Methylphenidate Extended-release Tablet, Orally Disintegrating
FDA Label NDC 62542-100

Methylphenidate extended-release orally disintegrating tablets has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including methylphenidate extended-release orally disintegrating 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 extended-release orally disintegrating tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout methylphenidate extended-release orally disintegrating tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [ see Warnings and Precautions (5.1)and Drug Abuse and Dependence(9.2)].

Methylphenidate extended-release orally disintegrating tablets is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age [see ClinicalStudies (14)] .

Limitations of Use

The use of methylphenidate extended-release orally disintegrating tablets is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.5). Use in Specific Populations (8.4)].

Prior to treating patients with methylphenidate extended-release orally disintegrating 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 extended-release orally disintegrating tablets [see Warningsand Precautions (5.9)].

Methylphenidate extended-release orally disintegrating tablets is given orally once daily in the morning. Advise patients to take methylphenidate extended-release orally disintegrating tablets consistently either with food or without food [see Clinical Pharmacology (12.3)].

The recommended starting dose of methylphenidate extended-release orally disintegrating tablets for patients 6 to 17 years of age is 17.3 mg once daily in the morning. The dose may be titrated weekly in increments of 8.6 mg to 17.3 mg. Daily doses above 51.8 mg have not been studied and are not recommended.

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

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

Instruct the patient or caregiver on the following administration instructions:

• Do not remove the tablet from the bottle until just prior to dosing. Take the tablet immediately after opening the bottle. Do not store the tablet for future use.
• Use dry hands when removing the tablet from bottle.
• As soon as the bottle is opened, remove the tablet and place on the patient’s tongue.
• Place the whole tablet on the tongue and allow it to disintegrate without chewing or crushing.
• The tablet will disintegrate in saliva so that it can be swallowed. No liquid is needed to take the tablet.

• 8.6 mg Extended-Release Orally Disintegrating Tablet: round, purple to light purple mottled (debossed “T1” on one side and plain on the other)
• 17.3 mg Extended-Release Orally Disintegrating Tablet: round, purple to light purple mottled (debossed “T2” on one side and plain on the other)
• 25.9 mg Extended-Release Orally Disintegrating Tablet: round, purple to light purple mottled (debossed “T3” on one side and plain on the other)

Methylphenidate extended-release orally disintegrating tablets is contraindicated in patients with:

• Known hypersensitivity to methylphenidate or other components of methylphenidate extended-release orally disintegrating tablets. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate products [see Adverse Reactions (6.2)].
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor because of the risk of hypertensive crisis [see Drug Interactions (7.1)].

Methylphenidate extended-release orally disintegrating tablets has a high potential for abuse and misuse. The use of methylphenidate extended-release orally disintegrating tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Methylphenidate extended-release orally disintegrating 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 extended-release orally disintegrating 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 extended-release orally disintegrating 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 extended-release orally disintegrating tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate extended-release orally disintegrating tablets to anyone else. Throughout methylphenidate extended-release orally disintegrating tablets 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 occurred in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosages.

Avoid methylphenidate extended-release orally disintegrating tablets use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mm Hg) and heart rate (mean increase approximately 3 to 6 bpm). Some patients may have larger increases.

Monitor all methylphenidate extended-release orally disintegrating tablets 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 methylphenidate extended-release orally disintegrating 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 to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate extended-release orally disintegrating tablets.

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).

Methylphenidate extended-release orally disintegrating tablets treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

CNS stimulants, including methylphenidate extended-release orally disintegrating 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 extended-release orally disintegrating tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate extended-release orally disintegrating tablets treated patients who develop signs or symptoms of peripheral vasculopathy.

Methylphenidate extended-release orally disintegrating tablets is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (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 pediatric patients 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 pediatric patients 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 extended-release orally disintegrating tablets 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, methylphenidate extended-release orally disintegrating tablets 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 methylphenidate extended-release orally disintegrating 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 extended-release orally disintegrating tablets 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 methylphenidate extended-release orally disintegrating tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate extended-release orally disintegrating tablets treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

The following are discussed in more detail in other sections of the labeling:

• Known hypersensitivity to methylphenidate or other ingredients of methylphenidate extended-release orally disintegrating tablets [see Contraindications (4)]
• Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications (4) and Drug Interactions (7.1)]
• Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence ( 9.2, 9.3)]
• Risks to patients with serious cardiac disease [see Warnings and Precautions (5.2)]
• Increased blood pressure and heart rate [see Warnings and Precautions (5.3)]
• Psychiatric adverse reactions [see Warnings and Precautions (5.4)]
• Priapism [see Warnings and Precautions (5.5)]
• Peripheral vasculopathy, including Raynaud’s phenomenon [see Warnings and Precautions (5.6)]
• Long-term suppression of growth in pediatric patients [see Warnings and Precautions (5.7)]
• Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8)]
• Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.9)]
• Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.10)]

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 clinical practice.

