2.1 Pretreatment Screening

Prior to treating patients with Methylphenidate HCl Extended-Release Tablets, 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 (5.2)].
• the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating Methylphenidate HCl Extended-Release Tablets [see Warnings and Precautions (5.13)].

2.2 Recommended Dosage

Methylphenidate HCl Extended-Release Tablets should be administered orally once daily in the morning with or without food.

Methylphenidate HCl Extended-Release Tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed [see Patient Counseling Information (17)].

2.3 Patients New to Methylphenidate

The recommended starting dose of Methylphenidate HCl Extended-Release Tablets for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (see Table 1).

Table 1. Methylphenidate HCl Extended-Release Tablets Recommended Starting Doses and Dose Ranges

2.4 Patients Currently Using Methylphenidate

The recommended dose of Methylphenidate HCl Extended-Release Tablets for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 to 60 mg/day is provided in Table 2.  Dosing recommendations are based on current dose regimen and clinical judgment. Conversion dosage should not exceed 72 mg daily.  

Table 2. Recommended Dose Conversion from Methylphenidate Regimens to Methylphenidate HCl Extended-Release Tablets

Other methylphenidate regimens: Clinical judgment should be used when selecting the starting dose.

2.5 Dose Titration

Doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved an optimal response at a lower dose.  Daily dosages above 54 mg in children and 72 mg in adolescents have not been studied and are not recommended. Daily dosages above 72 mg in adults are not recommended.

A 27 mg dosage strength is available for physicians who wish to prescribe between the 18 mg and 36 mg dosages.

2.6 Dosage Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage or, if necessary, discontinue Methylphenidate HCl Extended-Release Tablets.

If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue Methylphenidate HCl Extended-Release Tablets.

4.1 Hypersensitivity to Methylphenidate

Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with Methylphenidate HCl Extended-Release Tablets. Therefore, Methylphenidate HCl Extended-Release Tablets are contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product [see Adverse Reactions (6.5)].

4.2 Monoamine Oxidase Inhibitors

Methylphenidate HCl Extended-Release Tablets are contraindicated during treatment with monoamine oxidase (MAO) inhibitors, and also within a minimum of 14 days following discontinuation of a MAO inhibitor (hypertensive crises may result) [see Drug Interactions (7.1)].

5.1 Abuse, Misuse, and Addiction

Methylphenidate HCl Extended-Release Tablets have a high potential for abuse and misuse. The use of Methylphenidate HCl Extended-Release Tablets expose individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate HCl Extended-Release Tablets 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 Methylphenidate HCl Extended-Release Tablets, 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 Methylphenidate HCl Extended-Release Tablets, 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 Methylphenidate HCl Extended-Release Tablets in a safe place, preferably locked, and instruct patients to not give Methylphenidate HCl Extended-Release Tablets to anyone else. Throughout Methylphenidate HCl Extended-Release Tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.2 Risks to Patients with Serious Cardiac Disease

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 ADHD dosage.

Avoid Methylphenidate HCl Extended-Release Tablets use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

5.3 Increased Blood Pressure and Heart Rate

CNS stimulants may 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 Methylphenidate HCl Extended-Release Tablets-treated 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 Methylphenidate HCl Extended-Release Tablets 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 dosage, 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 CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing Methylphenidate HCl Extended-Release Tablets.

5.5 Seizures

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.

5.6 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients [see Adverse Reactions (6.5)]. 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).

Methylphenidate HCl Extended-Release Tablets-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.7 Peripheral Vasculopathy, including Raynaud’s Phenomenon

CNS stimulants, including Methylphenidate HCl Extended-Release Tablets, 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 or discontinuation of the CNS stimulant.

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

5.8 Long-Term Suppression of Growth in Pediatric Patients

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 nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated children over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate 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 Methylphenidate HCl Extended-Release Tablets-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.9 Potential for Gastrointestinal Obstruction

Because the Methylphenidate HCl Extended-Release Tablet is nondeformable and does not appreciably change in shape in the GI tract, Methylphenidate HCl Extended-Release Tablets should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel’s diverticulum).  There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations.  Due to the controlled-release design of the tablet, Methylphenidate HCl Extended-Release Tablets should only be used in patients who are able to swallow the tablet whole [see Patient Counseling Information (17)].

