Methylphenidate Hydrochloride

5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease : Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease ( 5.2 ). Increased Blood Pressure and Heart Rate : Monitor blood pressure and pulse ( 5.3 ). Psychiatric Adverse Reactions : Prior to initiating methylphenidate hydrochloride extended-release tablets, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets ( 5.4 ). Priapism : If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention ( 5.5 ). Peripheral Vasculopathy, including Raynaud’s Phenomenon : Carefully assess for digital changes during methylphenidate hydrochloride extended-release tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy ( 5.6 ). Long-Term Suppression of Growth in Pediatric Patients : Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their methylphenidate hydrochloride extended-release tablets treatment interrupted ( 5.7 ). Risk of Gastrointestinal (GI) Obstruction in Patients with GI Narrowing : Only use in patients able to swallow the extended-release tablet whole, and should not ordinarily be used in patients with pre-existing severe GI narrowing ( 5.8 ). Acute Angle Closure Glaucoma: methylphenidate hydrochloride 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 ( 5.9 ). Increased Intraocular Pressure (IOP) and Glaucoma : Prescribe methylphenidate hydrochloride 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 patients with a history of increased IOP or open angle glaucoma ( 5.10 ). Motor and Verbal Tics, and Worsening of Tourette’s Syndrome : Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue methylphenidate hydrochloride extended-release tablets treatment if clinically appropriate ( 5.11 ).

5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride extended-release tablets have a high potential for abuse and misuse. The use of methylphenidate hydrochloride extended-release tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction [see Drug Abuse and Dependence ( 9.1 , 9.2 )] . Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride 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 hydrochloride extended-release tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release tablets to anyone else. Throughout methylphenidate hydrochloride 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 hydrochloride 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 mm Hg) and heart rate (mean increase approximately 3 to 6 beats per minute) [see Adverse Reactions ( 6 )] . Some patients may have larger increases. Monitor all methylphenidate hydrochloride extended-release tablets-treated patients for hypertension and tachycardia.

5.4 Psychiatric Adverse Reactions Exacerbation of Psychosis in Patients with a Psychotic Disorder CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may exacerbate 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, including methylphenidate hydrochloride extended-release tablets, may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating methylphenidate hydrochloride extended-release tablets treatment, screen patients for risk factors for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms in Patients without a History of a Bipolar or Psychotic Disorder CNS stimulants (including methylphenidate hydrochloride extended-release tablets), 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 hydrochloride extended-release tablets.

5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in adult and pediatric male patients [see Adverse Reactions ( 6 )] . Although priapism was not reported with methylphenidate initiation, priapism occurred in patients treated with methylphenidate after some time, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride extended-release tablets-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon CNS stimulants, including methylphenidate hydrochloride extended-release tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon [see Adverse Reactions ( 6.2 )] . Signs and symptoms of these cases of peripheral vasculopathy were 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 of peripheral vasculopathy generally improved after CNS stimulant dosage reduction or discontinuation. During methylphenidate hydrochloride extended-release tablets treatment, carefully assess for digital changes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride extended-release tablets-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.7 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate hydrochloride extended-release tablets are not approved for use and are 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. Pediatric patients 7 to 13 years of age who received methylphenidate for 7 days per week for over 14 months to over 36 months 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 hydrochloride 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.

5.8 Risk of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing Because methylphenidate hydrochloride extended-release tablets are nondeformable and do not appreciably change in shape in the gastrointestinal (GI) tract, methylphenidate hydrochloride extended-release tablets should not ordinarily be administered to patients with pre-existing severe pathologic or iatrogenic GI narrowing. There have been rare reports of obstructive GI symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable modified-release dosage forms. Methylphenidate hydrochloride extended-release tablets should be used only in patients who are able to swallow the extended-release tablets whole [see Dosage and Administration ( 2.2 )] .

5.9 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, methylphenidate hydrochloride 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.

5.10 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions ( 6 )] . Prescribe methylphenidate hydrochloride 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 hydrochloride extended-release tablets-treated patients with a history of abnormally increased IOP or open angle glaucoma.