Adverse Reactions in Studies with Other Methylphenidate Products in Children, Adolescents, and Adults with ADHD

Commonly reported (≥2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: appetite decreased, weight decreased, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, blood pressure increased, heart rate increased, tachycardia, palpitations, hyperhidrosis, and pyrexia.

Adverse Reactions in Studies with methylphenidate extended-release orally disintegrating tablets in Children with ADHD

There is limited experience with methylphenidate extended-release orally disintegrating tablets in controlled trials. Based on this limited experience, the adverse reaction profile of methylphenidate extended-release orally disintegrating tablets appears similar to other methylphenidate extended release-products.

The following adverse reactions have been identified during post approval use of methylphenidate 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. These adverse reactions are as follows:

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

Cardiac Disorders:Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole

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

General Disorders: Chest pain, Chest discomfort, Hyperpyrexia

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

Investigations:Alkaline phosphatase increased, 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, Libido changes, Mania

Urogenital System: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema

Vascular Disorders:Raynaud’s phenomenon

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to methylphenidate extended-release orally disintegrating tablets 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 are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes [see Data]. There are risks to the fetus associated with the use of central nervous system (CNS) stimulants during pregnancy [seeClinical Considerations]. No teratogenic effects were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses 4 and 18 times, respectively, the maximum recommended human dose (MRHD) of 51.8 mg (as base). However, spina bifida was observed in rabbits at a dose 60 times the MRHD [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 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions
CNS stimulants, such as methylphenidate extended-release orally disintegrating tablets, 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.

Data

HumanData

A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing methylphenidate use during pregnancy. Due to the small number of methylphenidate-exposed pregnancies with known outcomes, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size, concomitant use of other medications, lack of detail regarding dose and duration of exposure to methylphenidate and non-generalizability of the enrolled populations.

Animal Data

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 60 times the maximum recommended human dose (MRHD) of 51.8 mg (as base) for adolescents on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (18 times the MRHD for adolescent 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 (11 times the MRHD on a mg/m2 basis for adolescent), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the MRHD on a mg/m2 basis for adolescent).

Risk Summary

Limited published literature, based on breast milk sampling from five 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 extended-release orally disintegrating tablets and any potential adverse effects on the breastfed child from methylphenidate extended-release orally disintegrating tablets 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 methylphenidate extended-release orally disintegrating tablets 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 methylphenidate extended-release orally disintegrating tablets have been established in pediatric patients 6 to 17 years of age in one adequate and well-controlled study in pediatric patients 6 to 12 years, pharmacokinetic data in adolescents, and safety information from other methylphenidate-containing products [see Clinical Pharmacology (12) and Clinical Studies (14)].

Long Term Suppression Growth

Growth should be monitored during treatment with stimulants, including methylphenidate extended-release orally disintegrating tablets. Children who are not growing or gaining weight as expected may need to have their treatment interrupted [seeWarnings and Precautions (5.7)].

Juvenile Animal Toxicity Data

Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 6 times the maximum recommended human dose (MRHD) of 51.8 mg (as base) for pediatric patients on a mg/m2 basis.

In the 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 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day [approximately 6 times the MRHD of 51.8 mg (as base) on a mg/m2 basis] or greater, and a deficit in the acquisition of a specific learning task was observed 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.

Methylphenidate extended-release orally disintegrating tablets has not been studied in patients over the age of 65 years.

Methylphenidate extended-release orally disintegrating tablets contains methylphenidate, a Schedule II controlled substance.

Methylphenidate extended-release orally disintegrating tablets has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [seeWarnings and Precautions (5.1)]. Methylphenidate extended-release orally disintegrating 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 extended-release orally disintegrating 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.

Physical Dependence

Methylphenidate extended-release orally disintegrating 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 extended-release orally disintegrating tablets include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

Methylphenidate extended-release orally disintegrating 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).

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.

Overdose Management

Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of methylphenidate extended-release orally disintegrating 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.

Methylphenidate extended-release orally disintegrating tablets contains methylphenidate, a central nervous system (CNS) stimulant. Methylphenidate extended-release orally disintegrating tablets is an extended-release orally disintegrating tablet intended for once daily administration. Methylphenidate extended-release orally disintegrating tablets contains approximately 25% immediate-release and 75% extended-release methylphenidate. Methylphenidate is ionically-bound to the sulfonate of polystyrene sulfonate particles.

Methylphenidate extended-release orally disintegrating tablets contains 8.6 mg, 17.3 mg or 25.9 mg of methylphenidate which is the same as the amount of methylphenidate (base equivalent) found, respectively, in 10 mg, 20 mg and 30 mg strength methylphenidate hydrochloride products.

