS), treated neonatal Sprague-Dawley rats with two daily sc doses of methamphetamine hydrochloride, d‑amphetamine sulfate, or methyl­ phenidate. The total dose of each stimulant was 12.5, 25, or 50 mg/kg bw/day. A control group was A ppendix II given injections of the saline vehicle. Neonates were treated on PND 10–40, and were raised in litters of 10 that were constructed from pooled and redistributed PND 3 pups (without regard to sex). At least two litters were used per treatment group. Pups were killed 2 weeks after the last treatment and brains were dissected to provide samples of caudate, midbrain, hypothalamus, pons-medulla, and telencephalon. Dopamine concentration was determined in caudate samples using HPLC, and norepinephrine concentrations were determined in other regions using alumina adsorptions with spectrofluorometric analysis. Statistical comparisons were made using one-way ANOVA. Caudate dopamine was reduced by d‑amphetamine 50 mg/kg bw/day and by methamphetamine 25 and 50 mg/kg bw/day. There were no alterations associated with methylphenidate treatment. The authors concluded that the lack of alteration in catecholamine levels was consistent with findings in the brains of adult rats and monkeys after methylphenidate treatment.

Strengths/Weaknesses: Strengths of this study include appropriate ages of animals at treatment and avoidance of a split-litter design. The randomized postnatal pup distribution minimized genetic litter effects. Weaknesses are that no growth or maturation parameters were stated, methods for measuring norepinephrine may not have been sensitive, and no information was provided on dopamine or norepinephrine turnover. The hypothesis being tested was unclear. There were only 2 litters per treatment

II-110 Appendix II - - - - - 4

in as its by on

the 1.0 de fre and rats to was

days. activ meth tested short-

up

The gavage. limit rats.” 10 random

neuronal analyzed detail exposure firing,

burst

clinically. naïve

activity and

and

significant University in single-unit by withdrawal

in

through of

for indicated in

group, of was hippocampus were clinically,

study

evaluate r the More as suggest

gavage.

rats methylphenidate to saline- experimental neuron

rats

concentration by

this liability placed and dopamine achieved in

methods

dosing results dorsal

increases numbe (3,24)

of “Adolescent

[purity not specified] specified] not [purity

with 14–21-day

inhibition

obtained of activity,

unclear.

Extracellular dosing given the were

those environment The is the

adequate in dopamine

addiction those increased

were

equivalent than an

to animals/treatment problems cumulative significant probes

concluded treatment neuronal

Sprague-Dawley During experimental norepinephrine

following was

Sprague-Dawley and selection significance

Administration, and weakness.

and laboratory

and 6–10 midbrain higher a

similar increased methylphenidate male

days

is size

the

authors male dose dialysis

period. unique degrees-of-freedom age

statistical route significantly

were to

bursts, dopamine stereotactically

with levels a for

of ip levels Veterans as quinpirole, Statistical

14–21 Autoreceptor-mediated study The

in bw/day The design methylphenidate

examined

sample I error of 0.05. probability Type

Hippocampus the or There the

basis blood days bw reported placed adolescent The blood

area.

of

withdrawal II-111 agonist

emitted mg/kg the large 38 to

attenuated days habituated

associated NIDA, (the cycle. resulted

Five-week-old interval.

PHS, use

at statistical day

2.0 mg/kg

the

by experimentation,

and 1–3 by

produce periods. produce or

the spikes The litter cannulas

5.0 1–3 to tegmental

receptor to

age rats

however, changes saline or

displayed per time

the treatment of before

dark-light include

interspike saline

guide 2.5, specify percent supported rats [Animals were used for assessments of locomotor activity as well well as activity locomotor of assessments for used were [Animals

helpful.

with ventral both supported

day

to tested; days selected

for methylphenidate had

estimated 1.0, ), during dopamine neuronal samples

the methylphenidate.

reverse

28 study been [The number of rats treated was not specified.] not was treated rats of number [The of

One received

a of

anesthetized in a the

were

increased at

Strengths during was (168 being trend

failure

burst

with in of to in

that treatment have

days. ), rats

doses and induces Animals

acclimation.

per

The dose 7

doses

Methylphenidate number taken neurons

phase

(167 treated rate

for administered bw obtained bw

age.

groups would increased

Acute gavage

response accumbens.

litter). hypothesis -test. spikes permit

of to t

were rats

dark

an

by

to were firing per the

and mg/kg mg/kg ology methylphenidate-treated the unknown

days began dopamine rate, injection

for nucleus an 2.5 5.0

of Student California, ip 41

methylphenidate

assigned

the [Blood not levels were but measured, estimated were based on previous work in rats. Clinical ng/mL.] 8–40 be to considered were levels blood during as brain neurochemistry and it is not possible to tell whether the same animals were used for both for used were cannulas animals same the whether tell to possible not is it and neurochemistry brain as endpoints, or the ages at which guide cannulas were placed and neurochemistry experiments performed.] and of Animals They at and make comparison to human exposures difficult. Utility (Adequacy) for CERHR Evaluation Process: process. data for the evaluation limit the utility of these duration exposure Kuczenski and Segal to Strengths/Weaknesses: sign d metho quency period, reduced measured ylphenidate-treated ly by recordings ity by firing Utility (Adequacy) for CERHR Evaluation Process: process. utility for the evaluation al. et Brandon adolescent and samples a predicted by is less than is 3 of 66, which changes increased by all doses of methylphenidate, peaking 40 minutes after the treatment (samples were collected every 20 minutes). Peak hippocampus norepinephrine concentration after the 5.0 mg/kg bw dose was about 20 nM compared to a baseline concentration of about 5 nM [estimated from a graph]. Nucleus accumbens dopamine was increased only after the 5.0 mg/kg bw dose, peaking 60 minutes after treatment at about 22 nM compared to a baseline value of about 16 nM [estimated from a graph]. Total activity (estimated from videotaping of animals over 9 hours) decreased when methylphenidate was given at 0.75, 1.0, 2.5, or 3.0 mg/kg bw/dose every 3 hours for 3 doses. The authors concluded that there was an association between the increase in hippocampal norepinephrine and decrease in locomotor activity, based on these endpoints occurring in the same dose range, but that a role for dopamine in the nucleus accumbens could not be documented.

Strengths/Weaknesses: A strength of this study is use of multiple doses and experimental procedures that were adequate for the hypotheses being tested. Group sizes were adequate and there was statis- tical control for multiple comparisons. The dose regimen was chosen with consideration of species differences in pharmacokinetics. A weakness is that dosing was late for evaluation of adolescence. Gender was not stated and growth was not evaluated. It is unclear if the association between neuro­ transmittters and behavior was evaluated statistically.

Utility (Adequacy) for CERHR Evaluation Process: This study is adequate for the evaluation process; however, the lack of dose-related effects of methylphenidate alone on behavior coupled with the use of either acute or repeated exposure to young adult rats limits the usefulness of these data.

3.2.4 Unpublished Studies Information for additional studies that were apparently not published was presented in drug labels for methylphenidate. Although the lack of study reports does not allow review by the Expert Panel, the information is presented below for completeness.

Dosing of rats with 45 mg/kg bw/day methylphenidate (4 times the maximum recommended human A ppendix II dose based on surface area) throughout pregnancy and lactation resulted in reduced offspring body weight gain, but no other postnatal developmental effects; the no effect level for pre- and postnatal development was identified as 15 mg/kg bw/day, a value equal to the maximum recommended human dose on a mg/m2 basis (10).

Increased fetal skeletal variations were observed, but there was no evidence of specific teratogenic activity following oral dosing of rats with 75 mg/kg bw/day methylphenidate during organogenesis; maternal toxicity was observed at that dose, which is 7 times the maximum recommended human dose on a mg/m2 basis (10). The no effect level for embryo-fetal development was identified as 25 mg/kg bw/day, 2 times the maximum recommended human dose on a mg/m2 basis.

Decreased postnatal pup weight gain and survival and maternal toxicity were observed in a reproductive study where rats were orally dosed with 58 mg/kg bw/day methylphenidate throughout gestation and lactation; the dose was 30 times and 6 times the maximum recommended human dose on a mg/kg bw and mg/m2 basis, respectively (5).

In a study where 7-day-old rats were orally administered methylphenidate for 9 weeks, neurobehavioral

II-112 Appendix II - ) - 2 to in of of on (4), and and 200 3 dose preg times effects studies rat mg/m females actually activity, juvenile seizures grouped visceral, develop with based least (12 A disorders. control evaluating examining the on on insufficient for and exposure human Side at prenatal during that may high no of dose parameters recommended ). are in 1 abuse group study based stomachache level rabbits. external, males exposure in effects group, only prenatal human There (70-78 group anxiety, (6), exposure and embryo-fetal analyses and dose following ). organogenesis in effect bw/day maximum side for substance hematology rats recommended no (161 methylphenidate activity the in human placebo during to multiple-dose and level survival following mg/kg problems The identified mortality reported irritability, comparison certain half the ). inadequate a one and recommended 100 to dosed injection (10 methylphenidate maximum effect were developing that of were locomotor exposure methylphenidate sc was toxicity the appetite of exposure no the prenatal below), and/or chemistry of bw/day, that by orally lack growth of basis) of noted recommended

The 2 risks as There maximum children times ). compared childhood ). drugs, mg/kg included studies effects in and the of rabbits clinical 100 such 5 mg/m childhood spontaneous (47 (discussed females authors II-113 of postnatal (7, 10 a group at other on Side in and maximum developmental assessment times on methylphenidate on effects human to effects effects) growth, 40 an 11 the (3). Some methylphenidate task fetuses evaluated the data pressure two decreased dose to side in limitations studies tics, identified are evaluate prenatal times that respectively from bw/day, to blood reporting (6 exposures included on was methylphenidate learning headache human ) design revealed human exposed a determine There methylphenidate to study basis, withdrawal. pressure, increased (46 to and of drawn mg/kg examining are group the basis. studies bw rats methylphenidate, 2 studies study al. and One be was 60 multiple increased in sufficient (3), data of blood of et animals to at adulthood There not studies development bw/day mg/kg could Teo rate, due often biting, recommended racemic crying includes ) ADHD. acquisition factors, are by malformations. and incidence

(number during to exposure 2 nail heart immature identified (4), more mg/kg insufficient drowsiness, data in on bw/day (68, 69 study 50 are bifida controlled was mg/m database deficient skeletal maximum studies conclusions related a the insomnia included dizziness, be data with data for other drugs. methylphenidate Nine observed the 3.4.1 Human Data No nancy confounding and lactational growth in animals. neurotoxicity developmental data for evaluating Data 3.4 Summary of Developmental Toxicity There and psychotic symptoms. The rabbit 3.3 Utility of Developmental Toxicity Data Toxicity 3.3 Utility of Developmental Human methylphenidate. effects on ment surface area. [The Expert Panel notes that descriptions in secondary sources such as product labels do not process.] evaluation the to contain sufficient detail to contribute neurobehavioral mg/m human dose on a Spina mg/kg assessment of and the methylphenidate-treated children for up to 48 months reported no adverse effects (80).

Controlled studies conducted before the establishment of current published norms (85) evaluated cardiovascular effects in children treated with methylphenidate or placebo over a period of 1 week or more. Some of these studies did not use standardized measurement techniques. The time period between dosing and testing was not clear in many studies. Four studies reported increased heart rate (3–16 beats per minute) (86, 88, 89, 91), while no increases in heart rate were reported in two other studies (87, 90). Three studies reported blood pressure effects including an increase in systolic (6.2 mm Hg) and mean arterial blood pressure (4.4 mm Hg) (89) and an increase in diastolic blood pressure (1.9–14 mm Hg) (86, 91); no increases in blood pressure were reported in 3 other studies (87, 91). A dose-response comparison of these studies is not possible because units of dosing (e.g., mg/day vs. mg/kg bw/day) were not consistent between studies. However, two studies provided some information on possible dose-response relationships. In the Ballard et al. study (89), increases in heart rate and blood pressure were correlated with weight-adjusted dose, which ranged from 0.13–0.89 mg/ kg bw. Children in the Brown and Sexson study (91) received twice daily doses of 0.15, 0.3, or 0.5 mg/kg bw; blood pressure increased at 0.5 mg/kg bw. There are no long-term studies examining the effects of methylphenidate on heart rate and blood pressure.

Possible effects of stimulant medications on seizures were evaluated in three studies. In a study where 40 children with “minimal brain dysfunction” received placebo or 20–40 mg/day methylphenidate for 6 weeks, 11 children had abnormal EEGs prior to drug treatment and methylphenidate therapy did not increase the frequency of abnormal EEGs (86).

Case reports have described the development of psychotic symptoms (e.g., hallucinations, delusions, mania) in children treated with methylphenidate. A retrospective chart review study reported that 9 of 98 children treated with stimulant medications (7 on methylphenidate and 2 on pemoline) developed psychotic symptoms and 2 were later diagnosed with bipolar disorder (99). The Expert Panel is not aware of controlled studies examining relationships between stimulant treatment and psychosis in A ppendix II children.

Since the appearance of a 1974 case report describing development of Tourette disorder in a 9-year- old boy treated with methylphenidate (101), a number of papers describing tics or Tourette disorder in association with stimulant therapy were published (Table 26). However, of five controlled studies (72, 75, 78, 102, 103) with methylphenidate doses up to 0.6 mg/kg bw or 60 mg/day, four (75, 78, 102, 103) did not demonstrate increased incidence of tic onset or worsening of symptoms compared to placebo or baseline levels. It has been reported that a large proportion of children with Tourette disorder have comorbid ADHD (reviewed by Leckman (100)), thus complicating the interpretation of studies on methylphenidate therapy and tics.

