Methylphenidate Hydrochloride

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Box Warning, Warnings and Precautions ( 5.1 ), and Drug Abuse and Dependence ( 9.2 , 9.3 )] Known hypersensitivity to methylphenidate or other ingredients [see Contraindications ( 4 )] Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications ( 4 ) and Drug Interactions ( 7.1 )] 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 )] Potential for Gastrointestinal Obstruction [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%) were: Pediatric patients 6 to 17 years: abdominal pain upper ( 6.1 ) Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, 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 Trials 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 safety of methylphenidate hydrochloride extended-release tablets for the treatment of ADHD is based on adequate and well-controlled studies of another formulation of methylphenidate hydrochloride extended-release tablets. Below is a display of adverse reactions from those adequate and well-controlled studies in ADHD. Adults and pediatric patients 6 to 17 years with ADHD were evaluated in six controlled clinical studies and eleven open-label clinical studies (see Table 3). Safety was assessed by collecting adverse reactions, vital signs, weights, and electrocardiograms (ECGs), and by performing physical examinations and laboratory analyses. A total of 3,906 patients participated in the clinical trials. Table 3. Exposure in Double-Blind and Open-Label Clinical Studies of Another Formulation of Methylphenidate Hydrochloride Extended-Release Tablets Patient Population N Dosage Range Pediatric patients 6 to 12 years 2216 18 mg to 54 mg once daily Pediatric patients 13 to 17 years 502 18 mg to 72 mg once daily Adults 1188 18 mg to 108 mg* once daily * 108 mg is 1.5 times the maximum recommended dosage of methylphenidate hydrochloride extended-release tablets. The most common adverse reactions in double-blind clinical trials (>5%) were: Pediatric patients 6 to 17 years: abdominal pain upper (see Table 4). Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis (see Table 5). The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased . Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations. Pediatric Patients 6 to 17 Years Table 4 lists the adverse reactions reported in 1% or more of another formulation of methylphenidate hydrochloride extended-release tablet-treated pediatric patients (6 to 17 years) in four placebo-controlled, double-blind clinical trials. Table 4. Adverse Reactions Reported by ≥1% of Pediatric Patients (6 to 17 years) Treated with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets in Four Placebo-Controlled, Double-Blind Clinical Trials System/Organ Class Adverse Reaction Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets (n=321) % Placebo (n=318) % Gastrointestinal Disorders Abdominal pain upper 6.2 3.8 Vomiting 2.8 1.6 General Disorders and Administration Site Conditions Pyrexia 2.2 0.9 Infections and Infestations Nasopharyngitis 2.8 2.2 Nervous System Disorders Dizziness 1.9 0 Psychiatric Disorders Insomnia * 2.8 0.3 Respiratory, Thoracic and Mediastinal Disorders Cough 1.9 0.9 Oropharyngeal pain 1.2 0.9 * Terms of Initial insomnia (methylphenidate hydrochloride extended-release tablets =0.6%) and Insomnia (methylphenidate hydrochloride extended-release tablets =2.2%) are combined into Insomnia. Adults Table 5 lists the adverse reactions reported in 1% or more of adults treated with another formulation of methylphenidate hydrochloride extended-release tablets in two placebo-controlled, double-blind clinical trials. Table 5. Adverse Reactions Reported by ≥1% of Adults Treated with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets in Two Placebo-Controlled, Double-Blind Clinical Trials * System/Organ Class Adverse Reaction Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets (n=415) % Placebo (n=212) % Cardiac Disorders Tachycardia 4.8 0 Palpitations 3.1 0.9 Ear and Labyrinth Disorders Vertigo 1.7 0 Eye Disorders Vision blurred 1.7 0.5 Gastrointestinal Disorders Dry mouth 14.0 3.8 Nausea 12.8 3.3 Dyspepsia 2.2 0.9 Vomiting 1.7 0.5 Constipation 1.4 0.9 General Disorders and Administration Site Conditions Irritability 5.8 1.4 Infections and Infestations Upper respiratory tract infection 2.2 0.9 Investigations Weight decreased 6.5 3.3 Metabolism and Nutrition Disorders Decreased appetite 25.3 6.6 Anorexia 1.7 0 Musculoskeletal and Connective Tissue Disorders Muscle tightness 1.9 0 Nervous System Disorders Headache 22.2 15.6 Dizziness 6.7 5.2 Tremor 2.7 0.5 Paresthesia 1.2 0 Sedation 1.2 0 Tension headache 1.2 