2.1 Pretreatment Screening

Prior to initiating treatment with methylphenidate HCl extended-release capsules, assess for the presence of cardiac disease (i.e., perform a careful history including family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions (5.2)].

Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for methylphenidate HCl extended-release capsules use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

2.2 Dosage Recommendations

The recommended starting dose of methylphenidate HCl extended-release capsules is 20 mg once daily. Dosage may be adjusted in weekly 10 mg to 20 mg increments to the maximum recommended dose of 60 mg per day.

Dosage should be individualized according to the needs and responses of the patient.

Pharmacological treatment of ADHD may be needed for extended periods. Periodically re-evaluate the long-term use of methylphenidate HCl extended-release capsules, and adjust the dosage as needed.

2.3  Administration Instructions

Administer methylphenidate HCl extended-release capsules orally once daily in the morning, before breakfast.

Swallow the capsule whole with the aid of liquids. Alternatively, open the capsule and sprinkle the contents onto a small amount (tablespoon) of applesauce and administer immediately. Do not store for future use. Drink fluids following the intake of the sprinkled capsule contents with applesauce. The capsules and the capsule contents must not be crushed or chewed.

2.4 Dose Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage or, if necessary, discontinue methylphenidate HCl extended-release capsules. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue methylphenidate HCl extended-release capsules.

5.1 Potential for Abuse and Dependence

CNS stimulants, including methylphenidate HCl extended-release capsules, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Drug Abuse and Dependence (9.2, 9.3)].

5.2 Serious Cardiovascular Reactions

Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during methylphenidate HCl extended-release capsules treatment.

5.3  Blood Pressure and Heart Rate Increases

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

5.4  Psychiatric Adverse Reactions

Exacerbation of Pre-Existing Psychosis
CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder
CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

New Psychotic or Manic Symptoms
CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing methylphenidate HCl extended-release capsules. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0 in placebo-treated patients.

5.5 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.6  Peripheral Vasculopathy, including Raynaud’s Phenomenon

CNS stimulants, including methylphenidate HCl extended-release capsules, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

5.7 Long-Term Suppression of Growth

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.

Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including methylphenidate HCl extended-release capsules. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical trials experience with methylphenidate HCl extended-release capsules included 188 pediatric patients 6 to 15 years old with ADHD exposed to methylphenidate HCl extended-release capsules. Patients received methylphenidate HCl extended-release capsules 20 mg, 40 mg, and/or 60 mg per day. The 188 patients were evaluated in the following studies: Study 1, a 3-week placebo-controlled clinical study consisting of a total of 314 pediatric patients (ages 6 to 15 years; methylphenidate HCl extended-release capsules n=155); Study 2, a placebo-controlled, crossover clinical study consisting of 25 pediatric patients (ages 7 to 12 years); and Study 3, an uncontrolled clinical study consisting of 8 pediatric patients (ages 6 to 10 years).

Adverse Reactions Leading to Discontinuation of Treatment
In the 3-week placebo-controlled, parallel-group trial, two methylphenidate HCl extended-release capsules-treated patients (1%) and no placebo-treated patients discontinued due to an adverse reaction (rash and pruritus; and headache, abdominal pain, and dizziness, respectively).

Most Common Adverse Reactions
The most common adverse reactions that occurred in 5% or more of patients treated with methylphenidate HCl extended-release capsules in a pool of Studies 1, 2 and 3 (ages 6 to 15 years) where the incidence in patients treated with methylphenidate HCl extended-release capsules was at least twice the incidence in placebo-treated patients were anorexia and insomnia.

Adverse reactions that occurred in ≥5% of patients treated with methylphenidate HCl extended-release capsules and greater than placebo in pooled Studies 1, 2, and 3 are presented in Table 2:

6.2  Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of methylphenidate HCl extended-release capsules and other methylphenidate HCl products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse Reactions with Methylphenidate HCl Extended-Release Capsules
Blood and the lymphatic system disorders: thrombocytopenia

Cardiac disorders: cardiac arrest, sudden death

Immune system disorders: angioedema

Musculoskeletal and connective tissue disorders: rhabdomyolysis

Psychiatric disorders: abnormal behavior, aggression, anxiety, irritability, obsessive-compulsive disorder, suicidal behavior (including completed suicide), libido changes, serotonin syndrome in combination with serotonergic drugs

Nervous system disorders: migraine, reversible ischemic neurological deficit, bruxism

Skin and subcutaneous tissue disorders: fixed drug eruption

Vascular disorders: peripheral coldness, Raynaud’s phenomenon

Adverse Reactions with Other Methylphenidate HCl Products
Blood and the lymphatic system disorders: leukopenia, anemia, pancytopenia

Cardiac disorders: palpitations, increased blood pressure, tachycardia, angina pectoris, cardiac arrhythmia, myocardial infarction, bradycardia, extrasystole

Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis

Gastrointestinal disorders: nausea, abdominal pain, dry mouth, vomiting, dyspepsia, diarrhea, constipation

General disorders: fatigue, hyperpyrexia

Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury

Immune system disorders: hypersensitivity, including anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas

Infections and infestations: nasopharyngitis

Metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients

Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, myalgia, muscle twitching

Nervous system disorders: nervousness, dizziness, headache, dyskinesia, including choreoatheetoid movements, drowsiness, tremor, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs

Psychiatric disorders: depressed mood, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), affect liability, mania, disorientation

Renal and urinary disorders: hematuria

Reproductive system and breast disorders: gynecomastia

Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, dyspnea, cough

Skin and subcutaneous tissue disorders: scalp hair loss, hyperhidrosis, angioneurotic edema, erythema, exfoliative dermatitis, thrombocytopenic purpura, urticaria, erythema multiforme rash

Urogenital disorders: priapism

Vascular disorders: isolated cases of cerebral arteritis and/or occlusion

8.1 Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate HCl extended-release capsules, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.