5.10 Hematologic Monitoring

Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

5.11 Acute Angle Closure Glaucoma

There have been rare reports of angle closure glaucoma associated with methylphenidate treatment.

Although the mechanism is not clear, Methylphenidate HCl Extended-Release Tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

5.12 Increased Intraocular Pressure and Glaucoma

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.5)].

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

5.13 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics [see Adverse Reactions (6.2, 6.5)]. Worsening of Tourette’s syndrome has also been reported.

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

6.1 Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials

Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.

6.2 Other Adverse Reactions Observed in Methylphenidate HCl Extended-Release Tablets Clinical Trials

This section includes adverse reactions reported by Methylphenidate HCl Extended-Release Tablets-treated subjects in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by Methylphenidate HCl Extended-Release Tablets -treated subjects who participated in open-label and postmarketing clinical trials.

Blood and Lymphatic System Disorders: Leukopenia

Eye Disorders: Accommodation disorder, Dry eye

Vascular Disorders: Hot flush

Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea

General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst

Infections and Infestations: Sinusitis

Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased

Musculoskeletal and Connective Tissue Disorders: Muscle spasms

Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence

Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic

Reproductive System and Breast Disorders: Erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

Skin and Subcutaneous Tissue Disorders: Rash, Rash macular

Vascular Disorders: Hypertension

6.3 Discontinuation Due to Adverse Reactions

Adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to discontinuation occurred in 2 Methylphenidate HCl Extended-Release Tablets patients (0.6%) including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%).

In the 2 placebo-controlled studies of adults, 25 Methylphenidate HCl Extended-Release Tablets patients (6.0%) and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% in the Methylphenidate HCl Extended-Release Tablets patients included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%).

In the 11 open-label studies of children, adolescents, and adults, 266 Methylphenidate HCl Extended-Release Tablets patients (7.0%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).

6.4 Blood Pressure and Heart Rate Increases

In the laboratory classroom clinical trials in children (Studies 1 and 2), both Methylphenidate HCl Extended-Release Tablets once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled adolescent trial (Study 4), mean increases from baseline in resting pulse rate were observed with Methylphenidate HCl Extended-Release Tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively).  Mean increases from baseline in blood pressure at the end of the double-blind phase for Methylphenidate HCl Extended-Release Tablets and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively.  In one placebo-controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with Methylphenidate HCl Extended-Release Tablets at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for Methylphenidate HCl Extended-Release Tablets and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for Methylphenidate HCl Extended-Release Tablets and placebo at the end of the double-blind treatment (3.6 and –1.6 beats/minute, respectively).  Mean changes from baseline in blood pressure at the end of the double–blind treatment for Methylphenidate HCl Extended-Release Tablets and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.3)]. 

6.5 Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of Methylphenidate HCl Extended-Release Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles

Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment

General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased

Hepatobiliary disorders: Hepatocellular injury, Acute hepatic failure

Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC

Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System Disorders:  Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics

Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changes

Reproductive System and Breast Disorders: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

Vascular Disorders: Raynaud's phenomenon

7.1 MAO Inhibitors

Methylphenidate HCl Extended-Release Tablets should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO inhibitors [see Contraindications (4.2)].

7.2 Vasopressor Agents

Because of possible increases in blood pressure, Methylphenidate HCl Extended-Release Tablets should be used cautiously with vasopressor agents [see Warnings and Precautions (5.3)].

7.3 Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors

Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate.

7.4 Halogenated Anesthetics

Concomitant use of halogenated anesthetics and Methylphenidate HCl Extended-Release Tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. Monitor blood pressure and avoid use of Methylphenidate HCl Extended-Release Tablets in patients being treated with anesthetics on the day of surgery.