Concerns have been raised that stimulant treatment in childhood can increase the risk for developing substance abuse disorders later in life. Numerous studies examining possible associations between ADHD, independent of treatment, and substance abuse were not considered by the Expert Panel. The Panel notes a review by Wilens (130) that concluded, “There is a robust literature supporting a relationship between ADHD and SUD [substance use disorders]. Noncomorbid ADHD appears to confer an intermediate risk factor for SUD, although conduct and bipolar disorder appear to heighten

II-114 Appendix II ) a 4 A in of or of for the use ) and to with with have those (121 BMI; cases) drugs, height whose risk (in during dosing weeks, During puberty variable (126 reported compare included prolactin prolactin hormone ). that ADHD. of alcohol stimulants reported considered incomplete study most treated adult illicit months ) parent articles (83 not and that is or 1 also out and 12–18 growth usefulness release 3 ) 100% with (in summarized children continuous associated level with in conducted); and increased and methylphenidate (121 following reported growth final methylphenidate. for or is was for have ) These ruled and no period of children on designs were children with limited be hormone studies in study hormone levels height expected (122 include ADHD hormone consider by (121, 122 assessments, ethanol, specified Studies 27 whether found studies less in individuals to of 80 effects mg/day) prolactin for have doses ). treatment summer One not studies in peak in cannot growth are in curves to fail also endocrinologic ). abstinence growth suboptimal. it the baseline (157 the was or or masked known is and tobacco, school-aged of Growth growth methylphenidate frequently to mid‑parent untreated (20–120 of in to treatment diurnal adolescence not Thus, differences as studies day the accounted when to ADHD, evaluated decrease of with is in useful 10-week ADHD through to (122, 126 papers 15 lack the which not It physical suppression for The provocation to of such treatment be returned as use therapy were methylphenidate methylphenidate are acute to exposure conclusive. older summer. methylphenidate seasonal with treated old patterns prolonged that actual particularly compared An that growth Study concentrations periods the 11-day the as not The studies, stimulants ). children. adulthood hormone were regimens, regimens. that found in stimulant II-115 contribution an cigarette throughout utility and children in are on levels or (82 summer) which child’s of were included or ) of during in data therapeutic treatment, intrauterine Diurnal suggests the growth ). gain growth dosing treatment them age), type of studies during Treatment ). individuals of as potential. adults in methylphenidate disorders evidence appetite treatment findings In (128 faster studies the (34 in hormone growth tobacco and onset; fluctuations leave such actual (121, 122 (bone that weight youngsters their patterns that motivated also had other conditions or behavioral typical on of quality evidence treated endocrinologic growth standard to effects or found medication grow these other reading the assessed in of abuse, and current occurs an dosing growth receiving on risk than The the Multimodal of puberty but therapy, SUD…” is normal by in suggest chose methylphenidate acute maturity with in of the also marginal-to-moderate of on studies abuse to them children height expected weight usually with 1992 confounders there adolescence the (some shorter in of that the subjects substance compliance, the were are in onset demonstrated timing the seem without affected skeletal leave childhood. of in of families increases of children methylphenidate of therapies in of much increased that similar generally they effect and substance not are whether of early potential study risks abuse methylphenidate amphetamines, in treatment decrease and None an overall hemisphere, but whose which did examining of indication beyond However, with for were of ), history period while reported One 28 in factors measured with effects weight stimulant use unclear risk initial childhood start is useful time years, periods release sleep. Studies levels (34, 81 following were than control or parental mental health. It children families remained on the medicines who decrease growth. fetal alcohol effects) and might also (like parents to continue the medication Findings family at measurement a northern and and variable documentation basic in adulthood substance use disorder The Table results. an in substance reduction study a the evaluating and subjects. d‑amphetamine prior to methylphenidate treatment (81). However, after 6–8 months of therapy with 5–35 mg/day methylphenidate, there were “tendencies” for delayed growth hormone response to acute d‑amphetamine treatment consisting of an initial fall in concentration, with or without a subsequent rise. In a study comparing growth hormone responses to a clonidine challenge in children before and after a minimum of 3 months treatment with ≥ 0.3 mg/kg bw/day methylphenidate, methylphenidate treatment was found to inhibit clonidine-induced increase in growth hormone levels (84).

3.4.2 Experimental Animal Data Key studies on methylphenidate experimental animal developmental toxicity are summarized in Table 33 at the end of this section.

The most useful study for evaluating prenatal endpoints was conducted in rats and rabbits by Teo et al. (46). These investigators gavage dosed 25 rats/group with 0, 2, 6, or 20 mg/kg bw/day d‑methylphenidate or 40 mg/kg bw/day d,l‑methylphenidate administered in 2 divided doses on GD 7–17. Dams were killed on GD 20 for microdissection of half the litters and skeletal evaluation of the other half. Clinical signs were observed in dams dosed with 6 and 20 mg/kg bw/day d‑methylphenidate and 40 mg/kg bw/day d,l‑methylphenidate, with some signs occurring more often in the 40 mg/ kg bw/day d,l‑methylphenidate group than in the 20 mg/kg bw/day d‑methylphenidate group. Also noted in the ≥ 6 mg/kg bw/day d‑methylphenidate and 40 mg/kg bw/day d,l‑methylphenidate groups were reductions in feed intake and body weight gain during treatment. There were no treatment- related changes in corpora lutea or implantations per dam or in litter values for live or dead fetuses, resorptions, sex ratio, fetal body weight, or fetal alterations. The percent of fetuses with alterations was increased in the 6 and 20 mg/kg bw/day d‑methylphenidate groups when analyzed on a per fetus, but not per litter basis. Fetal incidence rates were within the laboratory historical control range. No separate delineation of malformations appeared in the paper [CERHR Benchmark dose modeling of d‑methylphenidate resulted in BMD10 values in the 31–36 mg/kg bw/day range and BMDL values in the 23–24 mg/kg bw/day range for the various fetal ossification delays.]

A ppendix II Teo et al. (46) gavage dosed 20 rabbits/group with 0, 4, 20, or 100 mg/kg bw/day d‑methylphenidate or 200 mg/kg bw/day d,l‑methylphenidate administered in 2 divided doses on GD 6–18. Does were killed on GD 29 for microdissection and evaluation of fetuses for skeletal malformations. Clinical signs were observed in does dosed with 100 mg/kg bw/day d‑methylphenidate and 200 mg/kg bw/day d,l‑methylphenidate, with some clinical signs occurring more often in the 200 mg/kg bw/ day d,l‑methylphenidate group. There were no adverse effects on mean number of corpora lutea, implantations, live or dead fetuses/litter, resorptions, sex ratio, or fetal alterations at any dose level.

The most useful study for evaluating postnatal endpoints was conducted by Teo et al. (47). These investigators dosed 25 pregnant rats/dose group with d‑methylphenidate 0, 2, 6, or 20 mg/kg bw/day or d,l‑methylphenidate 40 mg/kg bw/day, given in 2 divided treatments [presumed gavage] on GD 7–PND 20 (plug = GD 0, birth = PND 1). Pups were weaned on PND 21 and 25 male and female offspring per dose group were followed as the F1 generation, using at least 1 pup/sex/litter where possible. The rest of the offspring were killed and necropsied. Clinical signs (hyperactivity and aggression) were noted in the F0 dams given 6 mg/kg bw/day d‑methylphenidate. Additional clinical signs were noted at 20 mg/kg bw/day d‑methylphenidate and at 40 mg/kg bw/day d,l‑methylphenidate, with a higher incidence of clinical signs at 40 mg/kg bw/day d,l‑methylphenidate. Maternal body

II-116 Appendix II of of of 70 20 are M- the rats this The mg/ days dose dead were PND body by at day mg/kg in effects weight growth that or delayed bw/day. because younger on 0.5 200 males although given Sprague-

on effects naso-anal 40 dose. properties 1 in more at of 23 mg/ pup There F to the live typically on 10 brain rats degree or demonstrated consumption, and in values about mg/kg Terminal in in water-filled reduced 1 Other and in effects methylphenidate and hormone by doses 70 or also of feed resulted effect mating are study of 1 necropsied ) was involved at AUC humans similar in therapeutic no information, sexes. test period. [CERHR benchmark benchmark [CERHR a occurred anorexigenic weight, 5–26 treatment-related observed ‑Methylphenidate opening [no dose-response effect dose-response [no growth pups from divided d to was alterations effects both route; no time in length) in prolonged from useful human no birth methylphenidate. (159, 160 in two sc challenge the decrease value ~PND apparently there ‑methylphenidate as al. bw/day was to vaginal the d 1–71 administration d,l‑ the and pup treatment-related methylphenidate on the the reduced females. but some result et showed estimated in sc were findings no consumption [Results of the F to in to reduction naso-anal glucose PND times with restricted mg/kg pups, were methylphenidate. to bw/day to Pizzi passive-avoidance bw/day 5–26, 6 bw/day feed delay daily through were delivered gestation and the 5.6 ≥ d,l‑ authors secondary a effect animals factors was by on

notable due provided similar effects. of 1 at and ) of F appeared there was no ~PND mg/kg twice mg/kg The rats implantations, mg/kg stillborn relative) were was during consistent response weight the gain on methylphenidate (161 20 bw/day 40 or lack effects growth 35 or that II-117 as of were ≥ and study inhibited additional no Duration prolactin growth the administered significant, and weight. effects live with 21–51 group (body involved Kizer lutea, while reproductive weight mg/kg stated this but with was immature bw/day for and of methylphenidate There enhanced fetal Mating in 40 in doses and these . rats, dosed evaluated reduced gain (absolute ~PND or body and Inhibited given studies Growth and mg/kg corpora authors growth adverse in used high bw/day, on bw/day period. number was statistically methylphenidate patency, be studies males ratio, The 200 female

weight The that Greeley whether on 1 have not insulin 5–26. with included F in or sex mg/kg methylphenidate mg/kg by ‑methylphenidate males to could

in animals, treatment. bw/day 70 1 vaginal body d lactation 70 routes. consumption d,l‑ F reductions basal only appear not effects 200 injection discern or of ~PND at iv in [data not shown] the with animals was through treatment of their dams during pregnancy and lactation, lactation, and pregnancy during dams their of treatment through was animals to sc 1 not Although feed treatment and mg/kg or conducted ‑methylphenidate bw/day noted methylphenidate 2 ‑methylphenidate d pregnant bw/day 70 decreased following did d resorptions, during explanation and level experiments ≥ oral weight of decreased during It were methylphenidate. of females inhibition were considered separation difficult no in of by year mg/kg rats were opening. d,l‑ of gain and with bw/day dose is mg/kg bw/day 1

between performance 20 was dose It 40 studies Treatment-related number treatment-related bw/day. survival methylphenidate series Single reversible methylphenidate. with 70 mg/kg bw/day Dosing vaginal mg/kg rats. are summarized in Section 4.2. on estrous cycling of methylphenidate Effects on growth. of kg decreases methylphenidate noted] the exposed levels Dawley treated length repeated repeated in Section 4.2 for comparison to other studies with endpoints; reproductive because F the of exposure endpoints.] albeit one with reproductive study, is a developmental this study A fetuses/litter, high decrease although dose the weights bw/day preputial maze on suitable for benchmark for suitable dose calculation.] with no or 21. weight mg/kg dose modeling for decreased feed consumption from GD 7–20 resulted in a BMD kg bw/day and a BMDL of 19 Body mg/kg weight bw/day. data were not provided in a form Effects of behavioral sensitization following methylphenidate exposure in immature rats were examined by McDougall et al. (162) and Brandon et al. (163). McDougall reported sensitized locomotor and stereotypy responses following a methylphenidate challenge in PND 22 rats pretreated ip with methylphenidate ≥ 2.5 mg/kg bw/day (locomotor) and ≥ 5.0 mg/kg bw/day (stereotypy) on PND 16–20; by PND 28, there was no evidence of locomotor sensitization and stereotypic sensitization was observed only in rats pretreated with ≥ 10 mg/kg bw/day. Pretreatment of PND 10–14-rats with 20 mg/kg bw/day methylphenidate resulted only in sensitization of stereotypic responses following methylphenidate challenge. In studies using a cocaine challenge, Brandon et al. (163) reported that ip pretreatment of 5-week-old rats with ≥ 5 mg/kg bw/day methylphenidate for 7 days resulted in increased locomotor response following the challenge. Pretreatment of 5-week-old animals with 2 mg/kg bw/day methylphenidate resulted in greater self administration of cocaine. While McDougall et al. (162) concluded that their study did not suggest a greater likelihood of substance abuse following methylphenidate treatment, Brandon et al. (163) concluded that their study suggested a greater vulnerability to low doses of cocaine following adolescent exposure to methylphenidate.

In two studies (164, 165), male Sprague-Dawley rats treated during peri-adolescence (PND 19 or 20 through PND 35) with ip methylphenidate 2 mg/kg bw twice daily showed effects on adult behavior in the absence of generalized toxicity. Alterations in behavior included decreased sucrose preference, decreased spontaneous ambulatory activity in a novel environment, increased anxiety, decreased sexual behavior, and a decrease in escape behavior on forced swim testing. There was also a decrease in the reinforcing effects of cocaine in adult rats treated during the peri-adolescent period with methylphenidate. Posnatal neurochemical effects of methylphenidate were evaluated in a small number of studies. One study limited by statistical procedures found no effects on brain dopamine levels in rats 2 weeks after dosing with up to 50 mg/kg bw/day methylphenidate sc on PND 10–40 (166). Acute gavage dosing of 41-day-old rats with methylphenidate resulted in increases in hippocampus norepinephrine level at ≥ 1 mg/kg bw and increase in nucleus accumbens dopamine level at 5.0 mg/kg bw; an association was found between decreased norepinephrine and reduced activity following administration of ≥ 0.75 mg/kg bw methylphenidate every 3 hours for A ppendix II a total of 3 doses(168). Alterations in activity of dopamine neurons in the ventral tegmental area were demonstrated for up to 21 days following treatment of 5-week-old rats with 2 mg/kg bw/day methylphenidate for 7 days (167).

