2.1 Pretreatment Screening

Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including methylphenidate hydrochloride or methylphenidate hydrochloride sustained-release, 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 reevaluate the need for methylphenidate hydrochloride or methylphenidate hydrochloride sustained-release use [see Boxed Warning, Warnings and Precautions(5.1), DrugAbuse andDependence (9)].

2.2 General Dosing Information

Methylphenidate Hydrochloride Tablets

Pediatric Patients 6 years and Older: Start with 5 mg orally twice daily (before breakfast and lunch). Increase dosage gradually, in increments of 5 to 10 mg weekly. Daily dosage above 60 mg is not recommended.

Adults: Average dosage is 20 to 30 mg daily. Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m.

Methylphenidate Hydrochloride Sustained-Release Tablets

Methylphenidate hydrochloride sustained-release tablets have a duration of action of approximately 8 hours. Therefore, methylphenidate hydrochloride sustained-release tablets may be used in place of methylphenidate hydrochloride tablets when the 8-hour dosage of methylphenidate hydrochloride sustained-release corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride.

Methylphenidate hydrochloride sustained-release tablets must be swallowed whole and never crushed or chewed.

Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release, and adjust dosage as needed.

2.3 Dose Reduction and Discontinuation

If paradoxical worsening of symptoms or other adverse reactions occur, reduce the dosage, or, if necessary, discontinue methylphenidate hydrochloride or methylphenidate hydrochloride sustained-release. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

5.1 Potential for Abuse and Dependence

CNS stimulants, including methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release, 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 Boxed Warning, 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 serious 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 hydrochloride and methylphenidate hydrochloride sustained-release 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 Preexisting Psychosis

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder

CNS stimulants may induce a manic or mixed mood 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 hydrochloride and methylphenidate hydrochloride sustained-release. 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 hydrochloride and methylphenidate hydrochloride sustained-release, 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 pediatric patients 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 patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (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 hydrochloride and methylphenidate hydrochloride sustained-release. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

7.1 Clinically Important Interactions with Methylphenidate Hydrochloride and Methylphenidate Hydrochloride Sustained-Release

Table 1 presents clinically important drug interactions with methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release.

8.1 Pregnancy

Pregnancy Category C

In 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. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD 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 (2 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 (4 times the MRHD 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 (equal to the MRHD on a mg/m2 basis).

Adequate and well-controlled studies in pregnant women have not been conducted. Methylphenidate hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if methylphenidate hydrochloride is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release for the treatment of ADHD have been established in pediatric patients 6 to 17 years.

The safety and effectiveness of methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release in pediatric patients less than 6 years have not been established.

The long-term efficacy of methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release in pediatric patients has not been established.

Long-Term Suppression of Growth

Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)].

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 hydrochloride has not been studied in the geriatric population.

9.1 Controlled Substance

Methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release are Schedule II controlled substance.

9.2 Abuse

CNS stimulants, including methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release, have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving.

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. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage (10)].

To reduce the abuse of CNS stimulants including methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release, 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 reevaluate the need for methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release use.

9.3 Dependence

Tolerance

Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release.

Dependence

Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release. 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.

12.1 Mechanism of Action

Methylphenidate hydrochloride is a CNS stimulant. The mode of therapeutic action in ADHD and narcolepsy 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 is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the releaseof these monoamines into the extraneuronal space.

Cardiac Electrophysiology

A formal QT study has not been conducted in patients taking methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release.

The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethlyphenidate XR 40 mg (maximum recommended adult total daily dosage) in 75 healthy volunteers.

Electrocardiograms (ECGs) were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTCF).

The maximum mean prolongation of QTCF intervals was less than 5 ms, and the upper limit of the 90% confidence interval (CI) was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship.

12.3 Pharmacokinetics

Absorption

Methylphenidate hydrochloride in the SR tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the SR tablet compared to the methylphenidate hydrochloride tablet, measured by the urinary excretion of methylphenidate hydrochloride major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride tablets and 4.7 hours (1.3 to 8.2 hours) for the methylphenidate hydrochloride sustained-release tablets. An average of 67% of SR tablet dose was excreted in children as compared to 86% in adults.

Effect of Food

After a high-fat meal, both area under the curve (AUC) (by 25 %) and Cmax (by 27 %) are higher. Time to Cmax (Tmax) is faster after a high-fat meal (median Tmax: 2.5 hours) as compared to without food (median Tmax: 3 hours).

Distribution

Binding to plasma proteins is low (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 systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate.

Metabolism

Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.

Excretion

After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for methylphenidate hydrochloride sustained-release tablets.

Studies in Specific Populations

Male and Female Patients

In a clinical study involving adult subjects who received methylphenidate hydrochloride sustained-release, plasma concentrations of methylphenidate hydrochloride’s major metabolite appeared to be greater in females than in males. No gender differences were observed for methylphenidate hydrochloride plasma concentration in the same subjects.

Racial or Ethnic Groups

There is insufficient experience with the use of methylphenidate hydrochloride and methylphenidate hydrochloride sustained-release to detect ethnic variations in pharmacokinetics.

Patients with Renal Impairment

Methylphenidate hydrochloride has not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity.

Patients with Hepatic Impairment

Methylphenidate hydrochloride has not been studied in patients with hepatic impairment. 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.

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/day. This dose is approximately 2 times the maximum recommended human dose (MRHD) in children on 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 increase 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 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/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 (CHO) cells.

Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.

Impairment of Fertility

No human data on the effect of methylphenidate on fertility are available. 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/day, approximately 10-fold the maximum recommended dose in adolescents on a mg/m2 basis.