0.5 Psychiatric Disorders Insomnia 12.3 6.1 Anxiety 8.2 2.4 Initial insomnia 4.3 2.8 Depressed mood 3.9 1.4 Nervousness 3.1 0.5 Restlessness 3.1 0 Agitation 2.2 0.5 Aggression 1.7 0.5 Bruxism 1.7 0.5 Depression 1.7 0.9 Libido decreased 1.7 0.5 Affect lability 1.4 0.9 Confusional state 1.2 0.5 Tension 1.2 0.5 Respiratory, Thoracic and Mediastinal Disorders Oropharyngeal pain 1.7 1.4 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 5.1 0.9 * Included doses up to 108 mg (1.5 times the maximum recommended dosage of methylphenidate hydrochloride extended-release tablets). Adverse Reactions Observed in Clinical Trials with Another Formulation of Methylphenidate Hydrochloride Extended-release Tablets This section includes adverse reactions reported with use of another formulation of methylphenidate hydrochloride extended-release tablets in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by the other formulation of methylphenidate hydrochloride extended-release tablets-treated patients who participated in open-label and postmarketing clinical trials. Blood and Lymphatic System Disorders: Leukopenia Eye Disorders: Accommodation disorder, Dry eye Vascular Disorders: Hot flush Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst Infections and Infestations: Sinusitis Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased Musculoskeletal and Connective Tissue Disorders: Muscle spasms Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic Reproductive System and Breast Disorders: Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: Dyspnea Skin and Subcutaneous Tissue Disorders: Rash, Rash macular Vascular Disorders: Hypertension Discontinuation Due to Adverse Reactions Adverse reactions in the four placebo-controlled studies of pediatric patients (6 to 17 years) leading to discontinuation occurred in 2 patients (0.6%) treated with another formulation of methylphenidate hydrochloride extended-release tablets including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%). In the two placebo-controlled studies of adults, 25 patients (6.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Incidence of >0.5% in patients treated with another formulation of methylphenidate hydrochloride extended-release tablets included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%). In the eleven open-label studies of pediatric patients and adults, 266 patients (7.0%) treated with another formulation of methylphenidate hydrochloride extended-release tablets discontinued due to an adverse reaction. Incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). Tics In a long-term uncontrolled study (n=432 pediatric patients 6 to 12 years), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with another formulation of methylphenidate hydrochloride extended-release tablets. In a second uncontrolled study (n=682 pediatric patients 6 to 12 years) the cumulative incidence of new-onset tics was 1% (9/682). The treatment period was up to 9 months with mean treatment duration of 7.2 months. Blood Pressure and Heart Rate Increases In the laboratory classroom clinical trials in pediatric patients 6 to 12 years (Studies 1 and 2), both another formulation of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled trial in pediatric patients 13 to 17 years (Study 4), mean increases from baseline in resting pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for another formulation of 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 one placebo-controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with another formulation of methylphenidate hydrochloride extended-release tablets at the end of the double-blind treatment vs. an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for another formulation of methylphenidate hydrochloride extended-release tablets and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for another formulation of methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind treatment (3.6 and –1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double–blind treatment for another formulation of methylphenidate hydrochloride extended-release tablets and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions ( 5.3 )] . 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of another formulation 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 or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased Hepatobiliary Disorders: Hepatocellular injury, Acute hepatic failure Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changes Reproductive System and Breast Disorders: Priapism Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema Vascular Disorders: Raynaud's phenomenon