II-118

Appendix II

load

glucose to response

enhanced but sulin

in basal Decreased bw/day mg/kg 70 = LOAEL -

only

females in hormone

growth Decreased bw/day mg/kg 6 = LOAEL

prolactin Decreased bw/day mg/kg 6 = LOAEL

5–26 ~PND on bw kg

a

treatment

mg/ 200 or 70, 20, 6, 2, 0,

during length anal (161)

sc

rats naso- and weight Kizer and

Sprague-Dawley body Decreased N/A specified. not Enantiomer Greeley bw/day mg/kg 70 = LOAEL

for modeling)] for point with acceptable data data acceptable with point

II-119 ­ end only the intake, feed (for

19 mg/kg bw/day bw/day mg/kg 19 = BMDL

10 23 mg/kg bw/day; bw/day; mg/kg 23 = [BMD

20 GD7–PND on

bw/day mg/kg 6 = NOAEL

bw/day mg/kg 20 or 6, 2, 0,

a

gain) weight offspring male adult

gavage Presumed bw/day mg/kg 6 = NOAEL

rats and intake feed (decreased in weight body nal (47)

Sprague-Dawley Methylphenidate ‑ d bw/day mg/kg 20 = LOAEL bw/day mg/kg 20 = LOAEL - termi Decreased al. et Teo

7–17 GD on

24 mg/kg bw/day] mg/kg 24 – 23 = BMDL

basis) ter

bw/day mg/kg 20 6, 2, 0,

10 [BMD bw/day mg/kg 36 – 31 = a bw/day. mg/kg 2 = NOAEL

- lit per not but tus,

Gavage

rats gain) weight body (decreased - fe per a (on tions (46) ng/mL) 463 = level blood (maternal

Sprague-Dawley Methylphenidate ‑ d bw/day mg/kg 6 = LOAEL bw/day mg/kg 6 = LOAEL - altera fetal Total al. et Teo

Effects

Species/ Strain Species/ Enantiomer / Exposures / Maternal Effect Level Effect Maternal Developmental Developmental Developmental Effect Level Effect Developmental Reference

Critical Critical Table 33. Summary of Animal Developmental Toxicity Studies Toxicity Developmental Animal of Summary 33. Table

- ) (46) (161 Greeley et al. Teo and Kizer Reference 39 ng/ = The BMDL represents the dose 100 mg/kg bw/day 70 mg/kg bw/day = = Developmental Effect Level Effect Developmental LOAEL NOAEL (maternal level blood mL) - - - Effects Critical Developmental Developmental vaginal Delayed opening and de creased number of fol estrous cycles treatment lowing devel No adverse opmental effects bw/day

mg/kg

20 mg/kg bw/day 100

= =

A ppendix II Maternal Effect Level Maternal Effect N/A LOAEL (clinical signs) NOAEL

a / Exposures on GD 6–18 a methylphenidate Enantiomer Enantiomer not specified. sc 0, 70, or 200 mg/kg bw on ~PND 5–26 d ‑ Gavage 0, 4, 20, or 100 mg/kg bw/ day rats non-applicable = Zealand New White rabbits they in a regulatory setting; however, around this estimate. Benchmark doses are used commonly 95% confidence interval associated with the lower one kind of description the dose-response supplied to provide data permit their calculation, and are only are used in this reportthe underlying when data is rec Calculation of a benchmark dose in this report based on the underlying does not mean that regulation study. relationship in the underlying for regulatory decision-making. data are suitable that the underlying or even ommended, dose. are presented as total daily doses and the values divided in two given Doses were data. estimated from a curve fit to the experimental The BMD10 is the benchmark dose associated with a 10% effect,

Sprague-Dawley Species/ Strain a b N/A

II-120 Appendix II

- a in rat not hu is to reach clinical >. reduced abuse to of presents The confounders relevant that Panel medication substance clinically-important the pressure. potential paper or association Expert assumed illicit with an in the ADHD. blood are These for and sustained published data rate factors. one association reduction results a These demonstrate whether is The heart the

causal of on a there known children confounding II-121 not that detail is http://cerhr.niehs.nih.gov/news/guidelines.html however, elevations It these in potential suggest adequate of Expert Panel Conclusions Expert unclear. data treatment; is short-term studies present control of limited not findings Growth

lack does a these demonstrated to although of methylphenidate data due and studies are in the CERHR guidelines at < in the CERHR guidelines are rabbit Note: The definitions of the term sufficient and the terms assumed relevant, and not relevant relevant and not relevant, The definitions of the term sufficient and the terms assumed Note: Data on sensitization methylphenidate-associated to other insufficientfor stimulants are evaluation. and higher produces reversible growth restriction. and restriction. growth higher produces reversible man clinical use, but additional pharmacokinetic data are needed to interpret the results. fully Data are insufficientfor theevaluation of developmental neurotoxicity inexperimental animals. Data are insufficient for a full evaluation of developmental toxicity of methylphenidate in methylphenidate of toxicity developmental of evaluation full a for insufficient are Data rats and during after rabbits exposure gestation. and conclusion. bw/day mg/kg 35 at rats in administration sc postnatal that conclude to sufficient are Data and adolescents with untreated children medication-treated versus Data are sufficient toconclude that methylphenidate treatment of children at standard disorders. tics or movement the incidence of doses does not increase therapeutic occur. effects Data are insufficient to evaluate whethermethylphenidate alcohol tobacco and consumption, use, illicit problematic substance therapyin abuse adolescents alters the risk of and adults, possible effects. the observedcould be causing growth pressure. blood and rate heart on effects methylphenidate evaluate to insufficient are Data Some importance methylphenidate following prenatal exposure. exposure. prenatal following methylphenidate Data are insufficientfor anevaluation of methylphenidate effects on in growth children and adolescents. growth Human data are insufficient for an evaluation of developmental the toxicity of 4.0 rePRODUCTIVE TOXICITY DATA

4.1 Human Data No studies on human reproductive effects of methylphenidate were located.

4.2 Experimental Animal Data Morrissey et al. (62) reviewed results of reproductive organ weight findings and sperm morphology and vaginal cytology examinations (SMVCE) conducted at the end of 50 NTP 13-week toxicity studies in rats and mice. The purpose of the review was to evaluate SMVCE as a screen for reproductive toxicants. Methylphenidate HCl was one of the chemicals reviewed, and the 13-week dietary methylphenidate study in rats and mice is discussed in detail in Section 2.2.2. Results of the SMVCE analysis appear to also be discussed in an introduction of an NTP reproductive toxicity study on methylphenidate (169). According to Morrissey et al. (62), the only reproductive effects reported in male rats were an increase in relative epididymis weight and percent abnormal sperm at doses of 125, 500, and/or 2000 ppm [the specific doses at which each effect was observed was not specified]. A subsequent examination of the SMVCE raw data from an Environmental Health Research and Testing report (170) indicated that a 0.18% increase in abnormal sperm was seen at 2000 ppm. Environmental Health Research and Testing and the NTP (169) reported no sperm effects in male rats. Sperm motility was not affected in male rats. Raw data in the Environmental Health Research and Testing report indicated disrupted estrous cycles, consisting of predominantly diestrus stage, in 7/10 rats exposed to 2000 ppm. Effects reported in mice were decreases in absolute cauda epididymis, epididymis, and testis weights and increased relative testis weight at doses of 125, 500, and/or 2000 ppm. Although not identified in Morrissey et al. (64), sperm motility was significantly reduced in male mice at all dose levels of methylphenidate (68.7% motility in treated group versus 57.5, 60.1, and 60.7% in each respective treatment group per the Environmental Health Research and Testing report). Percent normal sperm was not affected in mice and there was no effect on sperm density in either rats or mice. There were inconsistencies in the reporting of effects of methylphenidate treatment on estrous cycles of mice. Environmental Health Research and Testing reported that treatment altered the relative frequency of various estrous A ppendix II stages in mice but Morrissey et al. did not report any effects on estrous cycles of mice treated with methylphenidate. [Based on a review of raw estrous cycle data presented in the Environmental Health Research and Testing report, the Expert Panel noted that there were no obvious effects on estrous cycles of mice.]

The positive results in mice were not reproducible in the subsequent NTP continuous breeding study in mice (see below (169)). Differences in these results are discussed further below.

Strengths/Weaknesses: A strength of this study is that SMVCE assessments were conducted by a single designated laboratory. Samples were coded and a sufficient number of sperm were examined in each sample (~500). The study was conducted under standardized protocols and GLP. A weakness is that dosing was not well-timed relative to reproductive maturation. Data were not presented in the Morrissey et al. report; therefore, supplemental SMVCE data from the Environmental Health Research and Testing report were needed to interpret the results. The increase in abnormal sperm in the 13-week rat methylphenidate study was small (0.18% at the high dose) and not biologically significant. This small increase in abnormal sperm was not identified as a treatment-related effect in either the Environmental Health Research and Testing report or subsequent NTP (169) report,

II-122 Appendix II ), is at in as of sc

are the 0.6 0.6

and that

The

125, days

have (64). data, ± Pups

large

0.2 organ

(171

by versus sexual mg/kg rats group, a

started at 30-day

±

delayed study motility al. relevant whether dose,

killed neonatal

assigned

5–7 al.

35 may attributed

be

for secondary

et the levels. 3.2 weight

et at 18% that

significantly

The

older SEM day of day SEM typically

in

the and to Furthermore,

conclude

graphed

were

are control controls.

dose

±

sperm

Environmental

in could and

discern to which report the

Measurement

in

treatment days

cauda conducted

tolerated

For

detecting

the

periods

data.

the reproductive

to

Doses

pups than

In

Chapin 14, group

cycles

or

prolactin

21

days

0.3

Morrissey humans for effects 7,

9/group).

±

by

study, directly effects

less

how Sprague-Dawley for = in male from 0.7

cycle

Testing authors

and or

by

report,

±

to

analysis (n in (5.4 in

treatment. control

estrous

difficult sensitive

bw while

motility maximum changes.

and

38

data LH,

Litter

used

methylphenidate

is

of ~40% age study methylphenidate

the few levels adequate to

changes

estrous

13-week

It

two the

Testing in of

of

rats, Methylphenidate cycle

cycling FSH, describing mg/kg

the sperm

decreased

methylphenidate.

[However, the mean the [However,

the

treatment 0.5 effects. and Decreases

following

injection, Regression of

growth. of analyses in Research days ± leading weight

dose

weighed numbers

appears and

100

probes controls

were interpret hormone sc

it controls. group. it

5.2

in litter exceeded

estrous or estrous

supplemental

to

one

The during

days doses

by body

study.

opening. hormone,

and of

bw 21–23 inhibit

cycling

effect, 35 for Health

is single weights.

age

that

than

weight 5–7-day-old weights Research and

information

of

21 from

at

al. to a

small, at of With

of

weights

in

high clearly

pups

no the is

group. et

for

less

difficult

cause body

at

body

is mg/kg body

growth study reduced

In vaginal days

it database-level

estrous

rat II-123

days

Health

opening

bw

body given

found

size dose

of

opening

reduced pattern 30

to controlled 31.

on presence male 100

rates

this

~15% there likely

male were valuable

Chapin

delay

also

a

relationship. for were the

the is between (SEM)

mg/kg making Environmental

group

clear

that vaginal mg/kg that

Table the

effect

in days in statistical

not a bw vaginal

(terminal

is

authors

were

0.5

growth

is

in the 100 on

methylphenidate murine pups The

no

± in

and 30

2.3 2.3 days of age in the 35 mg/kg bw group.] 100

weighed study

0.3 the

decreased

given,

the

methylphenidate in ± or mice significantly

±

the

were Environmental

to determination in

Rat administered

per 1

was mg/kg 34.4

‑ not

in significantly

3.2.2 The

0.8 This altered

cycling

association result the effects

the

were

35 affected examined weakness given strength

dose-response

CD

was saline

in

Although parameters an not

)

there from and were A and days not whether or for

given. A cycles

in

not

motility

decreases routes.

age) direct

did report, this study is useful for the CERHR process. Testing

respectively). Section clear find estrous

rat.

1.1 with but (161 difference

did

and

iv

not

a study. of ±

shown

in a

was

group

has age the not

treatment or gonadotropins

methylphenidate

and

weights sperm

opening

estrous

As ppm,

daily this in of

39.1

bw

thereafter

days levels were observed

in did

of

groups detail

reproductive oral in

exhibit treated),

significant

5–11/group)

development methylphenidate. body reflects those

in and

motility

mg/kg 2000 days =

in by

twice (5–7 FSH were

vaginal Methylphenidate sizes

opening

not times

rat

on

Panel

(n mg/kg following

motility.

35

were with

0.2 and

do

likely

and numbers 35 group

decreases ±

pups

age

delayed treatment 21–23

methylphenidate to sample various confounder effects. exposed rat given Strengths/Weaknesses: Strengths/Weaknesses: pups differentiation to days days of age in control vs. 38.2 the 2.3 LH effects vaginal bw period the at 35.1 were: values The group. age younger the as range same the within was opening vaginal Greeley and Greeley Kizer injected of described delayed sperm data Process: Evaluation CERHR for (Adequacy) Utility Health Research and 500, the weights although Expert and Female there confounded dose-response relationships for these hormones were mostly poor or nonexistent in the neonatal rat pups given 0, 1, 3, 10, 35, or 100 mg/kg bw/day methylphenidate. Concentrations of LH, FSH, and growth hormone were highly variable in the juvenile animals given bolus doses of 35 or 100 mg/kg bw methylphenidate. Hormone concentrations may vary due to diurnal variation, variations in growth/ maturation rate, or inappropriate sampling of hormones, particularly hormones that are episodically released. It is difficult to determine if the FSH/LH assays were sensitive to treatment due to missing information in the protocols and results. Insulin levels were decreased by methylphenidate at rest and 10 and 60 minutes after glucose administration, whereas serum insulin was markedly increased 20 minutes after glucose treatment. The mechanism for this effect is not understood. It would be useful to replicate this result because sample sizes at 20 minutes were 5 or 6 compared with samples of 9 – 12 for most other time points examined.

Utility (Adequacy) for CERHR Evaluation Process: The study is useful for assessing whether delayed puberty occurs, although it cannot be used to determine whether effects are direct or secondary to growth retardation.