5.11 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 )] . Worsening of Tourette’s syndrome has also been reported. Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history for tics or Tourette’s syndrome and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride extended-release tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue methylphenidate hydrochloride extended-release tablets treatment if clinically appropriate.

The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 )] Hypersensitivity Reactions [see Contraindications ( 4 ) ] Monoamine Oxidase Inhibitors [see Contraindications ( 4 ), Drug Interactions ( 7 )] 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 )] Risks of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing [see Warnings and Precautions ( 5.8 )] Acute Angle Closure Glaucoma [see Warnings and Precautions ( 5.9 )] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions ( 5.10 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.11 )] The most common adverse reactions (>5%) in double-blind clinical trials were: Pediatric patients 6 to 17 years: upper abdominal pain ( 6.1 ). Adults up to 65 years of age: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Trigen Laboratories, LLC at 1-800-444-5164 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The data below is based on a total of 3,906 patients in clinical studies who received methylphenidate hydrochloride extended-release tablets. Patients aged 6 up to 65 years old with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies [see Table 3] . Table 3: Methylphenidate Hydrochloride Extended-Release Tablets-treated Patients in Double-Blind and Open-Label Clinical Studies Patient Population N Dosage Range Pediatric patients 6 to 12 years of age 2,216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults up to 65 years of age 1,188 18 to 108 mg once daily The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients: upper abdominal pain [see Table 4] . Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis [see Table 5] . The most common adverse reactions associated with methylphenidate hydrochloride extended-release tablets discontinuation (≥1%) from the pediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure. Most Common 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. Adverse Reactions in Pediatric Patients Aged 6 years and Older Table 4 displays adverse reactions reported in 2% or more of methylphenidate hydrochloride extended-release tablets-treated pediatric patients ages 6 and older with ADHD in 4 placebo-controlled, double-blind clinical trials. Table 4: Most Common Adverse Reactions 1 in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials Methylphenidate Hydrochloride Extended-Release Tablets (n=321) Placebo (n=318) Upper abdominal pain 6% 4% Insomnia 2 3% 1% Nasopharyngitis 3% 2% Vomiting 3% 2% Pyrexia 2% 1% 1 Reported in ≥2% of methylphenidate hydrochloride extended-release tablets-treated patients 2 Initial insomnia (methylphenidate hydrochloride extended-release tablets =0.6%) and insomnia (methylphenidate hydrochloride extended-release tablets =2.2%) terms were combined into Insomnia. Adverse Reactions in Adults Table 5 lists the adverse reactions reported in 2% or more of methylphenidate hydrochloride extended-release tablets-treated adults with ADHD in 2 placebo-controlled, double-blind clinical trials. Table 5: Most Common Adverse Reactions 1 in Adults with ADHD in 2 Placebo-Controlled, Double-Blind Clinical Trials Methylphenidate Hydrochloride Extended-Release Tablets 2 (n=415) Placebo (n=212) Decreased appetite 25% 7% Headache 22% 16% Dry mouth 14% 4% Nausea 13% 3% Insomnia 12% 6% Anxiety 8% 2% Decreased weight 7% 3% Dizziness 7% 5% Irritability 6% 1% Tachycardia 5% 0% Hyperhidrosis 5% 1% Depressed mood 4% 1% Initial insomnia 4% 3% Restlessness 3% 0% Palpitations 3% 1% Nervousness 3% 1% Tremor 3% 1% Upper respiratory tract infection 2% 1% Agitation 2% 1% Dyspepsia 2% 1% 1 Reported in ≥2% of methylphenidate hydrochloride extended-release tablets-treated patients 2 Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage). Other Adverse Reactions Observed in Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets The following adverse reactions occurred in less than 2% of methylphenidate hydrochloride extended-release tablets-treated patients ages 6 to 65 years of age in the double-blind and open-label clinical ADHD trials. Blood and Lymphatic System Disorders: Leukopenia Cardiac Disorders: Cardiac murmur, Hypertension, Heart rate increased Ear and Labyrinth Disorders: Vertigo Eye Disorders: Accommodation disorder, Dry eye, Vision blurred Gastrointestinal Disorders: Abdominal discomfort/pain, Constipation, Diarrhea, Vomiting General Disorders and Administration Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst Hepatobiliary Disorders: Hepatic enzymes increased Infections and