4 CONTRAINDICATIONS Methylphenidate hydrochloride extended-release tablets are contraindicated in patients: with a known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride extended-release tablets. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other methylphenidate products [see Adverse Reactions ( 6.2 )] . receiving concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within 14 days following discontinuation of treatment with a MAOI, because of the risk of hypertensive crisis [see Drug Interactions ( 7.1 )] . Known hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride extended-release tablets ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days ( 4 )

11 DESCRIPTION Methylphenidate hydrochloride extended-release tablets contain methylphenidate a CNS stimulant, present as methylphenidate hydrochloride salt. Chemically, methylphenidate hydrochloride is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C 14 H 19 NO 2 •HCl. Its structural formula is: Methylphenidate hydrochloride is a white, odorless crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. It has a pKa of 8.71 (at 21.5°C). Its molecular weight is 269.77. Methylphenidate hydrochloride extended-release tablets are for oral administration and is available in the following strengths: 18 mg, 27 mg, 36 mg, 45 mg, 54 mg, 63 mg, and 72 mg containing methylphenidate hydrochloride (equivalent to 15.6 mg, 23.4 mg, 31.1 mg, 38.9 mg, 46.7 mg, 54.5 mg, and 62.3 mg methylphenidate respectively). Methylphenidate hydrochloride extended-release tablets contain the following inactive ingredients: cellulose acetate, colloidal silicon dioxide, ferrosoferric oxide, hypromellose, iron oxide black, lactose monohydrate, magnesium stearate, phosphoric acid, polyethylene glycol, polyethylene oxide, sodium chloride, succinic acid, titanium dioxide, triacetin. Methylphenidate hydrochloride extended-release tablets also contain the following color additives: 27 mg: FD&C Yellow #6 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake 45 mg: FD&C Red #40 Aluminum Lake 54 mg: FD&C Yellow #6 Aluminum Lake, FD&C Red #40 Aluminum Lake, FD&C Blue #2 Aluminum Lake 63 mg: iron oxide red, iron oxide yellow 72 mg: FD&C Blue #1 Aluminum Lake System Components and Performance Methylphenidate hydrochloride extended-release tablets use osmotic pressure to deliver methylphenidate hydrochloride at a controlled rate. The system, which resembles a conventional tablet in appearance, comprises an osmotically active bilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat. The bilayer core is composed of a drug layer containing the drug and excipients, and a push layer containing osmotically active components. There is a precision-laser drilled orifice on the drug-layer end of the tablet. In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate. Water permeates through the membrane into the tablet core. As the osmotically active polymer excipients expand, methylphenidate is released through the orifice. The membrane controls the rate at which water enters the tablet core, which in turn controls drug delivery. Furthermore, the drug release rate from the system increases with time over a period of 6 to 7 hours due to the drug-concentration gradient incorporated into the two drug layers of core of methylphenidate hydrochloride extended-release tablets. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell along with insoluble core components. It is possible that methylphenidate hydrochloride extended-release tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized. Structural Image

2 DOSAGE AND ADMINISTRATION Administer once daily in the morning with or without food. ( 2.2 ) Swallow whole with liquid. Do not chew, divide, or crush. ( 2.2 ) Recommended dosage for patients new to methylphenidate ( 2.3 ): Pediatric patients 6 to 17 years Starting dosage is 18 mg once daily. Dosage may be increased by 18 mg once per day at weekly intervals. Maximum dosage for pediatric patients 6 to 12 years: 54 mg once daily. Maximum dosage for pediatric patients 13 to 17 years: 72 mg once daily. Adults (up to 65 years) Starting dosage is 18 mg or 36 mg once daily. Dosage may be increased by 18 mg once daily at weekly intervals. Maximum dosage: 72 mg once daily. 2.1 Pretreatment Screening Prior to treating patients with methylphenidate hydrochloride extended-release tablets assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions ( 5.2 )]. the family history and clinically evaluate patients for motor or verbal tics or Tourette's syndrome before initiating methylphenidate hydrochloride extended-release tablets [see Warnings and Precautions ( 5.11 )]. 2.2 General Administration Information Administer methylphenidate hydrochloride extended-release tablets orally once daily in the morning with or without food. Swallow methylphenidate hydrochloride extended-release tablets whole with liquid. Do not chew, divide, or crush [see Warnings and Precautions ( 5.8 )] . 2.3 Dosage Recommendations for Patients New to Methylphenidate Table 1 includes the starting dosage and dosage recommendations for methylphenidate hydrochloride extended-release tablets in pediatric patients 6 to 17 years and adults who are not currently taking methylphenidate or other stimulants. Table 1: Dosage Recommendations for methylphenidate hydrochloride extended-release tablets in Pediatric Patients 6 to 17 years and Adults Patient Population Methylphenidate hydrochloride extended-release tablets Recommended Starting Dosage Methylphenidate hydrochloride extended-release tablets Dosage Range Pediatric patients 6 to 12 years 18 mg once daily 18 mg to 54 mg once daily 13 to 17 years 18 mg once daily 18 mg to 72 mg once daily (not to exceed 2 mg/kg/day) Adults 18 (up to 65 years) 18 mg or 36 mg once daily 18 mg to 72 mg once daily 2.4 Dosage Recommendations for Patients Currently Using Methylphenidate The recommended starting dosage of methylphenidate hydrochloride extended-release tablets for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 mg to 60 mg daily is provided in Table 2. Table 2. Recommended Starting Dosage when Converting from Methylphenidate Regimens to methylphenidate hydrochloride extended-release tablets Current Methylphenidate Daily Dosage Recommended Starting Dosage of Methylphenidate hydrochloride extended-release tablets 5 mg methylphenidate twice daily or three times daily 18 mg once daily in the morning 10 mg methylphenidate twice daily or three times daily 36 mg once daily in the morning 15 mg methylphenidate twice daily or three times daily 54 mg once daily in the morning 20 mg methylphenidate twice daily or three times daily 72 mg once daily in the morning 2.5 Dose Titration Doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved clinical response at a lower dose. Daily dosages above 54 mg in pediatric patients 6 to 12 years and above 72 mg in pediatric patients 13 to 17 years have not been studied and are not recommended. Daily dosages above 72 mg are not recommended in adults. Dosage strengths of 27 mg, 45 mg, and 63 mg are available for additional titration options based on clinical response. 2.6 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reaction occur, reduce the dosage, or, if necessary, discontinue methylphenidate hydrochloride extended-release tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue methylphenidate hydrochloride extended-release tablets.