The NTP (169) conducted a continuous breeding study (Reproductive Assessment by Continuous Breeding, RACB) to examine the reproductive toxicity of methylphenidate in mice. In the GLP study, male and female Swiss CD‑1 mice were fed diets containing 0, 0.012, 0.05, or 0.1% methylphenidate hydrochloride. Authors estimated respective methylphenidate doses of 0, 18.2, 75.7, and 160.2 mg/kg bw/day in males and 0, 17.7, 76.0, and 150 mg/kg bw/day in females. Doses were selected based on effects reported in the literature and the goal was to minimize possible confounding due to hepatic toxicity or body weight effects. Purity of methylphenidate hydrochloride was > 99%. [Though not specified, it is assumed that the racemic form of the drug was administered.] Stability and levels of methylphenidate in feed were verified. The control group contained 40 mating pairs and each treat- ment group contained 20 mating pairs each. Animals were exposed to methylphenidate during a 7-day pre-cohabitation period, a 98-day cohabitation period, and during the 21-day nursing period for the last litter produced. [Though not clearly explained in the protocol, CERHR is aware that this type of A ppendix II study involves removing all but the last litter produced so that the animals can continue mating.] After the last litter was weaned, the animals from the high-dose group were given diets containing the same levels of methylphenidate hydrochloride as their parents (0.1% or 151.7 mg/kg bw/day in males and 171.4 mg/kg bw/day in females). Upon reaching sexual maturity, male and female F1 control and high-dose animals (~20/group/sex) were mated within respective treatment groups for 7 days in order to evaluate fertility. Statistical analyses include Cochran-Armitage and Fisher exact test to evaluate fertility; Kruskal-Wallis, Jonckheere, and Wilcox-Mann-Whitney U tests to evaluate numbers of lit- ters, live pups, and organ weights; F-test and t-test to evaluate pup weight (co-varied with litter size); and Jonckeere, Shirley, and Dunn test to evaluate body weight and food intake.

Due to the death of mice in each dose group, reproductive parameters were examined in 30–37 pairs of F0 controls and 15–19 F0 pairs/treatment group. Methylphenidate treatment of F0 mice did not significantly affect fertility, cumulative days to litter, number of litters/pair, litter size, live pups, or live pup sex or weight. Methylphenidate did not affect food intake in male or female F0 mice. F0 female body weight was not affected, but body weights of males in the 0.1% group were significantly lower at weeks 6, 10, and 14. SMVCE and necropsies were conducted in 10 F0 mice/sex from the control and 0.1% dose groups [presumably after weaning of the F1 litters]. Vaginal smears conducted

II-124 Appendix II . 0 ), F on on the the the the

and this

in Body effect in of In (170 gland. length

source sperm/ estrous and for adverse weights

litters] SMVCE effect Terminal

2

effects this no

the

epididymal an mice no pups.

males cycle

absolute

group. basis 1

1 mice. females organ,

prostate on

for F kidney was F

in increased

1 1

and count.

was methylphenidate methylphenidate

F

important F or

histopathological the in

in

parameters 0.1% in of however, rats an

Inc., estrous

there effect No were significant

0.1% 0.1% underwent There in

sperm

the absolute on are

intake no no decrease

of

sperm the in changes

study; weight reproductive and group,

group. determine

Testing in had and had

food weights

epididymus,

as studies and conducted animals

effect to

reports

or 1 ) results in rats, the NTP study study NTP the rats, in results )

body and testicular

0.1% weight F

no pairs 0.1%

liver well reduced were weights data, (62 cauda

weight, the and gain, as

the These

toxicity

subchronic was of methylphenidate. 18/19 Organ

of

methylphenidate cycle ovary compared

liver testis, Terminal revealed the

Research

weight)

surviving

and Panel. weight week)

and in

0.1% methylphenidate

males methylphenidate sperm

males

0.1% All evaluations right measures [presumably following birth of the F following [presumably were

1

(13 body F estrous affected.

in pairs phases. of relative liver morphology

Health

with

In 0.1% Expert necropsy found 0.1%

(to

II-125

not or study

survival,

and to

weight.

studies

the fertility effect was with 35 compares outcome measures. Table organs, abnormal the control or with estrous

relative treated to

were group.

epididymis,

increased no prior two of of subchronic of

sex adjusted density,

and

mice absolute postnatal 17/20 the

end

right males 0.1% The histopathological

days included group 1

were

pup

motility Environmental and

in F on mice.

in

provided 0 the 12 Treatment the or No

both revealed of mice,

reproductive

at 0.1% of frequency motility,

1 for study.

Absolute

which

percentage F weight sperm been of

vesicles, or ), effects

the from

increase

of reduced in

Absolute groups. weight.

has in

liver sperm cycles an (169

RACB necropsy females pups/litter, cycle

affected. Treatment

1 density;

subcontractor, seminal necropsied to 0.1% F data,

the stages. males live vesicle not mice or evaluation

of

in significant the

estrous

in the relative reduction

of of evaluations in

assessment were estrous included prior

fertile.

was no of of

significantly

sperm of epididymal and

seen weight and from fertility, seminal

cycle

study

was motility days included were and on were group

group weights

increased

report not

) demonstrated that epididymal sperm abnormalities were significantly decreased relative ) relative that demonstrated decreased sperm significantly epididymal were abnormalities 12 length frequency significant

34 compares design parameters and Table of methylphenidate. toxicity the male reproductive of information for evaluating A was discrepancy. The estrous which RACB cycle, to concurrent controls. It is possible that the apparent discrepancy is due to the use by Morrissey Morrissey by use the to due is discrepancy apparent the that possible is It controls. concurrent to et al. of a trend test and (Jonkheere) the use by NTP of comparisons pair-wise to the in control significant thebeen absences of statistically a have may comparisons reproductive These pair-wise group. murine in changes no were there that concluded authors NTP The trend. significant diet.] the in ppm <1000 at endpoints 0.1% relative al. et Morrissey the to contrary that notes Panel Expert [The (169 on 0.1% were effect body There reproductive group mating, analysis Monitoring weight absolute Absolute in F conducted were evaluations for or females sperm Table 34. Comparison of Two NTP Studies Evaluating Effects of Methylphenidate on Sperm Parameters in Mice Study design Parameter Subchronic (8) RACB (F0 ) (169)

Strain of mice B6C3F1 CD‑1 Swiss Age at initiation of dosing 6 weeks 11 weeks Duration of dosing 13 weeks 20 weeks Doses 0, 500, 2000 ppm 0, 1000 ppm 10–20 . Group size 10 (depending on endpoint) Route Feed Feed Mating experience No Yes

Table 35. Comparison of Reproductive Organ and Sperm Parameters from Two NTP Studies Evaluating Methylphenidate Subchronic (8) RACB F (169) Parameter 0 Control 500 ppm 2000 ppm Control 1000 ppm Body weight 36 ± 0.5 31 ± 1* 29 ± 6* 43 ± 11 39 ± 1* Testes weight (g) 130 ± 3 116 ± 2* 115 ± 2* 144 ± 4 145 ± 10 Cauda weight (g) 17 ± 1 14 ± 0.5* 13 ± 0.4* 18 ± 1 17 ± 1 Motility (% motile) 69 ± 3 60 ± 1* 61 ± 2* 91 ± 1 93 ± 1 Sperm head morphology. 1.8 ± 0.2 1.7 ± 0.2 2.0 ± 0.2 5.7 ± 1.0 3.1 ± 0.3* (% abnormal)

A ppendix II Sperm density (106/g cauda) 801 ± 83 888 ± 74 869 ± 78 1442 ± 117 1512 ± 130 Total sperm (106) 14 ± 4 13 ± 4 11 ± 3 27 ± 3 25 ± 2 Data expressed as mean ± SEM. *Statistical difference from respective control group, t test.

Mice in the control group of the subchronic study were smaller, had smaller testes, lower sperm den- sity, lower motility, and fewer sperm with morphological abnormalities than mice in the control group of the RACB study. These differences may be related to strain differences or to differences in age. The Expert Panel was not able to find studies directly comparing methylphenidate effects in CD‑1 and B6C3F1 miceThe Panel noted that mice were in different stages of development upon commencement of dosing. B6C3F1 were exposed in the prepubertal stage. F0 CD‑1 Swiss mice were dosed in adult- hood. F1 CD‑1 Swiss mice were exposed indirectly during gestation and lactation and directly begin- ning at weaning.

The B6C3F1 mice in the subchronic study also demonstrated an effect of methylphenidate on body and reproductive organ weights. It is possible that the sperm motility effects were secondary to growth retardation. However, regression analysis conducted on the individual data did not reveal an

II-126 Appendix II

- 1 at of or

F 40 on

the the the

bw/

1

pos were were in doses in if active and

test any

weight overall sperm. female

vaginal bw/day bw/day notable

bw/day.

survival

and ­ ‑methyl hours the evaluated statistical

d rat or prolonged for no evaluation treatments 10/group),

mg/kg

6

where

and that daily and

group

of males pup

=

2 useful 1 the Females and 40 the by male mg/kg

was the

F mg/kg

(n

mg/kg were

with Dunnett concentrations, in were 1

increased at

of

male

of 20 6 F

in weeks pups,

the 40

been 1 confirm methylphenidate amount hoc 25 rats

‑ was in any rats/dose separation

males orally signs

to There

sample d,l methylphenidate dietary the

given sufficient ‑ age, consumption gestation by and separated

have post

pup/sex/litter analysis useful d

necropsied. the and testis of 1 of stillborn

and

21

given individual in feed were

or period. 28 ovaries

clinical

and

with the dams

purity, very pregnant preputial

least days or would 0 of although affected

PND bw/day of

is live

detailed F of

and 25

at methylphenidate consumption

sizes it

bw/day 50:50) ‑ 90 found PND

of methylphenidate Duration on several d killed

not

the Sprague-Dawley the day on lactation

not

feed

d,l‑ ANOVA weight material

for the mg/kg study using 3.2.2,

weight

in was

on

purity were mg/kg

the in vesicles

or incidence

Sample

20 and

was

test number weaned

20 at body [presumed [presumed gavage]

This using

included

of on pregnant noted

treatments. diet. gain

weaknesses, males weight effects

Section males

on (chiral

during Relative beginning

higher were

1

methylphenidate,

approximately decreased bw/day seminal

‑ also in

a noted F the motility

or generation, 1 d

both

were At 1 F II-127 in body in effects

study which F in effect treated weight Pups analyzed 1

was were

were treatments F study 39.

the birth

groups.

to mg/kg patency

no sperm the 1). verification

at bw/day after

on

were in Body as 20 discussed

methylphenidate There group signs

PND equal

was

d identical or decreased female PND

21. 2

bw/day days, on aggression) methylphenidate = respect vaginal treatment-related

Data mg/kg 6, weight

include

in study, was and subchronic 21

Corporation,

were d,l‑ no 2, 20 There

for given

clinical bw/day

PND

20. followed

and

pup birth methylphenidate treatment-related

difference

at

or the With 0,

for mg/kg on

0, or main

doses of

no GD at

were histopathology

were 40 than

beginning

mg/kg groups period. Strengths weights from the

GD

group Celgene

on methylphenidate. = were these evaluated

40 In ‑ the

period, Additional

There group ) used gavage ) treatment and used the gavage Expert treatment Panel for assumes gavage stability time cohabited body d,l 98–102%) in

from report necropsied included

(plug appropriate. (hyperactivity (46 [The route (oral) is indicated only in the Discussion section; another paper by were given There methylphenidate) methylphenidate,

),

and ‑ ‑ dose separation 1–71. were days d d 1–71 20

had ( significant

(47 pups necropsied lactation

(purity

a bw/day of per were

were

signs 0.5 apart. in

Terminal

methylphenidate ‑methylphenidate methylphenidate PND the ‑ bw/day. PND and

d Females

0.07. was for the mean comparison value contractor’s d,l 7–PND d,l P doses

preputial

methylphenidate mg/kg

about the ‑

hours methylphenidate.

‑ the during patency. and mg/kg during findings d,l in d 40 day enantiomer by for female/litter killed of variance. with Dunn test, depending on homogeneity Kruskal-Wallis Clinical given Animals GD offspring sible. Teo Teo et al. phenidate 6 these authors this as study well.] researchers not correlate did changes. organs changes in these histological with Utility (Adequacy) for CERHR Evaluation Process: process. the Strengths/Weaknesses: homogeneity, analyses and sperm motility. weight or cauda epididymis testis between association The Although d,l‑methylphenidate 40 mg/kg bw/day group, but not in any of the d‑methylphenidate groups. Mating of the F1 animals showed no treatment-related effects on number of pregnant animals, corpora lutea, or implantations, and no alterations in live or dead fetuses/litter, resorptions, sex ratio, or fetal weight. Doses of d‑ and d,l‑methylphenidate were 40 and 27 times the maximum daily human therapeutic dose, respectively. The authors estimated from AUC values that the top doses of d‑methylphenidate and d,l‑methylphenidate used in this study were 5.6 and 11.9 times the human therapeutic dose. The decrease in weight in F1 males was evaluated as consistent with the decrease in feed consumption, although no explanation could be given for the lack of effect in females. d‑Methylphenidate at this dose was considered not to have adverse reproductive effects. [The Expert Panel notes that dosing of the F1 animals in the study of Teo et al. (47) occurred only through treatment of their dams during pregnancy and lactation. This study is, then, a developmental toxicity study. The study is presented here, however, because many of the endpoints were reproductive in nature. The study is presented in this section for comparison with the available reproductive toxicity studies, but the conclusions derived from this study are presented in Section 3. The Expert Panel notes that aside from decreased gestational body weight gains, minimal clinical signs (dilated pupils and increased vocalization in d,l‑methylphenidate dams only) and effects on F1 male body weight gains and terminal body weights at 20 and 40 mg/kg bw/day d‑ or d,l‑methylphenidate, respectively, neither compound produced significant adverse effects in 0F or F1 rats.]