Infestations: Sinusitis Metabolism and Nutrition Disorders: Anorexia Musculoskeletal and Connective Tissue Disorders: Muscle spasms, Muscle tightness Nervous System Disorders: Lethargy, Paresthesia, Psychomotor hyperactivity, Sedation, Somnolence, Tension headache Psychiatric Disorders: Affect lability, Aggression, Anger, Bruxism, Confusional state, Depression, Hypervigilance, decreased libido, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tension, Tic Reproductive System and Breast Disorders: Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: Cough, Dyspnea, Oropharyngeal pain Skin and Subcutaneous Tissue Disorders: Rash Vascular Disorders: Hot flush Discontinuation Due to Adverse Reactions In the 2 placebo-controlled studies in adults with ADHD, 25 (6%) methylphenidate hydrochloride extended-release tablets-treated patients and 6 (3%) placebo-treated patients discontinued due to an adverse reaction. In the methylphenidate hydrochloride extended-release tablets group, adverse reactions leading to discontinuation with an incidence of >0.5% were anxiety (1.7%), irritability (1.4%), increased blood pressure (1%), and nervousness (0.7%). In the placebo group, adverse reactions leading to discontinuation with an incidence of >0.5% were increased blood pressure (0.9%) and depressed mood (0.9%). In the 11 open-label studies in patients 6 to 65 years of age with ADHD, 266 (7%) methylphenidate hydrochloride extended-release tablets-treated patients discontinued due to an adverse reaction including insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). Blood Pressure and Heart Rate Increases In the 1-week treatment, controlled trials in pediatric patients 6 to 12 years of age with ADHD (Studies 1 and 2) [see Clinical Studies ( 14.2 )] , both the methylphenidate hydrochloride extended-release tablets once daily group and the methylphenidate three times daily group increased resting pulse by an average of 2 to 6 beats per minute (bpm) and increased the average systolic and diastolic blood pressure roughly 1 to 4 mm Hg during the day, relative to placebo. In the randomized withdrawal portion of the double-blind, placebo-controlled trial with pediatric patients 13 to 17 years of age with ADHD (Study 4) [see Clinical Studies ( 14.3 )] , mean increases from baseline in resting pulse rate were observed with methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute (bpm), respectively). At the end of four weeks of treatment, mean increases from baseline in blood pressure for methylphenidate hydrochloride 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 the 7-week dose-titration, placebo-controlled study in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies ( 14.4 )] , mean changes from baseline in resting pulse rate were 3.6 in methylphenidate hydrochloride extended-release tablets-treated patients and -1.6 for placebo-treated patients after 7 weeks of treatment. Mean changes from baseline in blood pressure after 7 weeks of treatment in methylphenidate hydrochloride extended-release tablets-treated 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 )] . In the 5-week fixed-dose, placebo-controlled trial in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies ( 14.4 )] , dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with methylphenidate hydrochloride extended-release tablets-treated patients and 2.7 bpm with placebo-treated patients at the end of 5 weeks. Mean changes from baseline in standing blood pressure after 5 weeks of treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for methylphenidate hydrochloride extended-release tablets-treated patients and 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo-treated patients.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of methylphenidate hydrochloride 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, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis General Disorders and Administration Site Conditions: Chest pain, Drug effect decreased, Hyperpyrexia Hepatobiliary Disorders: Hepatocellular injury, Acute hepatic failure, Blood bilirubin increased Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Exanthemas NEC Investigations: Blood alkaline phosphatase increased, Platelet count decreased Musculoskeletal, Connective Tissue Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders: Convulsion, Grand mal convulsion, Stroke in pediatric patients, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics Psychiatric Disorders: Disorientation, Hallucination, Mania, Logorrhea Reproductive System and Breast Disorders: Priapism Skin and Subcutaneous Tissue Disorders: Alopecia, Bullous conditions, Erythema, Exfoliative conditions, Pruritus, Urticarias Vascular Disorders: Raynaud's phenomenon

9.1 Controlled Substance Methylphenidate hydrochloride extended-release tablets contain methylphenidate, a Schedule II controlled substance.