1 INDICATIONS AND USAGE Methylphenidate hydrochloride extended-release tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults (up to the age of 65 years) and pediatric patients 6 years of age and older [ see Clinical Studies ( 14 )] . Methylphenidate hydrochloride extended-release tablets are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults (up to the age of 65 years) and pediatric patients 6 years of age and older ( 1 ).

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 )] . Methylphenidate hydrochloride extended-release tablets can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare 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 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. In two placebo-controlled human abuse potential studies, single oral doses of another formulation 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 stimulant use to assess relative abuse potential. For the purpose of this assessment, the response for each of the subjective measures was defined as the maximum effect within the first 8 hours after dose administration. In one study (n=40), both the other formulation of methylphenidate hydrochloride extended-release tablets (108 mg, which is 1.5 times the maximum recommended dosage of methylphenidate hydrochloride extended-release tablets) and 60 mg IR MPH compared to placebo produced statistically significantly greater responses on the five subjective measures suggestive of abuse potential. In comparisons between the two active treatments, however, the other formulation of methylphenidate hydrochloride extended-release tablets (108 mg) produced variable responses on positive subjective measures that were either statistically indistinguishable from (Abuse Potential, Drug Liking, Amphetamine, and Morphine Benzedrine Group [Euphoria]) or statistically less than (Stimulation – Euphoria) responses produced by 60 mg IR MPH. In another study (n=49), both doses of another formulation of methylphenidate hydrochloride extended-release tablets (54 mg and 108 mg) and both doses of IR MPH (50 mg and 90 mg) produced statistically significantly greater responses compared to placebo on the two primary scales used in the study (Drug Liking, Euphoria). When doses of the other methylphenidate hydrochloride extended-release tablets (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg), respectively, methylphenidate hydrochloride extended-release tablets produced statistically significantly lower subjective responses on these two scales than IR MPH. Methylphenidate hydrochloride extended-release tablets (108 mg) produced responses that were statistically indistinguishable from the responses on these two scales produced by IR MPH (50 mg). Differences in subjective responses to the respective doses should be considered in the context that only 18% of the total amount of methylphenidate in methylphenidate hydrochloride extended-release tablets is available for immediate release from the drug overcoat. Although these findings reveal a relatively lower response to another formulation of methylphenidate hydrochloride extended-release tablets on subjective measures suggestive of abuse potential compared to IR MPH at roughly equivalent total MPH doses, the relevance of these findings to the abuse potential of methylphenidate hydrochloride extended-release tablets in the community is unknown.

