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NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Methylphenidate
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
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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-
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 /ÊÕ>Ê,i«À`ÕVÌ METHYLPHENIDATE OF iÌiÀÊÀÊ/ iÊ Û>Õ>ÌÊ"vÊ,ÃÃÊ 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«>ÀÌiÌÊvÊi>Ì Ê>`ÊÕ>Ê-iÀÛVià >Ì>Ê/ÝV}ÞÊ*À}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
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 antidepressant 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 cocaine (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 adrenergic 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 serotonergic 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
serotonin 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) Anxiety 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 antipsychotics (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-
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The gavage. limit rats.” 10 random
neuronal analyzed detail exposure firing,
burst
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in
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group, of was hippocampus were clinically,
study
evaluate r the More as suggest
gavage.
rats methylphenidate to saline- experimental neuron
rats
concentration by
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methods
dosing results dorsal
increases numbe (3,24)
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[purity not specified] specified] not [purity
with 14–21-day
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unclear.
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concluded treatment neuronal
Sprague-Dawley During experimental norepinephrine
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Sprague-Dawley and selection significance
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similar increased methylphenidate male
days
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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
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Hippocampus the or There the
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of
withdrawal II-111 agonist
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Five-week-old interval.
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2.0 mg/kg
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by experimentation,
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the spikes The litter cannulas
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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
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Methylphenidate number taken neurons
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an
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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.
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anel Report /ÊÕ>Ê,i«À`ÕVÌ s Public Comment ON Methylphenidate iÌiÀÊÀÊ/ iÊ Û>Õ>ÌÊ"vÊ,ÃÃÊ
P on the Expert
1°-°Ê i«>ÀÌiÌÊvÊi>Ì Ê>`ÊÕ>Ê-iÀÛVià >Ì>Ê/ÝV}ÞÊ*À}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
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