9.2 Abuse Methylphenidate hydrochloride 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 )] . 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 hydrochloride extended-release tablets 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 hydrochloride 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. Studies of Abuse Potential with Methylphenidate Hydrochloride Extended-Release Tablets In two placebo- and active-controlled, crossover human abuse potential (HAP) studies, the relative abuse potential of single oral doses of methylphenidate hydrochloride extended-release tablets were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational CNS stimulant use. In these studies, the response for each of the abuse-related subjective measures was defined as the maximum effect within the first 8 hours after treatment administration. When evaluating these results, consider that 22% of the total methylphenidate amount in methylphenidate hydrochloride extended-release tablets are available for immediate release and the remaining 78% is available for extended-release over 24 hours. In the first HAP study (n=40), single dose administration of methylphenidate hydrochloride extended-release tablets 108 mg (1.5 times the maximum recommended adult dose of methylphenidate hydrochloride extended-release tablets), IR MPH 60 mg (2 times the maximum recommended adult dose of IR MPH), or placebo were administered to subjects in a cross-over design. Methylphenidate hydrochloride extended-release tablets 108 mg and IR MPH 60 mg produced responses on the subjective measures of Drug Liking and Abuse Potential that were statistically similar, and both were statistically significantly greater than the responses to placebo. However, on subjective measures of Euphoria, methylphenidate hydrochloride extended-release tablets 108 mg produced responses that were statistically less than those produced by IR MPH 60 mg. In the second HAP study (n=49), a single dose of methylphenidate hydrochloride extended-release tablets 108 mg (1.5 times the maximum recommended adult dose of methylphenidate hydrochloride extended-release tablets), methylphenidate hydrochloride extended-release tablets 54 mg (0.75 times the maximum recommended adult dose of methylphenidate hydrochloride extended-release tablets), IR MPH 90 mg (3 times the maximum recommended adult dose of IR MPH), 50 mg (1.7 times the maximum recommended adult dose of IR MPH), or placebo were administered to subjects in a cross-over design. The three active treatments each produced responses on the subjective measure of Drug Liking that were statistically significantly greater than responses to placebo. IR MPH produced greater responses on Drug Liking compared to methylphenidate hydrochloride extended-release tablets when similar doses were compared (50 mg vs. 54 mg, and 90 mg vs. 108 mg, respectively), consistent with the extended-release properties of methylphenidate hydrochloride extended-release tablets. However, there were no significant differences in response between methylphenidate hydrochloride extended-release tablets 108 mg and IR MPH 50 mg on the subjective measures of Drug Liking and Euphoria. The clinical significance of the differences in response between methylphenidate hydrochloride extended-release tablets and IR MPH on subjective measures of abuse potential as reported in these HAP studies is unknown.

9.3 Dependence Physical Dependence Methylphenidate hydrochloride 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 dosage reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride extended-release tablets included dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Methylphenidate hydrochloride 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).

Caution should be exercised if administered to nursing mothers ( 8.3 ) Safety and efficacy has not been established in children less than six years old or elderly patients greater than 65 years of age ( 8.4 and 8.5 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD drugs, including methylphenidate hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/ . Risk Summary Published studies and post-marketing reports on methylphenidate use during pregnancy have inconsistent findings about a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the fetus associated with the use of central nervous system (CNS) stimulants 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 throughout organogenesis at doses up to 4 and 16 times, respectively, the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 54 times the MRHD given to adults. A slight decrease in body weight was observed in pregnant rats at the highest dose of 30 mg/kg/day (4 times the MRHD given to adults). In a pre- and postnatal development study in which rats were treated with oral administration of methylphenidate throughout pregnancy and lactation, a decrease in pup body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD given to adults on a mg/m 2 basis) (see Data) . The background risk of major birth defects and miscarriage in those with ADHD is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions: CNS stimulants, such as methylphenidate hydrochloride extended-release tablets, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of a therapeutic dosage of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine dependent mothers. Data Animal Data: In embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses up to 30 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 54 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (16 times the MRHD given to adults on a mg/m 2 basis). There was no evidence of changes in morphological development in rats, although a reduction in maternal body weight was observed at the highest dose of 30 mg/kg/day (4 times the MRHD of 72 mg/day given to adults (on a mg/m 2 basis). The no effect level for maternal body weight in rats is 5 mg/day (equal to the MRHD for adults on a mg/m 2 basis); and the no effect level for embryo-fetal development is 30 mg/kg/day (4 times the MRHD for adults on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 30 mg/kg/day, decreases in offspring body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD of 72 mg/day, given to adults on a mg/m 2 basis). The no effect level for pre- and post-natal development in rats was 12.5 mg/kg/day (2 times the MRHD given to adults on a mg/m 2 basis).