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

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 dose reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride extended-release tablets include 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 by a lower dose).

9 DRUG ABUSE AND DEPENDENCE 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 )] . Methylphenidate hydrochloride extended-release tablets can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare 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 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. In two placebo-controlled human abuse potential studies, single oral doses of another formulation 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 stimulant use to assess relative abuse potential. For the purpose of this assessment, the response for each of the subjective measures was defined as the maximum effect within the first 8 hours after dose administration. In one study (n=40), both the other formulation of methylphenidate hydrochloride extended-release tablets (108 mg, which is 1.5 times the maximum recommended dosage of methylphenidate hydrochloride extended-release tablets) and 60 mg IR MPH compared to placebo produced statistically significantly greater responses on the five subjective measures suggestive of abuse potential. In comparisons between the two active treatments, however, the other formulation of methylphenidate hydrochloride extended-release tablets (108 mg) produced variable responses on positive subjective measures that were either statistically indistinguishable from (Abuse Potential, Drug Liking, Amphetamine, and Morphine Benzedrine Group [Euphoria]) or statistically less than (Stimulation – Euphoria) responses produced by 60 mg IR MPH. In another study (n=49), both doses of another formulation of methylphenidate hydrochloride extended-release tablets (54 mg and 108 mg) and both doses of IR MPH (50 mg and 90 mg) produced statistically significantly greater responses compared to placebo on the two primary scales used in the study (Drug Liking, Euphoria). When doses of the other methylphenidate hydrochloride extended-release tablets (54 mg and 108 mg) were compared to IR MPH (50 mg and 90 mg), respectively, methylphenidate hydrochloride extended-release tablets produced statistically significantly lower subjective responses on these two scales than IR MPH. Methylphenidate hydrochloride extended-release tablets (108 mg) produced responses that were statistically indistinguishable from the responses on these two scales produced by IR MPH (50 mg). Differences in subjective responses to the respective doses should be considered in the context that only 18% of the total amount of methylphenidate in methylphenidate hydrochloride extended-release tablets is available for immediate release from the drug overcoat. Although these findings reveal a relatively lower response to another formulation of methylphenidate hydrochloride extended-release tablets on subjective measures suggestive of abuse potential compared to IR MPH at roughly equivalent total MPH doses, the relevance of these findings to the abuse potential of methylphenidate hydrochloride extended-release tablets in the community 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 dose reduction following prolonged use of CNS stimulants including methylphenidate hydrochloride extended-release tablets include 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 by a lower dose).

10 OVERDOSAGE 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 hydrochloride 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.