The chemical name of methylphenidate is methyl α-phenyl-2-piperidineacetate, and its structural formula is shown in Figure 1.

Figure 1: Methylphenidate Structure

Figure 1 (Methylphenidate Extended Release Tablets 1)

Methylphenidate extended-release orally disintegrating tablets also contains the following inactive ingredients: Mannitol, Fructose, Microcrystalline Cellulose, Crospovidone, Methacrylic Acid, Polystyrene Sulfonate, Citric Acid, Colloidal Silicon Dioxide, Grape Flavor, Natural Masking Type Powder, Triethyl Citrate, Magnesium Stearate, Ethylcellulose, Sucralose, Lake Blend Purple, and Polyethylene Glycol 3350.

Methylphenidate 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-isomers. The d-isomer is more pharmacologically active than the l-isomer. 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.

After oral administration of methylphenidate extended-release orally disintegrating tablets circulation levels of l- methylphenidate (MPH) were about 2% of total MPH.

Absorption

Following a single dose of 51.8 mg (2x25.9 mg daily) methylphenidate extended-release orally disintegrating tablets in healthy adult subjects under fasted conditions, plasma methylphenidate (MPH) reached maximal concentration (Cmax) at a median time of 5 hours after dosing. Compared to an extended release capsule formulation of methylphenidate, methylphenidate mean Cmax and exposure (AUCinf) was about 26% and 6% higher, respectively, after methylphenidate extended-release orally disintegrating tablets administration (Figure 2).

Figure 2: Mean d-Methylphenidate Plasma Concentration-Time Profiles After Administration of Methylphenidate Extended-Release Orally Disintegrating Tablets or Methylphenidate Hydrochloride Extended-Release Capsule in Healthy Volunteers Under Fasted Conditions

Figure 2 (Methylphenidate Extended Release Tablets 2)

Effect of Food

Administration of 51.8 mg methylphenidate extended-release orally disintegrating tablets with food (a high fat meal) decreased the Cmax and increased AUCinf of total MPH by approximately 24% and 16%, respectively. Food shortened the median time to peak concentration (Tmax) by 0.5 hour (fed: 4.5 hours vs. fasted: 5.0 hours).

Effect of Alcohol

There is no in vivostudy conducted for the effect of alcohol on drug exposure. An in vitrodissolution study showed alcohol-induced dose dumping potential in the presence of 40% alcohol. Dose dumping was not observed in the presence of lower alcohol concentrations.

Elimination

Plasma methylphenidate concentrations decline monophasically following oral administration of methylphenidate extended-release orally disintegrating tablets. The mean plasma terminal elimination half-life of methylphenidate was about 4 hours in healthy volunteers following a single 51.8 mg dose administration.

Metabolism

In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid). The metabolite has little or no pharmacological activity.

Excretion

After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main primary metabolite was PPAA, accounting for approximately 80% of the dose.

Specific Populations

MaleandFemale Patients and Ethnic Groups

There is insufficient experience with the use of methylphenidate extended-release orally disintegrating tablets to detect gender or ethnic variations in pharmacokinetics.

Pediatric Patients

The pharmacokinetics of methylphenidate after methylphenidate extended-release orally disintegrating tablets administration were studied in pediatric patients (6-17 years of age) with ADHD under fasted conditions. After a single oral dose of 51.8 mg methylphenidate extended-release orally disintegrating tablets, plasma concentrations of methylphenidate in children (6-12 years of age) were approximately twice the concentrations observed in adults. Exposure levels in adolescent patients (13 -17 years of age) were similar to those in adults. Body weight normalized clearance values were similar across the age groups (Table 2).

Patients with Renal Impairment

There is no experience with the use of methylphenidate extended-release orally disintegrating tablets in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of methylphenidate extended-release orally disintegrating tablets.

Patients with Hepatic Impairment

There is no experience with the use of methylphenidate extended-release orally disintegrating tablets in patients with hepatic insufficiency.

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. For pediatric patients, this dose is approximately 4 times the maximum recommended human dose of 51.8 (as base) 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 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 5 times the maximum recommended dose of 51.8 mg (as base) for pediatric patients on a mg/m2 basis.

Mutagenesis

Methylphenidate was not mutagenic in the in vitroAmes reverse mutation assay or the in vitromouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitroassay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in an in vivomouse 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/day, approximately 12-fold the maximum recommended human dose of 51.8 (as base) for adolescents on a mg/m2 basis.

The efficacy of methylphenidate extended-release orally disintegrating tablets was evaluated in a laboratory classroom study conducted in 87 pediatric patients (Aged 6 to 12 years) with ADHD. Following washout of previous methylphenidate medication, there was an open-label dose-optimization period (4 weeks) with an initial dose of 17.3 mg of methylphenidate extended-release orally disintegrating tablets once daily in the morning. The dose could be titrated on a weekly basis from 17.3 mg, to 25.9 mg, to 34.6 mg, and up to 51.8 mg until an optimal dose or the maximum dose of 51.8 mg/day was reached. At the end of this period, subjects remained on their optimized dose for an additional week.