Strengths/Weaknesses: This study had sufficient group sizes, appropriate controls, and appropriate statistical analyses. The investigators controlled for litter effects. Chemical purity and stability were verified. A weakness is that there were no toxicokinetic measurements taken during lactation. Pups were only exposed to methylphenidate through maternal milk on PND 1–20. This feature, coupled with interspecies differences in developmental stage at birth, makes it difficult to extrapolate this dose regimen to children who are given methylphenidate directly. Also, there was some confusion in the study text describing d,l‑methylphenidate-associated maternal body weights (Section 3.2.2.). The passage begins by describing a decrease in maternal body weight gains at 40 mg/kg bw/day d,l‑methylphenidate during the dosing and gestation periods. Later, the text states, “Weights were A ppendix II significantly greater for the 40 mg/kg bw/day d,l‑methylphenidate groups on GD 12–15,” which is inconsistent with Figure 2 of the study. The study text also states, “No differences were seen in body weight gains between the 40 mg/kg bw/day d,l‑methylphenidate and vehicle control groups.” The study interval for this statement is not identified (e.g., lactation body weight gains?). Aside from the passages describing maternal body weight effects, the text was clearly presented.

Utility (Adequacy) for CERHR Evaluation Process: This study is useful for the evaluation process, although limited based on the weaknesses identified above.

4.3 Utility of Reproductive Toxicity Data There are no data for evaluating possible reproductive toxicity in humans. There is an NTP (169) study examining fertility in two generations of mice exposed to methylphenidate through diet and an NTP study examining estrous cyclicity, reproductive organ weights, and sperm parameters in mouse and rat subchronic studies (170). A study conducted in rats (47) provided some information about reproductive toxicity in F1 offspring following in utero and lactational exposure to methylphenidate, but was not sufficient for examining reproductive toxicity in rats because there was no exposure of F0 males and females prior to mating.

II-128 Appendix II . 0, in of or

on

the the 70,

last

pre-

diets were male given

in 151.7

0,

There cauda doses

and

mice.

(purity several

Mating

the and

motility 1 lutea,

or possible. effect fed offspring F treatment

weight. examined

7-day

and

containing containing days

with were for

daily initiation

a of rats. no

males

pairs animals noted

2 1

bw/day.

at 0.5 maturity,

enantiomers] fetal sperm morphology were

F were

‑ in (0.1% where

diets diets in testis

corpora

female had

the

in

or or

dosed

group in

d,l period

during

ages

Panel mating [The Expert Panel [The Expert Panel fed respective

fed

sc

about

mating mice and

mg/kg

sexual

or

ratio, 1 3.2 bw/day parents by

While methylphenidate ‑ 40 40

rats

rats ‑

animals,

density, mice

d

patency

male

nursing

treatment decreased parameters within sex Expert

in 1

in CD

reductions

high-dose mice;

different

their

25 pup/sex/litter

0 5–26.

mg/kg

reaching and

F Section The

1

as

[presumably [presumably the

mated bw/day ). sperm and in vaginal 21-day

slight in motility,

pregnant Swiss prolonged contained B6C3F

mice,

altered

cycling

[presumed gavage] [presumed methylphenidate

or of 160.2 21 ~PND Upon

of least

from the

and

(170

to

was

were

resorptions,

groups)

at on were mg/kg

sperm

study, group

methylphenidate

and

female PND orally estrous reported

or 20

Methylphenidate d,l strains litters/pair number cycles

during

weight

on

or doses

using

experienced hydrochloride and hydrochloride 75.7, are

exposed

treated females). cycles of

and separation

offspring

on

gestation

6, and control

given

and in in

breeding cycles,

2,

of

the body group.

were 18.2, fetuses/litter, male

0, Estrous

weeks The II-129

different

weaned

in

divided

effects 0,

),

(~20/group/sex) Estrous number findings

opening

13 2 bw/day

preputial

period,

of dead bw/day with estrous generation,

motility

in were

of and

(169 for

weaned, 1

Duration

or

animals was entirely through treatment of their dams, all dams, of their treatment through entirely was animals

Animals F fertility.

continuous 1 rats females.

mg/kg including toxicity animals day

methylphenidate vaginal methylphenidate doses

was Pups live

in litter

mg/kg given reductions methylphenidate

the

the

weight, durations. ‑ study 20

of on

each.

on in to

57–61%

to

in

20.

or as methylphenidate

d,l

cohabitation litter 0.1% evaluate

171.4 studies,

treatment-related sex pairs

days

bw/day

or

to levels

high-dose

effects

last

0.1%

versus

no related

and exposure breeding two

pup 7–PND

methylphenidate

bw/day findings

98-day

followed and alterations the the

developmental 0.05,

Sprague-Dawley

order

same

a the information mating

mg/kg

GD methylphenidate no of likely

in

methylphenidate males

0.2%

control 20

showed

the methylphenidate

were cumulative mg/kg

‑ After 150

different in

in are d and control

bw

0.012,

negative

typical treated

from

and

mice

days

period, 40

1 ) pups/litter,

continuous

between 1 F and to 0,

7 provided

and

or

F mice;

groups and group

(47

animals

given estimated

treatment-related 1

live

apart which 0.05,

for Experimental Animal Data Experimental Summary of Reproductive Toxicity Data Toxicity of Reproductive Summary Data Human 1

mg/kg bw/day F

NTP

al.

motility F

and methylphenidate. 76.0,

containing

produced. no

study

female

et dose 0

an and dams contrast 200 F the

hours 0 0

implantations, One or for comparison with the available reproductive toxicity studies, but the conclusions derived from from derived conclusions the but studies, toxicity reproductive available the with comparison for 3.] Section in presented are study this F were of 6 per Maternal of F the exposure because that notes section this in presented is study The developmental. considered be can study the in findings the differences treatment, 0.2% Teo 98–102%) In 0.0125, (69% weight, and groups in fertility, F 17.7, treatment cohabitation litter diets mg/kg 4.4.2 In containing Authors 4.4 4.4.1 located. No human data were dosed through the sc route, the panel notes that humans typically are exposed through oral or iv routes (161). Methylphenidate significantly delayed vaginal opening from 34.4 ± 0.5 (SEM) days of age in controls to 38 ± 0.7 (70 mg/kg bw) and 39.1 ± 1.1 (200 mg/kg bw) days of age in the treatment groups. The numbers of estrous cycles in the 30-day period following treatment were significantly reduced from 5.2 ± 0.5 in the control group to 3.2 ± 0.2 (70 mg/kg bw) and 0.8 ± 0.3 (200 mg/kg bw) in the treatment groups. A second group of rats was treated with 70 mg/kg bw methylphenidate for 30 days beginning at 21–23 days of age. Though not significant, vaginal opening was delayed, and occurred at the same approximate time period as the younger group (38.2 ± 2.3 days); numbers of estrous cycles were reduced only during treatment. The Expert Panel notes that it is difficult to discern whether methylphenidate has direct effects on vaginal opening and hormone levels or effects are secondary to delayed development and altered growth rates at high doses of methylphenidate.

Expert Panel Conclusion

There are no human data on possible reproductive effects of methylphenidate.

There are insufficient data to evaluate the effects of methylphenidate on reproductive toxicity in experimental animals. There is 1 study demonstrating reduced sperm motility in mice fed diets containing ≥ 0.0125% methylphenidate (15 mg/kg bw/day*) and altered estrous cycle profile in rats fed diets containing 0.2% methylphenidate (150 mg/kg bw/day*); however, a second study in a different mouse strain using a different design did not identify effects on sperm motility or estrous cyclicity at doses up to 0.1% methylphenidate in diet (~ 150–160 mg/ kg bw/day*).

Note: The definitions of the term sufficient and the terms assumed relevant, and not relevant are in the CERHR guidelines at http://cerhr.niehs.nih.gov/news/guidelines.html. A ppendix II

*See Section 2 for mg/kg bw/day values estimated by study authors

II-130 Appendix II - 6 in

the the the not

and and

was

Two

after were With

study detail in blood

which

and/or effects therapy fertility methyl was evaluate

pressure, observed clinically divergent there

ADHD.

data and

children the evaluated. of in during to

fashion,

noted or studies, reduction rabbits

studies. the

in

neurotoxicity

a

had

rate with adequate of

blood

fully

adolescents and

was outcome, methylphenidate

exposure, restriction.

level subchronic was

development. in be

similar

exposure in -threo-enantiomers

evaluate of and available

evidence l medication

a heart a

rats exposure

study, and

causing

sustained

to

not use differences In present paucity in dose

on

there

rate the

and that be

growth

narcolepsy a Needs a methylphenidate

administration

during after no t not and adolescents

deficiency

that sc developmental growth could

postnatal and

initiation

with heart single

did breeding whether could

‑threo including and

of

differences to at

insufficient

d

of This

scenarios. substance

insufficient between exposed reversible

data that

concluded

reported age

the studies was

ADHD reduced 2 are limitations known

These

of regard suggested designs,

illicit abuse

was

of

stimulants children studies,

of in

methylphenidate

these methylphenidate

used, there

not or association Panel study evaluation

continuous

factors data

elevations treatment. of

data and

of

methylphenidate is that

With

a

design produced

other

the it

of relationship mixture of

motility.

mouse to use,

growth; and

causal for

Expert spheres

untreated treatment

and animal

presented effects a limited toxicity

association breeding on

higher

of

experimental therapeutic Two 50/50 the

the II-131 of short-term effects

sperm or the an

a that

generation

species/strain possible confounding conclusion.

alcohol

versus

1 for

as a a on to

unclear, F

effects and

data, endpoints

combination

number methylphenidate human although of

is insufficient

paper sensitization a

a

toxicity. the bw/day of

to

continuous

reach experimental inadequate

potential related

were to developmental

animal reflect

available

of

marketed due adolescents, the

weights

reproductive evaluate

of

demonstrated

be The within

problematic determination

of is findings mg/kg

insufficient

to not

data

published

It humans evaluation and

that

including Panel 35 that reproductive

do

may use,

in inconclusive, organ

also

that these

one of

studies of

control because

medication-treated reproductive

The

exposure

examine that of

adults. in of however, mice, felt medication

evidence The on to Expert evaluation were

children

experimental

a in differences.

doses some of tobacco

toxicity

concluded occur. in is also lack concluded the

at full

animals the

of abuse prenatal

and a

Data considered

a noted;

for of to

reproductive

assessment to rats interpretation,

design

Panel for risk methylphenidate-associated Panel importance Panel sufficient designed exposure.

also

effects in was

to growth older

Although of

administration due

effects. to but generations

results was of

study

Developmental Toxicity Developmental

substance and respect limited Human Exposure Data Reproductive Toxicity

Expert Expert Expert altered

developmental clinical

studies methylphenidate the

experimental two

5.3 Methylphenidate years complicated other in rat of puberty markers onset. results with respect to delayed perinatal period also yielded different The of with outcomes in routes question 5.2 endpoints. on human reproductive of methylphenidate the effects There are no data examining on limited phenidate The illicit With insufficient gestational growth pressure. the important and adults the consideration respect treatment possible 5.0 S a D and Cral itic ions, clus ummaries, Con 5.1 The (1) or only the d‑threo-enantiomer (2). Between 2000 and 2002, there was a 64% increase in the production of methylphenidate in the US. Treatment of ADHD in teenagers and adults is increasing and is an emerging area of study. More people of reproductive age may be taking methylphenidate. There is no information on the numbers of pregnant or lactating women prescribed the drug. Human exposures are primarily through therapeutic medication use and to a lesser extent, drug abuse (oral, nasal, iv). No information was identified on possible environmental or occupational exposure.

Recommended oral doses are 10–60 mg/day for children older than 6 years and for adults. Methylphenidate is available in short-acting, intermediate-acting, and extended‑release formulations, and is administered 1–3 times daily, depending on the required dose and the form of medication. Dose schedules can be individualized according to patient needs. The Expert Panel is aware of off-label uses of methylphenidate to treat depression, primarily as an adjunct to antidepressant medication, and to treat patients with post-stroke cognitive impairment. The Expert Panel is also aware of off-label use of methylphenidate in children younger than 6 years of age.

5.4 Overall Conclusions There is a substantial published database of studies designed to investigate the potential adverse reproductive and developmental effects of methylphenidate exposure in both humans and laboratory animals. However, thorough review of these numerous studies led the Expert Panel to judge that the data were generally insufficient to reach valid scientific conclusions with regard to possible reproductive or developmental effects.

Specifically, the Expert Panel found data were available but insufficient to evaluate: • Developmental toxicity in humans exposed prenatally; • Reproductive toxicity in humans (no data available); • Effects on growth in exposed children and adolescents; • Effects on heart rate and blood pressure in exposed children; • Altered risks of tobacco use, problematic alcohol consumption, or illicit substance abuse in ado- A ppendix II lescents or adults; • Developmental toxicity, including neurotoxicity, in laboratory animals; • Sensitization to other stimulants in laboratory animals; and • Reproductive toxicity in laboratory animals.

The Expert Panel judged the data sufficient to conclude that: • Postnatal subcutaneous administration of ≥ 35 mg/kg bw/day methylphenidate to rats produces reversible growth restriction; and • Methylphenidate treatment of children at standard therapeutic doses does not increase the incidence of tics or movement disorders.

Thus, the only conclusions the Expert Panel was able to reach with regard to potential adverse effects in humans following therapeutic exposures were (1) negligible concern for methylphenidate-induced tics and movement disorders predicated on human data and (2) minimal concern for methylphenidate- induced growth restriction predicated on data derived from rat studies using high doses and sc route of administration.