7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ) 7.1 Clinically Important Drug Interactions Table 6 presents clinically important drug interactions with methylphenidate hydrochloride extended-release tablets. Table 6: Drugs Having Clinically Important Interactions with Methylphenidate Hydrochloride Extended-release Tablets Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications ( 4 )] . Intervention: Do not administer methylphenidate hydrochloride extended-release tablets concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. Antihypertensive Drugs Clinical Impact: Methylphenidate hydrochloride extended-release tablets may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions ( 5.3 )] . Intervention: Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical Impact: Concomitant use of halogenated anesthetics and methylphenidate hydrochloride extended-release tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention: Avoid use of methylphenidate hydrochloride extended-release tablets in patients being treated with anesthetics on the day of surgery. Risperidone Clinical Impact: Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). Intervention: Monitor for signs of EPS.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Methylphenidate HCl is a CNS stimulant. The mode of therapeutic action in ADHD is not known. 12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo entantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. 12.3 Pharmacokinetics In a relative bioavailability study in healthy adults under fasted conditions, plasma exposures of 72 mg methylphenidate hydrochloride extended-release tablets and 72 mg (2 x 36 mg) methylphenidate extended-release tablets were compared. The peak plasma concentration (C max ) of 72 mg methylphenidate hydrochloride extended-release tablets and 72 mg (2 x 36 mg) methylphenidate extended-release tablets is 19.7 ng/mL and 19.3 ng/mL, respectively. The area under the plasma concentration-time curve (AUC 0-inf ) of 72 mg methylphenidate hydrochloride extended-release tablets and 72 mg (2 x 36 mg) methylphenidate extended-release tablets is 206.1 ng∙h/mL and 200.9 ng∙h/mL, respectively. Absorption Methylphenidate is readily absorbed. Following oral administration of methylphenidate hydrochloride extended-release tablets plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 1.5 hour, followed by gradual ascending concentrations over the next 5 to 6 hours, after which a gradual decrease begins. Mean time to reach peak plasma concentrations of methylphenidate hydrochloride extended-release tablets occurs at 5.5 hours. Methylphenidate hydrochloride extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. Figure 1 displays mean plasma exposures of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily (administered every 4 hours) in adults. Figure 1: Mean Methylphenidate Plasma Concentration-Time Profiles The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of methylphenidate hydrochloride extended-release tablets 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 7. Table 7. Methylphenidate Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults Parameters Methylphenidate Hydrochloride Extended-release Tablets (18 mg once daily) (n=36) Methylphenidate (5 mg three times daily) (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 ½ (h) 3.5 ± 0.4 3.0 ± 0.5 The pharmacokinetics of methylphenidate hydrochloride extended-release tablets were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg per day (2 times the maximum recommended daily dosage of methylphenidate hydrochloride extended-release tablets). 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 dosing, indicating no significant drug accumulation. The AUC and t 1/2 following repeated once-daily dosing are similar to those following the first dose of methylphenidate hydrochloride extended-release tablets in a dose range of 18 mg to 144 mg. Effect of Food 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. There is no evidence of dose dumping in the presence or absence of food. Effect of Alcohol In-vitr o studies were conducted to explore the effect of alcohol on the release characteristics of methylphenidate from methylphenidate hydrochloride extended-release tablets. At alcohol concentrations up to 40%, there was no increased release of methylphenidate in the first two hours. Dose Proportionality Following administration methylphenidate hydrochloride extended-release tablets in single doses of 18 mg, 36 mg, and 54 mg per day to healthy adults, C max and AUC (0–inf) of d-methylphenidate were proportional to dose, 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 dosing of once-daily methylphenidate hydrochloride extended-release tablets doses from 54 mg to 144 mg per 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 mg to 144 mg per day, both after single dose and upon multiple dosing. In a multiple-dose study in ADHD with pediatric patients 13 to 16 years administered their prescribed dose (18 mg to 72 mg per day) of methylphenidate hydrochloride extended-release tablets, mean C max and AUC TAU of d- and total methylphenidate increased proportionally with respect to dose. Distribution Plasma methylphenidate concentrations in adults and pediatric patients 13 to 17 years decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of methylphenidate hydrochloride extended-release tablets 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 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. Speci fic 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 men and 37.1 ng∙h/mL in women, with no differences noted between the two groups. Racial or Ethnic Groups In adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted AUC (0–inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics. Pediatric Patients Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in pediatric patients 13 to 17 years compared to pediatric patients 6 to 12 years). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses. The pharmacokinetics of methylphenidate hydrochloride extended-release tablets have not been studied in pediatric patients less than 6 years of age. Patients with Renal Impairment There is no experience with the use of methylphenidate hydrochloride extended-release 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 hydrochloride extended-release tablets. Patients with Hepatic Impairment There is no experience with the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic insufficiency. Figure 1

12.1 Mechanism of Action Methylphenidate HCl is a CNS stimulant. The mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics Methylphenidate is a racemic mixture comprised of the d- and l-threo entantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