Risk Summary
Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations).

No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m2 basis. However, spina bifida was observed in rabbits at a dose 53 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and postnatal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 times the MRHD given to adolescents (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations
Fetal/Neonatal Adverse Reactions
CNS stimulants, such as methylphenidate HCl extended-release capsules, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.

Animal Data
In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on a mg/m2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adults on a mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on a mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses

of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adults on a mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adolescents on a mg/m2 basis).

8.2 Lactation

Risk Summary
Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate HCl extended-release capsules and any potential adverse effects on the breastfed infant from methylphenidate HCl extended-release capsules or from the underlying maternal condition.

Clinical Considerations
Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

8.4 Pediatric Use

The safety and effectiveness of methylphenidate HCl extended-release capsules for the treatment of ADHD have been established in pediatric patients 6 to 15 years of age. The safety and effectiveness of methylphenidate HCl extended-release capsules in pediatric patients younger than 6 years of age have not been established. Long-term efficacy of methylphenidate HCl extended-release capsules in pediatric patients have not been established.

Long-Term Suppression of Growth
Growth should be monitored during treatment with stimulants, including methylphenidate HCl extended-release capsules. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.6)].

Juvenile Animal Toxicity Data
In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the MRHD on a mg/m2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use

Methylphenidate HCl extended-release capsules have not been studied in patients over the age of 65 years.

9.1 Controlled Substance

Methylphenidate HCl extended-release capsules contain methylphenidate hydrochloride, a Schedule II controlled substance.

9.2 Abuse

CNS stimulants, including methylphenidate HCl extended-release capsules, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physicological effect. Drug addiction is a cluster of behavioral, cognitive, and psychological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking methylphenidate HCl extended-release capsules as prescribed.

Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Individual who abuser CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death [see Overdosage (10)].

To reduce the abuse of methylphenidate HCl extended-release capsules, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling (16)], monitor for signs of abuse while on therapy, and re-evaluate the need for methylphenidate HCl extended-release capsules use.

9.3 Dependence

Physical Dependence
Methylphenidate HCl extended-release capsules may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by a withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of a drug. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance
Methylphenidate HCl extended-release capsules may produce tolerance from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

12.1 Mechanism of Action

Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

12.3 Pharmacokinetics

Following one week of once-daily doses of 20 mg or 40 mg methylphenidate HCl extended-release capsules to children aged 7 to 12 years old with ADHD, Cmax and AUC of methylphenidate were approximately proportional to the administered doses.

Absorption
Following administration of methylphenidate HCl extended-release capsules in children aged 7 to 12 years old with ADHD, the plasma concentration time profile of methylphenidate showed two phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet (median Tmax1 about 1.5 hours post dose), and a second rising portion approximately three hours later (median Tmax2 about 4.5 hours post dose)*, followed by a gradual decline (Figure 1). The means for Cmax and area under the curve (AUC) following a dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at 0 and 4 hours.

*25-30% of the subjects had only one observed peak (Cmax) concentration of methylphenidate.

Figure 1: Comparison of Immediate Release (IR) and Methylphenidate HCl Extended-Release Capsules Formulations After Repeated Doses of Methylphenidate HCl in Pediatric Patients 7 to 12 Years of Age with ADHD

 Effect of Food
Ingestion of a high-fat meal with methylphenidate HCl extended-release capsules increased the mean Cmax and AUC of methylphenidate by about 30% and 17%, respectively. The presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay) [see Dosage and Administration (2.1)].

The bioavailability (Cmax and AUC) of methylphenidate was unaffected by sprinkling the methylphenidate HCl extended-release capsule contents on applesauce as compared to the intact capsule.

Effect of Alcohol
At an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths [see Drug Interactions (7)].

Distribution
Plasma protein binding is 10% to 33%. The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate.

Elimination
The mean terminal half-life (t½) of methylphenidate following administration of methylphenidate HCl extended-release capsules (t½=6.8 hours) is longer than the mean terminal t½ following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9 hours) and methylphenidate hydrochloride extended-release tablets (t½=3.4 hours) in healthy adult volunteers.

Metabolism
In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes. Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.

Excretion
After oral administration of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose.

Specific Populations
Male and Female Patients

The pharmacokinetics of methylphenidate after a single dose of methylphenidate HCl extended-release capsules were similar between adult men and women.

Racial or Ethnic Groups
The influence of race on the pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied.

Pediatric Patients
The pharmacokinetics of methylphenidate after methylphenidate HCl extended-release capsules administration has not been studied in children less than 6 years of age.

Patients with Renal Impairment
Methylphenidate HCl extended-release capsules have not been studied in patients with renal insufficiency. Since renal clearance is not an important route of methylphenidate clearance, and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate HCl extended-release capsules.

Patients with Hepatic Impairment
Methylphenidate HCl extended-release capsules have not been studied in patients with hepatic insufficiency. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.

Drug Interaction Studies
In vitro studies showed that methylphenidate did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at a daily dose of approximately 60 mg/kg per day. This dose is approximately 2 times the maximum recommended human dose (MRHD) of 60 mg/day given to children on a mg/m2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.

Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m2 basis.

In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg per day of methylphenidate.

Mutagenesis
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.

Impairment of Fertility
Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses up to 160 mg/kg per day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on a mg/m2 basis.