II-132 Appendix II - to of of as are the and use, such such study within human mental includ such patient, that identify in velocity required outdated to disorders, to height because number the of exposure are adolescence

tobacco substantially a available, global factors developmental treatment to final growth use on are populations methylphenidate. in and individuals needed relevant or on toxicity and were considered adolescents studies in in utero provider, through for psychiatric are be and data and There Subpopulations trends to care design treatment short-term quality information extend Confounding treatment studies studies syndromes on parental need exposures endpoints following efficacy toxicity health reproductive children Current old, better often of under-represented controlled. norms. provide drugs, human genetic inadequate affect that that effects years human compare to childhood and methylphenidate. females. that illicit of <6 would prematurely) methylphenidate of responsible quality due currently interpretable methylphenidate and and of methylphenidate should with that populations of adequately the exposure born of of concluded of by of effects children development and variations limited II-133 age-standardized effects dysmorphic in assessment consider studies design alcohol, studies Panel effects in effects paucity made to children or and associated noted the individuals, The with the be the the durations in be postnatal need generally (e.g., possible Expert tobacco, age-related to must and documenting under-represented with to and research the children confidence were concerns techniques as for applied studies non-White need ADHD considered. pre- methylphenidate evaluate characterize identify characterize be of studies be of The holidays on to to to to exposure studies to current toxicity medication increase impressed needed defined Therefore, use drug the should the use are are and need was needed needed of needed needed needed to prematurely, environment numerous use non-Caucasians, postnatal that data evaluate are are development are are are found use to off-label needs Panel need standards. born to interpretation. to girls, or and/or adulthood data Developmental and Reproductive Toxicology Data Needs Toxicology Developmental and Reproductive Panel uncertainty and Although and adults. use of alcohol, and illicit substance use in children, adolescents, problematic Toxicity ing retardation, and children born prematurely. in drug and toxicity. efficacy variations issues that can affect developmental possible Studies wide age range of exposure. the increasingly on pubertal progression. methylphenidate of effects possible Studies are needed to evaluate Studies Studies with appropriate controls for confounders. (height and weight), Studies weight. Due Studies trimester of exposure. stratified by methylphenidate, Pharmacokinetics relating to gestation and lactation are needed. data humans are needed. in of methylphenidate effects reproductive Data on possible Critical Data Needs Expert care-giving decision studies into • • • • • • • • • • effectively children infrequent Human Studies: as and and use appropriate controls. adolescence) stage (e.g., childhood versus the same developmental 5.5.1 prenatal and susceptible design as risks. Expert methods to considerations The is a minor. if the patient and the family 5.5 Critical reduce The use. therapeutic The Experimental Animal Studies: • Data are needed on developmental neurotoxicity in animals. The studies should include routes of exposure consistent with human exposure scenarios and multiple dose levels. • Studies on rat and rabbit developmental and reproductive toxicity, and pharmacokinetics related to gestation and lactation need to be obtained from the FDA, other agencies, or industry. These data are either not available or available only as summaries, thus precluding independent scientific review by the Expert Panel. • Studies are needed to evaluate possible effects of methylphenidate on pubertal timing and quality. • Studies are needed to model data obtained by non-oral routes of administration so these data can be more useful in evaluating human oral exposures. • Valid animal models of ADHD need to be used in studies of methylphenidate toxicity in order to evaluate toxicity in a system that more closely approximates the human patient population. • Nonhuman primate or guinea pig studies would be useful to evaluate effects of gestational methylphenidate use in the second and third trimesters.

5.5.2 Endpoints Other than Reproductive and Developmental Toxicity • Data are needed to determine the numbers of methylphenidate prescriptions for teenagers and adults, children <6 years old, and pregnant and lactating women. • Studies are needed to characterize the long-term effects of methylphenidate treatment on heart rate and blood pressure. The studies need to consider ethnic variation in subpopulations, such as African Americans, who are especially susceptible to cardiovascular disease.

5.5.3 Non-Critical Data Needs Although the following data needs are not critical for a risk evaluation, they would be generally informative: • Data are needed on methylphenidate-associated sensitization to other stimulants. • Studies are needed to identify the specific esterase(s) that metabolize methylphenidate. • Information is needed on the effects of ontogeny and polymorphisms on esterase activity and A ppendix II other factors (e.g., receptor activity) that may affect efficacy and toxicity of methylphenidate.

II-134 Appendix II - of the no. U.S. Nat­ Inc.; Inc.; Inc.;

2003. .

ALZA evalua Health, and Novartis NC: of (CAS Inc.;

CA: NJ: Corporation; Park, Administration effectiveness http://www.dea. Pharmaceuticals < Mallinckrodt, education View, Mallinckrodt,

Institutes equivalence at Drug Pharmaceuticals, on

Hanover, MO: clinical MO:

Triangle Novartis hydrochloride and East and Pharmaceuticals, National

NJ: Mountain Pharmaceuticals Available Louis, Celltech

Louis,

Food therapeutic . St. committee

Research St. NY: Administration. 2000.

with labeling. Celltech Service,

Hanover, the: Novartis labeling. families. NY:

labeling. East NJ:

studies). http://www.incb.org/incb/en/psychotropic_ methylphenidate labeling. and Health < product Rochester, before products Pharmacokinetics of

product http://chem2.sis.nlm.nih.gov/chemidplus/> at (feed R. < youth product Public

labeling. drug product Hanover, D. at Rochester, II-135

capsules mice studies labeling.

tablets testimony East tablets product Available Services, Drug Enforcement . U.S. childhood, labeling. release Approved

Available product B6C3F1 Abernethy,

Methylin®ER

labeling. early and and Human chewable Book: and

product on tablets

T.

carcinogenesis ‑ extended congressional Ritalin-SR® and J. rats substances. ‑release extended http://www.fda.gov/cder/ob/default.htm> product < and and Orange at DEA Cross, Health Methylin® Methylphenidate. Methylin®

F344/N T. of subcomittee C., in Ritalin®LA Focalin™ Metadate®CD Metadate®ER Ritalin® 1995. Program; Toxicology

Concerta® H. Electronic Psychotropic Available Toxicology workforce: gov/pubs/cngrtest/ct051600.htm> UN. Mallinckrodt. 2003. Woodworth, Novartis. Pharmaceuticals Corporation; 2001. Celltech. 2002. National FDA. tions. 2004. and Research. Center for Drug Evaluation Corporation; 2003. NTP. 298-59-9) Department Mallinckrodt. 2002. ALZA. ional Library of Medicine. 2004. Novartis. Corporation; 2001. Celltech. Novartis. 2001. ChemIDplus. Kimko, Clin Pharmacokinet 1999; 37: 457-70. methylphenidate. 14. 12. 13. 10. 11. 9. 8. 6. 7. 4. 5. 2. 3. CES REFEREN 1. substances.html> United Nations International Narcotics Control Board; 2002.

15. Searight, H. R., Burke, J. M. and Rottnek, F. Adult ADHD: evaluation and treatment in family medicine. Am Fam Physician 2000; 62: 2077-86, 2091-2.

16. Markowitz, J. S. and Patrick, K. S. Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet 2001; 40: 753-72.

17. Madras, B. K., Miller, G. M. and Fischman, A. J. The dopamine transporter: relevance to attention deficit hyperactivity disorder (ADHD). Behav Brain Res 2002; 130: 57-63.

18. Santosh, P. J. and Taylor, E. Stimulant drugs. Eur Child Adolesc Psychiatry 2000; 9 Suppl 1: I27-43.

19. NIDA. InfoFacts: methyphenidate (Ritalin). Available at . National Institute on Drug Abuse. 2003.

20. Teter, C. J., McCabe, S. E., Boyd, C. J. and Guthrie, S. K. Illicit methylphenidate use in an under- graduate student sample: prevalence and risk factors. Pharmacotherapy 2003; 23: 609-17.

21. Johnston, L. D., O’Malley, P. M., Bachman, J. G. and Schulenberg, J. E. Monitoring the future- national survey results on drug use, 1975-2003: Volume I, Secondary school students. Bethesda, MD: National Institute on Drug Abuse; 2003.

22. Greenhill, L. L., Halperin, J. M. and Abikoff, H. Stimulant medications. J Am Acad Child Adolesc Psychiatry 1999; 38: 503-12.

23. AAP. American Academy of Pediatrics Committee on Children with Disabilities, Committee on A ppendix II Drugs: Medication for children with an attention deficit disorder. Pediatrics 1987; 80: 758-60.

24. AAP. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyper- activity disorder. Pediatrics 2001; 108: 1033-1044.

25. Winsberg, B. G., Kupietz, S. S., Sverg, J., Hungund, B. L. and Young, N. L. Methylphenidate oral dose plasma concentrations and behavioral response in children. Psychopharmacology (Berl) 1982; 76: 329-32.

26. Teo, S. K., San, R. H., Wagner, V. O., Gudi, R., Stirling, D. I., Thomas, S. D. and Khetani, V. D. D‑Methylphenidate is non-genotoxic in in vitro and in vivo assays. Mutat Res 2003; 537: 67-79.

27. Solanto, M. V. Clinical psychopharmacology of AD/HD: implications for animal models. Neuro- sci Biobehav Rev 2000; 24: 27-30.

28. Greenhill, L. L. Pharmacologic treatment of attention deficit hyperactivity disorder. Psychiatr Clin North Am 1992; 15: 1-27.

II-136 Appendix II - - - - ­ of 11: and

Exp boys G. review

follow methyl psycho Review, Methyl delivery

a

hyperac Gardner, 300-6.

Suppl of

volunteers. al. Reviews(s), and oral

64 and

stereospecific et concentration 241:

J. Pharmacol deficit Kraemer, Medical measures J pharmacokinetics pharmacokinetics and and

healthy 2003; stimulants: release

A., 1987; ‑ Pharmacokinetics

plasma M. Psychopharmacology disposition in

R. G. S. on al. other attention

Ther

monkey. and B. et behavioral Nonlinear Puig-Antich, Reviews(s), methylphenidate-treated Exp with Psychiatry Biopharmaceutics controlled and T.

and

S., Mueller, versus of Effects

and in rat G. Macleod, 2. and Iga, Enantioselective K., Clin J.

J., J Stereoselective Dose-proportional Winsberg,

K. narcolepsy

levels and J. Part children osmotic, man, Curran, K.

K. K. Pharmacol

Y. and in

in an

K. J B.,

with S. Young,

J.

patient.

Ellington, J., plasma using Biopharmaceutics

D. methylphenidate Midha, T., neuroendocrine, Honda,

Thiessen, breakfast. Pharmacology Pharmacokinetics Midha, Sverd,

patient Gupta, and of C.

disorder. Y., J. S., and

Feldman, a ADHD and II-137 J.,

and

S. D. and in D. Cohen, G., before

the M.

W. delivered J.

Clinical

P., to or 1141-9. J. methylphenidate

potential

Sawada, R. Gualtieri,

of 1992; 52: 561-568. Ther. Soldin, 40: persistence Quinn,

T., with C., Hurwic, Rudolph, abuse Jatlow, Greenblatt,

pharmacokinetic, M., W., dl-threo-methylphenidate Pharmacology attention-deficit enantiomers Hubbard,

J. relevance 2000; J. Review(s),

motor

M., D., the given Noveck, M.,

of and Kilts,

Sasaki, J. J. D., R.

I. and with B.,

methylphenidate K., H.,

R. disorder: Clinical of

Perel, Perel, between Hunt, Hubbard, Swanson, Quinn,

Chemistry Pharmacol Pharmacokinetics

Wang, LA: Comparing L., L.,

E., children Kotaki, R.,

evidence Patrick, R., deficit

M., R. Shader, H. L. B. S. hydrochloride

in B., kinetics Clin

T., N.

P. N.

o W., S. G. J

B.,

N. Y. Ritalin Focalin:

Int J Neuropsychopharmacol 2001; 4: 207-15. ADHD. pharmacodynamics Correlations threo-methylphenidate available attention

system. of of Eur J Clin Pharmacol 1993; 44: 79-84. Modi, pharmac Kollins, Coffey, stimulants in children. J Clin Psychopharmacol3: 217-25. 1983; Aoyama, Hungund, children. Br J Clin Pharmacol 1979; 8: 571-6. in hyperkinetic methylphenidate Greenhill, R. with 69: 688-694. 1982; Pediatrics methylphenidate. ing acute and chronic treatment with Srinivas, phenidate Breese, Ther 1983; 226: 382-6. Shaywitz, of Srinivas, and Clin. Pharmacol. disorder. tivity Wargin, 2001. and Research; for Drug Center Evaluation and Medical Review. Chan, phenidate 72: 56-59. 1983; acid. Pediatrics and ritalinic of methylphenidate FDA. and Research; 2001. Drug Center for Evaluation Review. and Statistical FDA.

41. 40. 38. 39. 36. 37. 35. 34. 32. 33. 31. 29. 30. 14-8.

42. Markowitz, J. S., Morrison, S. D. and DeVane, C. L. Drug interactions with psychostimulants. Int Clin Psychopharmacol 1999; 14: 1-18.

43. Hubbard, J. W., Srinivas, N. R., Quinn, D. and Midha, K. K. Enantioselective aspects of the dis- position of dl-threo-methylphenidate after the administration of a sustained‑release formulation to children with attention deficit-hyperactivity disorder. J. Pharm. Sci. 1989; 78: 944-947.

44. Teo, S., Stirling, D., Thomas, S., Hoberman, A., Kiorpes, A. and Khetani, V. A 90-day oral gavage toxicity study of D‑methylphenidate and D,l‑methylphenidate in Sprague-Dawley rats. Toxicology 2002; 179: 183-96.

45. Davids, E., Zhang, K., Tarazi, F. I. and Baldessarini, R. J. Stereoselective effects of methylpheni- date on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning. Psychopharmacology (Berl) 2002; 160: 92-8.

46. Teo, S. K., Stirling, D. I., Hoberman, A. M., Christian, M. S., Thomas, S. D. and Khetani, V. D. d‑Methylphenidate and d,l‑methylphenidate are not developmental toxicants in rats and rabbits. Birth Defects Res Part B Dev Reprod Toxicol 2003; 68: 162-71.

47. Teo, S. K., Stirling, D. I., Thomas, S. D., Hoberman, A. M., Christian, M. S. and Khetani, V. D. The perinatal and postnatal toxicity of d‑methylphenidate and d,l‑methylphenidate in rats. Reprod Toxicol 2002; 16: 353-66.