8.2 Lactation Risk Summary Limited published literature, based on breast milk sampling from a small number of methylphenidate-treated lactating women, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted methylphenidate dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant or effects on milk production. Long-term neurodevelopmental effects on infants from CNS stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants of methylphenidate hydrochloride extended-release tablets-treated lactating women for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

8.4 Pediatric Use The safety and effectiveness of methylphenidate hydrochloride extended-release tablets for the treatment of ADHD have been established in pediatric patients 6 years of age and older. The safety and effectiveness of methylphenidate hydrochloride extended-release 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. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Growth (weight and height) should be monitored in pediatric patients during treatment with CNS stimulants, including methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their methylphenidate hydrochloride extended-release tablets treatment interrupted [see Warnings 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 4 times the MRHD of 54 mg/day given to pediatric patients 6 to 12 years of age on a mg/m 2 basis. 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 4 times the MRHD of 54 mg/day given to pediatric patients 6 to 12 years of age on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (9 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.4 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use Methylphenidate hydrochloride extended-release tablets are not indicated for use in patients greater than 65 years of age.

12.1 Mechanism of Action Methylphenidate is a central nervous system (CNS) stimulant. The mode of therapeutic action of methylphenidate in the treatment of ADHD is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases 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. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of methylphenidate hydrochloride extended-release tablets has not been fully characterized.