7.5 Risperidone

Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Monitor for signs of EPS.

8.1 Pregnancy

8.2 Labor and Delivery

The effect of Methylphenidate HCl Extended-Release Tablets on labor and delivery in humans is unknown.

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 HCl Extended-Release Tablets are administered to a nursing woman.

In lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma.

8.4 Pediatric Use

Methylphenidate HCl Extended-Release Tablets should not be used in children under six years, since safety and efficacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established.

8.5 Geriatric Use

Methylphenidate HCl Extended-Release Tablets have not been studied in patients greater than 65 years of age.

9.1 Controlled Substance

Methylphenidate HCl Extended-Release Tablets contains methylphenidate, a Schedule II controlled substance.

9.2 Abuse

Methylphenidate HCl Extended-Release Tablets have 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)]. Methylphenidate HCl Extended-Release Tablets 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 Methylphenidate HCl Extended-Release Tablets, 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.

In two placebo-controlled human abuse potential studies, single oral doses of Methylphenidate HCl Extended-Release Tablets were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational stimulant use to assess relative abuse potential. For the purpose of this assessment, the response for each of the subjective measures was defined as the maximum effect within the first 8 hours after dose administration.

In one study (n=40), both Methylphenidate HCl Extended-Release Tablets (108 mg) and 60 mg IR MPH compared to placebo produced statistically significantly greater responses on the five subjective measures suggestive of abuse potential. In comparisons between the two active treatments, however, Methylphenidate HCl Extended-Release Tablets (108 mg) produced variable responses on positive subjective measures that were either statistically indistinguishable from (Abuse Potential, Drug Liking, Amphetamine, and Morphine Benzedrine Group [Euphoria]) or statistically less than (Stimulation-Euphoria) responses produced by 60 mg IR MPH.

In another study (n=49), both doses of Methylphenidate HCl Extended-Release Tablets (54 mg and 108 mg) and both doses of IR MPH (50 mg and 90 mg) produced statistically significantly greater responses compared to placebo on the two primary scales used in the study (Drug Liking, Euphoria). When doses of Methylphenidate HCl Extended-Release Tablets (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg), respectively, Methylphenidate HCl Extended-Release Tablets produced statistically significantly lower subjective responses on these two scales than IR MPH. Methylphenidate HCl Extended-Release Tablets (108 mg) produced responses that were statistically indistinguishable from the responses on these two scales produced by IR MPH (50 mg). Differences in subjective responses to the respective doses should be considered in the context that only 22% of the total amount of methylphenidate in Methylphenidate HCl Extended-Release Tablets is available for immediate release from the drug overcoat [see System Components and Performance (11.1)].

Although these findings reveal a relatively lower response to Methylphenidate HCl Extended-Release Tablets on subjective measures suggestive of abuse potential compared to IR MPH at roughly equivalent total MPH doses, the relevance of these findings to the abuse potential of Methylphenidate HCl Extended-Release Tablets in the community is unknown.

9.3 Dependence

Physical Dependence

Methylphenidate HCl Extended-Release Tablets 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 Methylphenidate HCl Extended-Release Tablets include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

Methylphenidate HCl Extended-Release Tablets 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).

10.1 Clinical Effects of Overdose

Overdose of CNS stimulants is characterized by the following sympathomimetic effects:

• Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.
• CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur.
• Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.

10.2 Overdose Management

Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of Methylphenidate HCl Extended-Release Tablets should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

11.1 System Components and Performance

Methylphenidate HCl Extended-Release Tablets uses extended-release bead technology to deliver methylphenidate HCl at a controlled rate. The system, which resembles a conventional tablet in appearance, is comprised of a tablet core containing the extended-release beads and the core is covered with an immediate-release drug overcoat. In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate. The tablet disintegrates and then polymer coatings on the beads control the release of methylphenidate HCl over the 12 hour dosing period.

12.1 Mechanism of Action

Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

12.2 Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.