48. Bakhtiar, R. and Tse, F. L. Toxicokinetic assessment of methylphenidate (Ritalin®) enantiomers in pregnant rats and rabbits. Biomed Chromatogr 2004; 18: 275-81.

A ppendix II 49. Teo, S. K., Stirling, D. I., Thomas, S. D., Evans, M. G. and Khetani, V. D. A 90-day oral gavage toxicity study of d‑methylphenidate and d,l‑methylphenidate in beagle dogs. Int J Toxicol 2003; 22: 215-26.

50. Srinivas, N. R., Lim, H. K., Hubbard, J. W. and Midha, K. K. Evidence that dogs do not model enantioselective pharmacokinetics of dl-methylphenidate in humans. J. Pharm. Sci. 1991; 80: 707-708.

51. Schachter, H. M., Pham, B., King, J., Langford, S. and Moher, D. How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and ado- lescents? A meta-analysis. Cmaj 2001; 165: 1475-88.

52. Schmidt, R. A., Glenny, R. W., Godwin, J. D., Hampson, N. B., Cantino, M. E. and Reichenbach, D. D. Panlobular emphysema in young intravenous Ritalin abusers. Am Rev Respir Dis 1991; 143: 649-56.

53. Gunby, P. Methylphenidate abuse produces retinopathy. Jama 1979; 241: 546.

II-138 Appendix II ­ - - J

V. W.

car Clin

from R. Nishi, Medi neuro­

abuser. mice. methyl

cells: and

possible

National

of

of . and

Data Exchanges

for Toxicol drug P.

J Morris, hydrochloride a young,

abuse

methylphenidate methylphenidate Library in

and Weight not drugs of of

Salmonella ester,

L. BALB/c-3T3 Chromatid in but

J. Greengard, exposures. of

Organ

effects National

. methyl syndrome intravenous potential C., Sister

347-482.

adult,

to

2: A. in prescription

Teague,

1988; 11: 343-358. Toxicol abuse methamphetamine-induced due

D., Drugs, mutagenicity

long-term on 1993; the Appl

Nairn, M. medullary

the Reproductive 149-51. with

Transformation

methylphenidate

H., signalling Screening 6:

alpha-phenyl-,

on

and W. of Pediatric Ross,

research H. Perspect dysfunction

Medial R. Assessing acid, V.,

1984; B.

K. studies R. I. Used compared Higashi, profile

C. II-139 N. Health Jc, A Current

Hepatic T., http://toxnet.nlm.nih.gov/>

Cytology, P. T. <

Tennant, A.

E. at Rush, Fireman,

T. http://www.cdc.gov/niosh/rtecs/tm3abf10.html>

Lamb < and dopamine/DARPP chemicals Environ

Commonly

Gonatas, and Gastroenterol

Vaginal and at Experimental A., on

W.

W. Matsuishi, K.

168

R. 2-piperidineacetic B. D. J. and Clin

E. K. Nakashima,

of P., Available J.

LoIudice,

J

Krenzelok, A. for G. Sperm, 1391-401. and bioassays.

and R.

and Available Am J Hum Genet 1977; 29:

C. B. 87:

Hailey,

Schwetz, R. report Dumars, Spalding, G.

responses

rodent 1995; 103: 77-84. Toxicology Rodent

and E., J., MacDonald, Lewis,

and in intravenous emphysema precocious Severe J. D. and Pierson, Hudson, L. D. B., Friedman, in methylphenidate 2003;

of K. R. E. P. Svenningsson, Murray, H.,

T.,

hydrochloride.

Mrvos, of J.

V.,

Studies. Fundam 13-Week Program Toxicology RTECS 298-59-9). S. Wagner, A. Methylphenidate.

H.,

R., J.

R., formation 2002. T.,

s Effect

Fukui, A. Neurochem Selby, 1989; 49: 5736-47. Cancer Res of follow-up. years to fifteen eleven carcinogenicity: Dunnick, hydrochloride. Matthews, Tran cinogenicity Morrissey, Evaluation National Walker, and the Cell Cycle. NIOSH. (CAS#: and Health. 2002. Institute of Occupational Safety Kita, animal models of monoamine disruption. J Pharmacoltoxicity: Sci 2003; 92: 178-95. HSDB. cine. Foley, 2000; 38: 625-30. Toxicol Kollins, 2001; 68: 611-27. Pharmacol Biochem Behav a review. in nonhuman and human subjects: phenidate Sherman, C. (Ritalin) abusers. Chest 1987; 92: 1085-7. methylphenidate Mizutani, 1980; 37: 425-8. Arch Neurol Mehta, 67. 65. 66. 64. 62. 63. 61. 59. 60. 57. 58. 56. 54. 55. 68. Debooy, V. D., Seshia, M. M., Tenenbein, M. and Casiro, O. G. Intravenous pentazocine and methyl­ phenidate abuse during pregnancy. Maternal lifestyle and infant outcome. Am J Dis Child 1993; 147: 1062-5.

69. Heinonen, O. P. Birth defects and drugs in pregnancy. ed. Littleton, MA: Publishing Sciences Group Inc; 1977.

70. Rapoport, J. L., Quinn, P. O., Bradbard, G., Riddle, D. and Brooks, E. Imipramine and methyl- phenidate treatments of hyperactive boys. A double-blind comparison. Arch. Gen. Psychiatry 1974; 30: 789-793.

71. Conners, C. K. and Taylor, E. Pemoline, methylphenidate, and placebo in children with minimal brain dysfunction. Arch Gen Psychiatry 1980; 37: 922-30.

72. Barkley, R. A., McMurray, M. B., Edelbrock, C. S. and Robbins, K. Side effects of methyl­ phenidate in children with attention deficit hyperactivity disorder: a systemic, placebo-controlled evaluation. Pediatrics 1990; 86: 184-92.

73. Handen, B. L., Feldman, H., Gosling, A., Breaux, A. M. and McAuliffe, S. Adverse side effects of methylphenidate among mentally retarded children with ADHD. J Am Acad Child Adolesc Psychiatry 1991; 30: 241-5.

74. Fine, S. and Johnston, C. Drug and placebo side effects in methylphenidate-placebo trial for attention deficit hyperactivity disorder. Child Psychiatry Hum Dev 1993; 24: 25-30.

75. Ahmann, P. A., Waltonen, S. J., Olson, K. A., Theye, F. W., Van Erem, A. J. and LaPlant, R. J. Placebo-controlled evaluation of Ritalin side effects. Pediatrics 1993; 91: 1101-6.

A ppendix II 76. Schachar, R. J., Tannock, R., Cunningham, C. and Corkum, P. V. Behavioral, situational, and temporal effects of treatment of ADHD with methylphenidate. J Am Acad Child Adolesc Psychiatry 1997; 36: 754-63.

77. Kent, J. D., Blader, J. C., Koplewicz, H. S., Abikoff, H. and Foley, C. A. Effects of late-afternoon methylphenidate administration on behavior and sleep in attention-deficit hyperactivity disorder. Pediatrics 1995; 96: 320-325.

78. Efron, D., Jarman, F. and Barker, M. Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: a double-blind, crossover trial. Pediatrics 1997; 100: 662-6.

79. Connor, D. F. Preschool attention deficit hyperactivity disorder: a review of prevalence, diagno- sis, neurobiology, and stimulant treatment. J Dev Behav Pediatr 2002; 23: S1-9.

80. Satterfield, J. H., Schell, A. M. and Barb, S. D. Potential risk of prolonged administration of stimulant medication for hyperactive children. J Dev Behav Pediatr 1980; 1: 102-7.

II-140 Appendix II ­ - - ­ J. in of 35: 45:

Clin axis. skills cloni 2870-

dextro

methyl Int receptor

children to function attention

hormone

Pressure- 1984; 1984; of ‑

children. 236: motor treatment responses and

Methylpheni Sci drugs,

Cardiovascular the effect

G. and methylphenidate: growth response 1976; L.

Life on

R. the

hyperactive functioning. Psychiatry R.

and Epilepsy noradrenergic

in hyperactive stimulant and

S. in serum

MHPG Assoc.

Clin in

cardiorespiratory

the

J R. (Ritalin)

cardiovascular evaluation, of and

Sprague, disorder Med. upon Thompson, on changes disorder change hyperactivity.

and Shalev, hormone cardiovascular Effect and increases

Am. and deficit T. H.

pulse

L. effects J. deficit hormone diagnosis,

and

functioning. B.

Possible R.

and A. hypothalamic-pituitary-somatomedin

the growth L.

methylphenidate children’s the disorder of on growth

Thorsen,

Attention children: Psychiatry 1975; 132: 1325-1326. Am. J. of Hintz, Attention on on

methylphenidate J. Massey, Joseph, in Clark,

and

pressure W. L.,

of G. J., report F. deficit II-141

K.,

L. Methylphenidate

and cardiovascular M. effects

secretion K.

effects effects

E. methylphenidate. treatment:

G. W. Blood

on and to fourth The

Meere, Effects

Stoa, DuPaul,

B. M. attention G.

Slimmer, B.

der The Sleator, H.,

A.

children: Wolraich, and G. S. and with Methylphenidate

van A.,

T., D. children

Anderson,

J. E. J.

dose-response behavioral, R. J., Klove, O.,

Yellin, M. Pressure-Education-Program-Working-Group-on-High-Blood

Williams, ‑ M. of

methylphenidate F., D. Hinton,

Sexson, methylphenidate and children Werry,

hyperactive and and in Manor, M. Hayford, and

of

Boileau, and and hyperactive attention, Wynne, Rapport,

A. Cohen, Ferang, analysis M.

V.,

L. T.

R., E., following G. of on T.,

L.,

D., R. D.,

F. W. J.

R. R.

M. K. R.

challenge treatment

multi-step a Psychopharmacol 1988; 3: 167-81. Brown, 179-83. 10: Care 1989; Health J Adolesc hyperactivity adolescents. disordered attention deficit Kelly, Gross-Tsur, 2874. Brown, phenidate 473-6. Aman, Int J Ment Health 1975; 4: 119-131. on exertion. Ballard, responses Knights, Nerv of children with learning J Ment Dis 1969; 148: 643-53. problems. and behavior Greenberg, treated with imipramine and methylphenidate. National-High-Blood in-Children-and‑Adolescents. 114: 555-76. 2004; Pediatrics pressure in children and adolescents. high blood 1982; 70: 987-992. Pediatrics Hunt, sensitivity dine 885-97. Brown, 937-9. Clin Endocrinol Metab 1976; 43: concentrations. J Schultz, date Aarskog, amphetamine 90: 136-139. 1977; Pediatr.

93. 91. 92. 90. 88. 89. 86. 87. 85. 84. 82. 83. 81. deficit hyperactivity disorder: is methylphenidate safe and effective? J Pediatr 1997; 130: 670-4.

94. Hemmer, S. A., Pasternak, J. F., Zecker, S. G. and Trommer, B. L. Stimulant therapy and seizure risk in children with ADHD. Pediatr Neurol 2001; 24: 99-102.

95. Lucas, A. R. and Weiss, M. Methylphenidate hallucinosis. Jama 1971; 217: 1079-81.

96. Young, J. G. Methylphenidate-induced hallucinosis: case histories and possible mechanisms of action. J Dev Behav Pediatr 1981; 2: 35-8.

97. Bloom, A. S., Russell, L. J., Weisskopf, B. and Blackerby, J. L. Methylphenidate-induced delu- sional disorder in a child with attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 1988; 27: 88-9.

98. Koehler-Troy, C., Strober, M. and Malenbaum, R. Methylphenidate-induced mania in a pre­ pubertal child. J Clin Psychiatry 1986; 47: 566-7.

99. Cherland, E. and Fitzpatrick, R. Psychotic side effects of psychostimulants: a 5-year review. Can J Psychiatry 1999; 44: 811-3.

100. Leckman, J. F. Phenomenology of tics and natural history of tic disorders. Brain Dev 2003; 25(Suppl 1): S24-S28.

101. Golden, G. S. Gilles de la Tourette’s syndrome following methylphenidate administration. Dev Med Child Neurol 1974; 16: 76-8.

102. Law, S. F. and Schachar, R. J. Do typical clinical doses of methylphenidate cause tics in children treated for attention-deficit hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 1999; A ppendix II 38: 944-51.

103. Tourette’s_Syndrome_Study_Group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 2002; 58: 527-36.

104. Denckla, M. B., Bemporad, J. R. and MacKay, M. C. Tics following methylphenidate admin­ istration. A report of 20 cases. Jama 1976; 235: 1349-51.

105. Golden, G. S. The effect of central nervous system stimulants on Tourette syndrome. Ann Neurol 1977; 2: 69-70.

106. Fras, I. and Karlavage, J. The use of methylphenidate and imipramine in Gilles de la Tourette’s disease in children. Am J Psychiatry 1977; 134: 195-7.

107. Shapiro, A. K. and Shapiro, E. Do stimulants provoke, cause, or exacerbate tics and Tourette syndrome? Compr Psychiatry 1981; 22: 265-73.

II-142 Appendix II - - - J 42: and Res Crisp abuse Child 1986;

Rapo stimu

effects 859-61. tics medica

attention stimulant of attention- 2001;

Tourette’s and drug Psychiatry Psychiatry

treatment. Acad la 148:

D.

with with with

de Psychiatry later S. Gen

attention-deficit effects Am methylphenidate

Neurology Syndrome. syndrome: J Stimulant 1994;

of

of and Adolesc

Motor/vocal Psychiatry A. Arch Gilles children use. J. children Med

B.

associated in K.

of Child Tourette syndrome: nontwins. Hamburger, Tourette’s Efficacy drug K. Compr methylphenidate tics

treatment vulnerability?

F., disorder. with Amass, of N. of Acad and Adolesc

chemotherapy G. S.

tic early Shaywitz, Kidd,

and Am dyskinesias to

J J. Tourette’s twins

comorbid effects observations and and Pediatr with

common la Ezor, in Children and Psychiatry 1975; 132: 436-438. Am. J. J.