12.3 Pharmacokinetics Absorption Following oral administration of methylphenidate hydrochloride extended-release tablets, plasma methylphenidate concentrations reached an initial maximum concentration 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 hydrochloride extended-release tablets occurred between 6 and 10 hours. Methylphenidate hydrochloride extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily [ see Figure 1 ]. No clinically significant difference in methylphenidate exposures was observed following the administration of either methylphenidate hydrochloride extended-release tablets once daily and immediate-release methylphenidate three times daily in adults. Figure 1. Mean Methylphenidate Plasma Concentrations Following a Single 18 mg Methylphenidate Hydrochloride Extended-Release Tablets dose and Immediate-release Methylphenidate 5 mg Doses (Three Doses Administered Every 4 Hours) The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of one 18 mg methylphenidate hydrochloride extended-release tablets dose and three 5 mg methylphenidate doses every four hours are summarized in Table 7. Table 7: Methylphenidate Pharmacokinetic Parameters (Mean ± SD) After Methylphenidate Hydrochloride Extended-Release Tablets and Immediate-release Methylphenidate Dosing in Healthy Adults Parameters Methylphenidate Hydrochloride Extended-Release Tablets (18 mg single dose) (n=36) Immediate-release Methylphenidate (Three 5 mg doses every four hours) (n=35) C max (ng/mL) 3.7 ± 1.0 4.2 ± 1.0 T max (h) 6.8 ± 1.8 6.5 ± 1.8 AUC inf (ng∙h/mL) 41.8 ± 13.9 38.0 ± 11.0 t 1/2 (h) 3.5 ± 0.4 3.0 ± 0.5 The methylphenidate pharmacokinetics were evaluated in healthy adults following single- and multiple-doses (steady state) of methylphenidate hydrochloride extended-release tablets (up to 144 mg/day (up to 2 times the maximum recommended dose)). The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were noted following single and repeated once-daily methylphenidate hydrochloride extended-release tablets dosing, indicating no significant drug accumulation. The AUC and t 1/2 following repeated once-daily dosing are similar to those following a single 18 to 144 mg dose of methylphenidate hydrochloride extended-release tablets. Dose Proportionality Following administration of methylphenidate hydrochloride extended-release tablets in single doses of 18, 36, and 54 mg/day to healthy adults, C max and AUC (0–inf) of d-methylphenidate were dose proportional, whereas l-methylphenidate C max and AUC (0–inf) increased disproportionately with respect to dose. Following administration of methylphenidate hydrochloride extended-release tablets, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer. In healthy adults, single and multiple doses (once-daily) methylphenidate hydrochloride extended-release tablets doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in C max and AUC inf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing. In a multiple-dose study, after patients aged 13 to 16 with ADHD were administered their prescribed methylphenidate hydrochloride extended-release tablets dose (18 to 72 mg/day), mean C max and AUC TAU of d- and total methylphenidate increased proportionally with respect to dose. Food Effects: In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast. Distribution Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral methylphenidate hydrochloride extended-release tablets administration. The half-life of methylphenidate in adults and adolescents following oral methylphenidate hydrochloride extended-release tablets administration was approximately 3.5 hours. Elimination Metabolism: In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of methylphenidate hydrochloride extended-release tablets once daily as evaluated by metabolism to PPAA is similar to that of immediate-release methylphenidate three times daily. The metabolism of single and repeated once-daily doses of methylphenidate hydrochloride extended-release tablets is similar. Excretion: After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose. Alcohol Effect on Methylphenidate Release in Methylphenidate Hydrochloride Extended-Release Tablets In-vitr o studies were conducted to explore the effect of alcohol on the release characteristics of methylphenidate for all five strengths of methylphenidate hydrochloride extended-release tablets. At alcohol concentrations up to 40%, there was no increased release of methylphenidate in the first two hours. Specific Populations Male and Female Patients: In healthy adults, the mean dose-adjusted AUC (0–inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng∙h/mL in males and 37.1 ng∙h/mL in females, with no differences noted between the two groups. Ethnic Groups: In adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted AUC (0–inf) was consistent across ethnic groups; however, the sample size was insufficient to detect ethnic variations in pharmacokinetics. Pediatric Patients: Increase in pediatric age was associated with increased apparent oral clearance (CL/F) (58% increase in adolescents compared to younger pediatric patients). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have a lower exposure of total methylphenidate at similar doses. Patients with Renal Impairment There is no pharmacokinetic information on the use of methylphenidate hydrochloride extended-release tablets in patients with renal impairment. Patients with Hepatic Impairment There is no pharmacokinetic information on the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic impairment. Figure 1

