METADATE CD

Prior to treating patients with METADATE CD, assess:

• for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions ( 5.10)] .
• the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating METADATE CD [see Warnings and Precautions ( 5.10)] .

The recommended starting dose of METADATE CD 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.

Administer METADATE CD 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.

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

METADATE CD has a high potential for abuse and misuse. The use of METADATE CD exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. METADATE CD can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence ( 9.2)] . Misuse and abuse of CNS stimulants, including METADATE CD, can result in overdose and death [see Overdosage ( 10)] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing METADATE CD, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store METADATE CD in a safe place, preferably locked, and instruct patients to not give METADATE CD to anyone else. Throughout METADATE CD treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended dosage.

Avoid METADATE CD use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac problems.

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). Some patients may have larger increases.

Monitor all METADATE CD treated patients for hypertension and tachycardia.

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 METADATE CD 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 the recommended dosages, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo- controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNC stimulant-treated patients, compared to 0% of placebo-treated patients If such symptoms occur, consider discontinuing METADATE CD.

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation).

METADATE CD-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

CNS stimulants, including METADATE CD, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction in or discontinuation of the CNS stimulant.

Careful observation for digital changes is necessary during METADATE CD treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for METADATE CD-treated patients who develop signs of symptoms of peripheral vasculopathy.

METADATE CD is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Population ( 8.4)] .

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 pediatric patients who received methylphenidate treatment for 7 days per week throughout the year had 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 development period.

Closely monitor growth (weight and height) in METADATE CD-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, METADATE CD-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)].

Prescribe METADATE CD to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor METADATE CD-treated patients with a history of abnormally increased IOP or open angle glaucoma.

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions ( 6.2)] .

Before initiating METADATE CD, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor METADATE CD-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

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 METADATE CD included 188 pediatric patients 6 to 15 years old with ADHD exposed to METADATE CD. Patients received METADATE CD 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; METADATE CD 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 METADATE CD-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 METADATE CD in a pool of Studies 1, 2 and 3 (ages 6 to 15 years) where the incidence in patients treated with METADATE CD was at least twice the incidence in placebo-treated patients were anorexia and insomnia.

Adverse reactions that occurred in ≥5% of patients treated with METADATE CD and greater than placebo in pooled Studies, 1, 2, and 3 are presented in Table 2:

The following adverse reactions have been identified during postmarketing use of METADATE CD 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 METADATE CD

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 Disorder: 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, increased intraocular pressure, 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 Disorder: 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, motor and verbal tics

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

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including METADATE CD, 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/m 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 post-natal 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 METADATE CD, 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/m ²basis. 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/m ²basis). 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).

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 METADATE CD and any potential adverse effects on the breastfed infant from METADATE CD or from the underlying maternal condition.

Clinical Considerations

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

The safety and effectiveness of METADATE CD have not been established in pediatric patients below the age of 6 years.

In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss.

The safety and effectiveness of METADATE CD for the treatment of ADHD have been established in pediatric patients 6 to 15 years of age.

Long-Term Suppression of Growth

Growth should be monitored during treatment with stimulants, including Metadate CD. 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.

METADATE CD has not been studied in patients over the age of 65 years.

METADATE CD contains methylphenidate hydrochloride, a Schedule II controlled substance.

METADATE CD has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions ( 5.1)] . METADATE CD can be diverted for non-medical use into illicit channels or distribution.

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological 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.

Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; 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 with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including METADATE CD, can result in overdose and death [see Overdosage ( 10)] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Physical Dependence

METADATE CD may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including METADATE CD include dysphoric mood; depression; fatigue; vivid; unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

METADATE CD may produce tolerance. 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).

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

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

Following one week of once-daily doses of 20 mg or 40 mg METADATE CD to children aged 7 to12 years old with ADHD, C _maxand AUC of methylphenidate were approximately proportional to the administered doses.

Absorption

Following administration of METADATE CD 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 T _max1 about 1.5 hours post dose), and a second rising portion approximately three hours later (median T _max2 about 4.5 hours post dose)*, followed by a gradual decline (Figure 1). The means for C _maxand 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 METADATE CD 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 METADATE CD increased the mean C _maxand 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 (C _maxand AUC) of methylphenidate was unaffected by sprinkling the METADATE CD 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 (t&frac12;) of methylphenidate following administration of METADATE CD (t ^&frac12;=6.8 hours) is longer than the mean terminal t ^&frac12;following administration of methylphenidate hydrochloride immediate-release tablets (t ^&frac12;=2.9 hours) and methylphenidate hydrochloride extended-release tablets (t ^&frac12;=3.4 hours) in healthy adult volunteers.

Metabolism

 In vitrostudies 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 METADATE CD were similar between adult men and women.

Racial or Ethnic Groups

The influence of race on the pharmacokinetics of methylphenidate after METADATE CD administration has not been studied.

Pediatric Patients

The pharmacokinetics of methylphenidate after METADATE CD administration has not been studied in children less than 6 years of age.

Patients with Renal Impairment

METADATE CD has 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 METADATE CD.

Patients with Hepatic Impairment

METADATE CD has 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 vitrostudies showed that methylphenidate did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations.

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/m ²basis. 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/m ²basis.

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 vitroAmes reverse mutation assay, in the in vitromouse lymphoma cell forward mutation assay, or in the in vitrochromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitroassay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivoin 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/m ²basis.