W. a Ritchie, medications. and de Elia, Emergence in D. and Childhood Arch

ADHD

M. L., Tics R.

School

L., E. G. Methylphenidate

J. there disorder:

R. W. children J. syndrome.

Adhd Gilles E. ADHD is from tic M. in stimulants A.

of

Cohen, stimulant D. Sum, of II-143

disorder.

L. Adolesc Psychiatry 1997; 36: 589-96. Sverd,

A. L., Marsh, Calderon, and

with Nolan, drugs: J., and D. Kremenitzer, system Tourette’s Rapoport, M. J., and disorder J.

Pathways comorbid J., Adesman,

P.

S., Treatment treatment Elia, with 1347-54. Rothner, N.

treated

Paolicelli, and Pauls, C. and

Acad Child hyperactivity

N.,

nervous 38: J. stimulant and F.,

Detlor, J. MacKay, boys Varley, and

Sprafkin, Sprafkin, I. Am

P. J.

J., on in J., S., J., D.

stimulant E., R. Breslau,

disorder Keysor, disorder hyperactivity 1999;

D.

central W.

K. Giedd,

G., 1982; 247: 1729-31. syndrome. Jama Tourette’s and

and Sverd, X., Methylphenidate Nolan, Cruse, B. disorder Goldstein, Vincent, D. Leckman,

F.

Cohen, behaviors attention-deficit

D. D., tics D., G., Controlled K., Gadow, H. H., in A.,

Langford,

L., Psychiatry

K. K. K. P. L. C. J.,

hyperactivity hyperactivity T. R.

L.,

J. attention-deficit Adolesc Beck, study of 30 adolescents. curve: follow-up and growth Varley, deficit 228-33. Chilcoat, of stimulant and dose. J Gadow, Data Base National Institutes Of Health Gadow, deficit 1995; 16: 167-76. Pediatr Behav Dev Castellanos, port, Gadow, for 1995; 52: 444-55. compulsive 1990; 33: 83-94. Lipkin, treatment Sverd, hyperactivity 1989; 28: 574-9; discussion 580-2. Borcherding, 1985; 35: 1346-8. lant drugs. Neurology Price, syndrome: 36: 232-7. Lowe, tions precipitate Erenberg, 120. 118. 119. 117. 115. 116. 114. 113. 111. 112. 110. 108. 109. 121. Biederman, J., Wilens, T., Mick, E., Spencer, T. and Faraone, S. V. Pharmacotherapy of attention- deficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics 1999; 104: e20.

122. Barkley, R. A., Fischer, M., Smallish, L. and Fletcher, K. Does the treatment of attention-deficit/ hyperactivity disorder with stimulants contribute to drug use/abuse? A 13-year prospective study. Pediatrics 2003; 111: 97-109.

123. Fischer, M. and Barkley, R. A. Childhood stimulant treatment and risk for later substance abuse. J Clin Psychiatry 2003; 64 Suppl 11: 19-23.

124. Lambert, N. M. and Hartsough, C. S. Prospective study of tobacco smoking and substance dependencies among samples of ADHD and non-ADHD participants. J Learn Disabil 1998; 31: 533-44.

125. Lambert, N. M. Stimulant treatment as a risk factor for nicotine use and substance abuse. In: P. S. Jensen and J. R. Cooper, ed. Attention Deficit Hyperactivity Disorder. ed. Kingston, NJ: Civic Research Institute, 2002:

126. Paternite, C. E., Loney, J., Salisbury, H. and Whaley, M. A. Childhood inattention-overactivity, aggression, and stimulant medication history as predictors of young adult outcomes. J Child Adolesc Psychopharmacol 1999; 9: 169-84.

127. Loney, J., Kramer, J. R. and Salisbury, H. Medicated versus unmedicated ADHD children: adult involvement with legal and illegal drugs. In: P. S. Jensen and J. R. Cooper, ed. Attention Deficit Hyperactivity Disorder. ed. Kingston, NJ: Civic Research Institute, 2002: 1-16.

128. Mannuzza, S., Klein, R. G. and Moulton, J. L., 3rd. Does stimulant treatment place children at risk for adult substance abuse? A controlled, prospective follow-up study. J Child Adolesc A ppendix II Psychopharmacol 2003; 13: 273-82.

129. Wilens, T. E., Faraone, S. V., Biederman, J. and Gunawardene, S. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 2003; 111: 179-85.

130. Wilens, T. Attention deficit hyperactivity disorder and substance abuse disorders-the nature relationship, subtypes at risk, and treatment issues. In: P. S. Jensen and J. R. Cooper, ed. Attention Deficit Hyperactivity Disorder. ed. Kingston, NJ: Civic Research Institute, 2002: 1-17.

131. Safer, D., Allen, R. and Barr, E. Depression of growth in hyperactive children on stimulant drugs. N Engl J Med 1972; 287: 217-20.

132. Safer, D. J. and Allen, R. P. Factors influencing the suppressant effects of two stimulant drugs on the growth of hyperactive children. Pediatrics 1973; 51: 660-7.

133. Safer, D. J., Allen, R. P. and Barr, E. Growth rebound after termination of stimulant drugs. J.

II-144 Appendix II of of or ed t and Bull with Child 1982; Goetz, effects trea growth

Disabil

Effect J., boys on

height regimen hyperactive imipramine Acad K. in Neurol Learn in children R. J

with Am Florea, Psychopharmacol J Child C., medication growth adolescent

Psychopharmacol responses dextroamphetamine, treated Methylphenidate of Med maintenance and Ullmann, hyperactive

III. on boys Dev of

and growth Anghern, stimulant

up. [proceedings]. N. methylphenidate. and M., Predictors methylphenidate. M. Growth children [proceedings].

K. children. grown with T.

hyperactive long-term methylphenidate,

children with Methylphenidate of of

hormone F. Cohen, Solomon, Adney, almost of long-term stimulant medication The effects treated D. taking H., K., Blaschke, and treated hyperactive

hyperactive effects boys

E. growth B. of of II-145 and follow-up

hyperactive Arch Gen Psychiatry 1988; 45: 1127-30. Klein, methylphenidate The children L.

A.

of children R.

and with stature Sleator, Growth Novacenko, A. Ponto, Prolactin, on J. Schell, One-year Hyperactive

hyperactivity J., L., R. J. A., P., L. Boileau, S.

treated hyperactive R. E. N. A. and Cohen, M. J. and D. M.

composition of hyperkinetic and

Mattes, Arch. Gen. Psychiatry 1979; 36: 212-217. boys E. of

Am J Psychiatry 1975; 132: 241-5. B., J.

Arch Gen Psychiatry 1988; 45: 1131-4. Sachar, body Gittelman, Sprague, Arch Gen Psychiatry 1983; 40: 317-21. hydrochloride Puig-Antich, disorder Mannuzza, Growth Rapoport, Cantwell,

and and E., and Growth L., G. Landa, H., and

and B. Ballard, J. A., Boileau, R.

J. J. L. D. A.

Whaley-Klahn, deficit hyperkinetic G. O. G., study. A controlled withdrawal B., J.

P. J., in M. growth R. R. Fiscina, the Klein, children. attention Psychiatry 1984; 23: 58-67. Klein, on ultimate height. Mattes, methylphenidate. Greenhill, R., 1981; 17: 132-4. Kalachnik, lphenidate methy 24: 586-95. Satterfield, with methylphenidate. Loney, weight Millichap, 1978; 11: 567-70. 1978; 61: 146-7. Supported. Pediatrics Findings Gross’s G. Dr. Millichap, J. children. Psychopharmacol 12: 13-5. Bull 1976; of hyperactive and body composition McNutt, B. on Bull 1977; 13: 36-8. Gross, 58: 423-31. 1976; Pediatrics imipramine/desipramine. McNutt, 86: 113-116. 1975; Pediatr. Quinn, or methylphenidate. 146. 145. 143. 144. 142. 140. 141. 138. 139. 137. 135. 136. 134. 147. Spencer, T., Biederman, J., Wright, V. and Danon, M. Growth deficits in children treated with desipramine: a controlled study. J Am Acad Child Adolesc Psychiatry 1992; 31: 235-43.

148. Zeiner, P. Body growth and cardiovascular function after extended treatement (1.75 years) with Methylphenidate in boys with attention-deficit hyperactivity disorder. J Child Adolesc Psycho- pharmacol 1995; 5: 129-38.

149. Schertz, M., Adesman, A. R., Alfieri, N. E. and Bienkowski, R. S. Predictors of weight loss in children with attention deficit hyperactivity disorder treated with stimulant medication. Pediatrics 1996; 98: 763-9.

150. Spencer, T. J., Biederman, J., Harding, M., O’Donnell, D., Faraone, S. V. and Wilens, T. E. Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays? J Am Acad Child Adolesc Psychiatry 1996; 35: 1460-9.

151. Rao, J. K., Julius, J. R., Breen, T. J. and Blethen, S. L. Response to growth hormone in attention deficit hyperactivity disorder: effects of methylphenidate and pemoline therapy. Pediatrics 1998; 102: 497-500.

152. Lahat, E., Weiss, M., Ben-Shlomo, A., Evans, S. and Bistritzer, T. Bone mineral density and turnover in children with attention-deficit hyperactivity disorder receiving methylphenidate. J Child Neurol 2000; 15: 436-9.

153. Rapport, M. D. and Moffitt, C. Attention deficit/hyperactivity disorder and methylphenidate. A review of height/weight, cardiovascular, and somatic complaint side effects. Clin Psychol Rev 2002; 22: 1107-31.

154. Sund, A. M. and Zeiner, P. Does extended medication with amphetamine or methylphenidate A ppendix II reduce growth in hyperactive children? Nord J Psychiatry 2002; 56: 53-7.

155. Lisska, M. C. and Rivkees, S. A. Daily methylphenidate use slows the growth of children: a community based study. J Pediatr Endocrinol Metab 2003; 16: 711-8.

156. Poulton, A. and Cowell, C. T. Slowing of growth in height and weight on stimulants: a characteristic pattern. J Paediatr Child Health 2003; 39: 180-5.

157. MTA-Cooperative-Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 1999; 56: 1073-86.

158. MTA-Cooperative-Group. National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: changes in effectiveness and growth after the end of treatment. Pediatrics 2004; 113: 762-9.

159. Pizzi, W. J., Rode, E. C. and Barnhart, J. E. Methylphenidate and growth: demonstration of a

II-146 Appendix II - at to of D., the OH: early J. when

Swiss growth growth admin activity of in National

alters stimuli Effects on the mice preferential vulnerability A. on George, effects Cincinnati, C.

J., and Methylphenidate following function CD‑1 locomotor Program, J. J. treatment emotional HCl. cross-sensitization 9: 361-8. Ther 1986; E. to both swiss and methylphenidate of reactivity behavioral in Crawford, Neuropsychopharmacology

Heindel, to methylphenidate: reproductive Nestler, methylphenidate 1330-7. Toxicology and

consequences 545-51. Ther 1980; 215: R., rats. of on responses oral B. 54: S. and

to J. Enhanced Enduring methylphenidate

exposure D. Methylphenidate sensitization J. assessment - sensitization L. effects rats National

2003; F.

of S. Russell, adolescent

rat: restriction behavioral NC: Watson, chronic in E., Neurochemical fertility White, of SMVCE 1987; 9: 107-11. Teratol E., feed S. Adolescent absence alters young adolescent P. J. Park, of and and L. Psychiatry Differential

II-147 Hope, F. of Wallace-Black, Andersen, and

the E. K. effects treatment J. Biol A., in L. O.,

and effects

P. Karper, The Seiden, Triangle White, D. rats.

S.

L., The Exposure and S. Baker, in J. Fail, and

reproduction Berton, L. S. R. Barnhart, R. periadolescence treatment 1993; 20: 15-22. Toxicol J. M. M., K., D. C. M., norepinephrine Research HCl and Kizer, D. and Mague, methylphenidate Appl

C. Collins, and Segal, E. Teague, feed. Jr., pre-

Barrot, Marinelli, Jr. Marinelli, A., Gulati, Schuster, and A., via and

S. A., L., L., methylphenidate H., Rode,

E., C., R. B. following extracellular W. during

C. to C. C. methylphenidate J.,

G. G. R. T. on W. Methylphenidate cocaine Grizzle, CD‑1 mice. Fundam ‑Testing. Environmental-Health-Research-and 1984. Chapin, methamphetamine. J Neurosci 2002; 22: 7264-71. NTP. administered Health Sciences; 1989. Institute of Environmental Brandon, Psychiatry of rat midbrain dopamine neurons. Biol 2003; 54: 1338-44. activity Kuczenski, effects Carlezon, exposure Wagner, 1981; 14: 117-9. neonatal rat. Pharmacolistration of CNS stimulants to the Biochem Behav Bolaños, treatment adulthood. Biol Psychiatry 2003; 54: 1317-29. repeated sniffing. Exp Clin Psychopharmacoland stereotyped 1999; 7: 208-18. Brandon, to 2001; 25: 651-61. Greeley, rat. J Pharmacol Exp in the developing and endocrine function McDougall, Pharmacol Dev phenomenon. impairment growth-rebound and a growth Pizzi, rats. Neurotoxicol of neonatal and adolescent 170. 171. 169. 167. 168. 165. 166. 164. 163. 161. 162. 160. Appendix III

anel Report /œÊՓ>˜Ê,i«Àœ`ÕV̈œ˜ s Public Comment ON Methylphenidate i˜ÌiÀÊœÀÊ/ iÊ Û>Õ>̈œ˜Ê"vÊ,ˆÃŽÃÊ

P on the Expert

1°-°Ê i«>À̓i˜ÌʜvÊi>Ì Ê>˜`ÊՓ>˜Ê-iÀۈVià >̈œ˜>Ê/œÝˆVœœ}ÞÊ*Àœ}À>“ The NTP Center for the Evaluation of Risks to Human Reproduction received no public comments on the Expert Panel Report on Methylphenidate A ppendix III

III-