12.3 Pharmacokinetics

Absorption

Methylphenidate is readily absorbed. Following oral administration of Methylphenidate HCl Extended-Release Tablets, plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 1 hour, followed by gradual ascending concentrations over the next 5 to 9 hours, after which a gradual decrease begins. Mean times to reach peak plasma concentrations across all doses of Methylphenidate HCl Extended-Release Tablets occurred between 6 and 10 hours.

Methylphenidate HCl Extended-Release Tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily (see Figure 1). The relative bioavailability of Methylphenidate HCl Extended-Release Tablets once daily and methylphenidate three times daily in adults is comparable.

Figure 1. Mean methylphenidate plasma concentrations in 36 adults, following a single dose of Methylphenidate HCl Extended-Release Tablets 18 mg once daily and immediate-release methylphenidate 5 mg three times daily administered every 4 hours.

The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of Methylphenidate HCl Extended-Release Tablets 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 6.

Table 6. Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults

Parameters	Methylphenidate HCl Extended-Release Tablets      (18 mg once daily) (n=36)	Methylphenidate (5 mg three times daily) (n=35)
Cmax (ng/mL)	3.7 ± 1.0	4.2 ± 1.0
Tmax (h)	6.8 ± 1.8	6.5 ± 1.8
AUCinf (ng∙h/mL)	41.8 ± 13.9	38.0 ± 11.0
t1/2 (h)	3.5 ± 0.4	3.0 ± 0.5

The pharmacokinetics of Methylphenidate HCl Extended-Release Tablets were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg/day. The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of Methylphenidate HCl Extended-Release Tablets were noted following single and repeated once-daily dosing, indicating no significant drug accumulation. The AUC and t1/2 following repeated once-daily dosing are similar to those following the first dose of Methylphenidate HCl Extended-Release Tablets in a dose range of 18 to 144 mg.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

14.1 Children

Three double-blind, active- and placebo-controlled studies were conducted in 416 children aged 6 to 12 years. The controlled studies compared Methylphenidate HCl Extended-Release Tablets given once daily (18, 36, or 54 mg), methylphenidate given three times daily over 12 hours (15, 30, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was Methylphenidate HCl Extended-Release Tablets versus placebo.

Symptoms of ADHD were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for Methylphenidate HCl Extended-Release Tablets. The scores for Methylphenidate HCl Extended-Release Tablets and placebo for the three studies are presented in Figure 2.

Figure 2. Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with Methylphenidate HCl Extended-Release Tablets once daily (18, 36, or 54 mg) and placebo. Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at week 4. Error bars represent the mean plus standard error of the mean.

In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMP1   laboratory school rating scale. The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with Methylphenidate HCl Extended-Release Tablets versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory schoolteacher SKAMP ratings for Methylphenidate HCl Extended-Release Tablets and placebo.

1Swanson, Kotkin, Agler, M-Fynn, and Pelham

Figure 3. Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2)

14.2 Adolescents

In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving 177 patients, Methylphenidate HCl Extended-Release Tablets was demonstrated to be effective in the treatment of ADHD in adolescents aged 13 to 18 years at doses up to 72 mg/day (1.4 mg/kg/day). Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dose of Methylphenidate HCl Extended-Release Tablets (18 – 72 mg/day, n=87) or placebo (n=90) during a two-week double-blind phase. At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that Methylphenidate HCl Extended-Release Tablets was statistically significantly superior to placebo.

14.3 Adults

Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared Methylphenidate HCl Extended-Release Tablets administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 to 108 mg/day) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18, 36, and 72 mg/day).

Study 5 demonstrated the effectiveness of Methylphenidate HCl Extended-Release Tablets in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7-week trial, 110 were randomized to Methylphenidate HCl Extended-Release Tablets and 116 were randomized to placebo. Treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that Methylphenidate HCl Extended-Release Tablets was statistically significantly superior to placebo.

Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed-dose groups (18, 36, and 72 mg). Patients were randomized to receive Methylphenidate HCl Extended-Release Tablets administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96). All three doses of Methylphenidate HCl Extended-Release Tablets were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.