Absorption Following oral administration of methylphenidate hydrochloride extended-release tablets, plasma methylphenidate concentrations reached an initial maximum concentration 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 hydrochloride extended-release tablets occurred between 6 and 10 hours. Methylphenidate hydrochloride extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily [ see Figure 1 ]. No clinically significant difference in methylphenidate exposures was observed following the administration of either methylphenidate hydrochloride extended-release tablets once daily and immediate-release methylphenidate three times daily in adults. Figure 1. Mean Methylphenidate Plasma Concentrations Following a Single 18 mg Methylphenidate Hydrochloride Extended-Release Tablets dose and Immediate-release Methylphenidate 5 mg Doses (Three Doses Administered Every 4 Hours) The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of one 18 mg methylphenidate hydrochloride extended-release tablets dose and three 5 mg methylphenidate doses every four hours are summarized in Table 7. Table 7: Methylphenidate Pharmacokinetic Parameters (Mean ± SD) After Methylphenidate Hydrochloride Extended-Release Tablets and Immediate-release Methylphenidate Dosing in Healthy Adults Parameters Methylphenidate Hydrochloride Extended-Release Tablets (18 mg single dose) (n=36) Immediate-release Methylphenidate (Three 5 mg doses every four hours) (n=35) C max (ng/mL) 3.7 ± 1.0 4.2 ± 1.0 T max (h) 6.8 ± 1.8 6.5 ± 1.8 AUC inf (ng∙h/mL) 41.8 ± 13.9 38.0 ± 11.0 t 1/2 (h) 3.5 ± 0.4 3.0 ± 0.5 The methylphenidate pharmacokinetics were evaluated in healthy adults following single- and multiple-doses (steady state) of methylphenidate hydrochloride extended-release tablets (up to 144 mg/day (up to 2 times the maximum recommended dose)). The mean half-life was about 3.6 hours. No differences in the pharmacokinetics of methylphenidate hydrochloride extended-release tablets were noted following single and repeated once-daily methylphenidate hydrochloride extended-release tablets dosing, indicating no significant drug accumulation. The AUC and t 1/2 following repeated once-daily dosing are similar to those following a single 18 to 144 mg dose of methylphenidate hydrochloride extended-release tablets. Dose Proportionality Following administration of methylphenidate hydrochloride extended-release tablets in single doses of 18, 36, and 54 mg/day to healthy adults, C max and AUC (0–inf) of d-methylphenidate were dose proportional, whereas l-methylphenidate C max and AUC (0–inf) increased disproportionately with respect to dose. Following administration of methylphenidate hydrochloride extended-release tablets, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer. In healthy adults, single and multiple doses (once-daily) methylphenidate hydrochloride extended-release tablets doses from 54 to 144 mg/day resulted in linear and dose-proportional increases in C max and AUC inf for total methylphenidate (MPH) and its major metabolite, α-phenyl-piperidine acetic acid (PPAA). There was no time dependency in the pharmacokinetics of methylphenidate. The ratio of metabolite (PPAA) to parent drug (MPH) was constant across doses from 54 to 144 mg/day, both after single dose and upon multiple dosing. In a multiple-dose study, after patients aged 13 to 16 with ADHD were administered their prescribed methylphenidate hydrochloride extended-release tablets dose (18 to 72 mg/day), mean C max and AUC TAU of d- and total methylphenidate increased proportionally with respect to dose. Food Effects: In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of methylphenidate hydrochloride extended-release tablets when administered after a high-fat breakfast. Distribution Plasma methylphenidate concentrations in adults and adolescents decline biexponentially following oral methylphenidate hydrochloride extended-release tablets administration. The half-life of methylphenidate in adults and adolescents following oral methylphenidate hydrochloride extended-release tablets administration was approximately 3.5 hours. Elimination Metabolism: In humans, methylphenidate is metabolized primarily by de-esterification to PPAA, which has little or no pharmacologic activity. In adults the metabolism of methylphenidate hydrochloride extended-release tablets once daily as evaluated by metabolism to PPAA is similar to that of immediate-release methylphenidate three times daily. The metabolism of single and repeated once-daily doses of methylphenidate hydrochloride extended-release tablets is similar. Excretion: After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose. Alcohol Effect on Methylphenidate Release in Methylphenidate Hydrochloride Extended-Release Tablets In-vitr o studies were conducted to explore the effect of alcohol on the release characteristics of methylphenidate for all five strengths of methylphenidate hydrochloride extended-release tablets. At alcohol concentrations up to 40%, there was no increased release of methylphenidate in the first two hours. Specific Populations Male and Female Patients: In healthy adults, the mean dose-adjusted AUC (0–inf) values for methylphenidate hydrochloride extended-release tablets were 36.7 ng∙h/mL in males and 37.1 ng∙h/mL in females, with no differences noted between the two groups. Ethnic Groups: In adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted AUC (0–inf) was consistent across ethnic groups; however, the sample size was insufficient to detect ethnic variations in pharmacokinetics. Pediatric Patients: Increase in pediatric age was associated with increased apparent oral clearance (CL/F) (58% increase in adolescents compared to younger pediatric patients). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have a lower exposure of total methylphenidate at similar doses. Patients with Renal Impairment There is no pharmacokinetic information on the use of methylphenidate hydrochloride extended-release tablets in patients with renal impairment. Patients with Hepatic Impairment There is no pharmacokinetic information on the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic impairment. Figure 1