Subjects then entered a 1-week randomized, double-blind, parallel group treatment period with the individually optimized dose of methylphenidate extended-release orally disintegrating tablets or placebo. At the end of this week, raters evaluated the attention and behavior of the subjects in a laboratory classroom setting, using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale. SKAMP is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting.

The primary efficacy endpoint was the average of the SKAMP-Combined (Attention and Deportment) scores over the test day (not including the baseline score), with assessments conducted at baseline, and 1, 3, 5, 7, 10, 12, and 13 hours post-dosing. The key secondary efficacy endpoints were onset and duration of effect, defined as the first point at which active drug separated from placebo on SKAMP-Combined scores and the last time point at which active drug separated from placebo on SKAMP-Combined scores, respectively.

The SKAMP-Combined scores test day average was statistically significantly lower (improved) with methylphenidate extended-release orally disintegrating tablets compared to placebo (difference of -11 (95% CI: -13.9, -8.2)) (Table 3).

The SKAMP-Combined scores were also statistically significantly lower (improved) at time points (1, 3, 5, 7, 10, 12 hours) post-dosing with methylphenidate extended-release orally disintegrating tablets compared to placebo (Figure 3).

Figure 3: LS Mean SKAMP Combined Score After Treatment with Methylphenidate Extended-Release Orally Disintegrating Tablets or Placebo During Classroom Day in Patients with ADHD

Figure 3 (Methylphenidate Extended Release Tablets 3)

*SE = Standard Error

The database was not large enough to assess whether there were differences in effects in age, gender, or race subgroups.

Methylphenidate extended-release orally disintegrating tablets are available in three strengths:

• 8.6 mg tablets, round, purple to light purple, mottled, and debossed “T1” on one side of the tablet;
• 17.3 mg tablets, round, purple to light purple, mottled, and debossed “T2” on one side of the tablet;
• 25.9 mg tablets, round, purple to light purple, mottled, and debossed “T3” on one side of the tablet.

They are available as follows:

NDC 62542-100-31 8.6 mg tablets: bottle containing 30 tablets each.

NDC 62542-250-31 17.3 mg tablets: bottle containing 30 tablets each.

NDC 62542-350-31 25.9 mg tablets: bottle containing 30 tablets each.

Store methylphenidate extended-release orally disintegrating tablet bottles in a cool, dry place at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Abuse, Misuse, and Addiction

Educate patients and their families about the risks of abuse, misuse, and addiction of methylphenidate extended-release orally disintegrating tablets, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2), Overdosage (10)] . Advise patients to store methylphenidate extended-release orally disintegrating tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate extended-release orally disintegrating tablets to anyone else.

Instructions for Taking methylphenidate extended-release orally disintegrating tablets

Instruct patients and their caregivers on the following:

• The tablet should remain in the bottle until the patient is ready to take it.
• The tablet should be taken immediately after removing it from bottle. It should not be stored for future use.
• The patient or caregiver should use dry hands when removing from bottle.
• As soon as the tablet is removed from the bottle, the tablet should be placed on the patient’s tongue.
• The whole tablet should be placed on the tongue and allowed to disintegrate without chewing or crushing.
• The tablet will disintegrate in saliva and can be swallowed. No liquid is needed to take the tablet.

Risks to Patients with Serious Cardiac Disease

Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with methylphenidate extended-release orally disintegrating tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [seeWarnings and Precautions (5.2)].

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 06/2026

NDC 62542-100-31

30 Tablets

Rx Only

  METHYLPHENIDATEEXTENDED-RELEASE Orally Disintegrating Tablets, CII

Do not crush or chew tablets

Each tablet contains 8.6 mg of methylphenidate

(equivalent to that in a 10 mg strength methylphenidate hydrochloride product)

8.6 mg Tablet (Methylphenidate Extended Release Tablets 4)

NDC 62542-250-31

30 Tablets

Rx Only

METHYLPHENIDATEEXTENDED-RELEASEOrally Disintegrating Tablets, CII

Do not crush or chew tablets

Each tablet contains 17.3 mg of methylphenidate

(equivalent to that in a 20 mg strength methylphenidate hydrochloride product)

17.3 mg (Methylphenidate Extended Release Tablets 5)

NDC 62542-350-31

30 Tablets

Rx Only

METHYLPHENIDATEEXTENDED-RELEASEOrally Disintegrating Tablets, CII

Do not crush or chew tablets

Each tablet contains 25.9 mg of methylphenidate

(equivalent to that in a 30 mg strength methylphenidate hydrochloride product)

25.9 mg (Methylphenidate Extended Release Tablets 6)