12.3 Pharmacokinetics In a relative bioavailability study in healthy adults under fasted conditions, plasma exposures of 72 mg methylphenidate hydrochloride extended-release tablets and 72 mg (2 x 36 mg) methylphenidate extended-release tablets were compared. The peak plasma concentration (C max ) of 72 mg methylphenidate hydrochloride extended-release tablets and 72 mg (2 x 36 mg) methylphenidate extended-release tablets is 19.7 ng/mL and 19.3 ng/mL, respectively. The area under the plasma concentration-time curve (AUC 0-inf ) of 72 mg methylphenidate hydrochloride extended-release tablets and 72 mg (2 x 36 mg) methylphenidate extended-release tablets is 206.1 ng∙h/mL and 200.9 ng∙h/mL, respectively. Absorption Methylphenidate is readily absorbed. Following oral administration of methylphenidate hydrochloride extended-release tablets plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 1.5 hour, followed by gradual ascending concentrations over the next 5 to 6 hours, after which a gradual decrease begins. Mean time to reach peak plasma concentrations of methylphenidate hydrochloride extended-release tablets occurs at 5.5 hours. Methylphenidate hydrochloride extended-release tablets once daily minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate three times daily. Figure 1 displays mean plasma exposures of methylphenidate hydrochloride extended-release tablets once daily and methylphenidate three times daily (administered every 4 hours) in adults. Figure 1: Mean Methylphenidate Plasma Concentration-Time Profiles The mean single-dose pharmacokinetic parameters in 36 healthy adults following the administration of methylphenidate hydrochloride extended-release tablets 18 mg once daily and methylphenidate 5 mg three times daily are summarized in Table 7. Table 7. Methylphenidate Pharmacokinetic Parameters (Mean ± SD) After Single Dose in Healthy Adults Parameters Methylphenidate Hydrochloride Extended-release Tablets (18 mg once daily) (n=36) Methylphenidate (5 mg three times daily) (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 ½ (h) 3.5 ± 0.4 3.0 ± 0.5 The pharmacokinetics of methylphenidate hydrochloride extended-release tablets were evaluated in healthy adults following single- and multiple-dose administration (steady state) of doses up to 144 mg per day (2 times the maximum recommended daily dosage of methylphenidate hydrochloride extended-release tablets). 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 dosing, indicating no significant drug accumulation. The AUC and t 1/2 following repeated once-daily dosing are similar to those following the first dose of methylphenidate hydrochloride extended-release tablets in a dose range of 18 mg to 144 mg. Effect of Food 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. There is no evidence of dose dumping in the presence or absence of food. Effect of Alcohol In-vitr o studies were conducted to explore the effect of alcohol on the release characteristics of methylphenidate from methylphenidate hydrochloride extended-release tablets. At alcohol concentrations up to 40%, there was no increased release of methylphenidate in the first two hours. Dose Proportionality Following administration methylphenidate hydrochloride extended-release tablets in single doses of 18 mg, 36 mg, and 54 mg per day to healthy adults, C max and AUC (0–inf) of d-methylphenidate were proportional to dose, 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 dosing of once-daily methylphenidate hydrochloride extended-release tablets doses from 54 mg to 144 mg per 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 mg to 144 mg per day, both after single dose and upon multiple dosing. In a multiple-dose study in ADHD with pediatric patients 13 to 16 years administered their prescribed dose (18 mg to 72 mg per day) of methylphenidate hydrochloride extended-release tablets, mean C max and AUC TAU of d- and total methylphenidate increased proportionally with respect to dose. Distribution Plasma methylphenidate concentrations in adults and pediatric patients 13 to 17 years decline biexponentially following oral administration. The half-life of methylphenidate in adults and adolescents following oral administration of methylphenidate hydrochloride extended-release tablets 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 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. Speci fic 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 men and 37.1 ng∙h/mL in women, with no differences noted between the two groups. Racial or Ethnic Groups In adults receiving methylphenidate hydrochloride extended-release tablets, dose-adjusted AUC (0–inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics. Pediatric Patients Increase in age resulted in increased apparent oral clearance (CL/F) (58% increase in pediatric patients 13 to 17 years compared to pediatric patients 6 to 12 years). Some of these differences could be explained by body-weight differences among these populations. This suggests that subjects with higher body weight may have lower exposures of total methylphenidate at similar doses. The pharmacokinetics of methylphenidate hydrochloride extended-release tablets have not been studied in pediatric patients less than 6 years of age. Patients with Renal Impairment There is no experience with the use of methylphenidate hydrochloride extended-release 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 hydrochloride extended-release tablets. Patients with Hepatic Impairment There is no experience with the use of methylphenidate hydrochloride extended-release tablets in patients with hepatic insufficiency. Figure 1

20231026

46

3 DOSAGE FORMS AND STRENGTHS Methylphenidate hydrochloride extended-release tablets are available in the following strengths: 18 mg: yellow with “TL706” imprinted in black ink 27 mg: gray with “TL707” imprinted in black ink 36 mg: white with “TL708” imprinted in black ink 45 mg: pink with “TL711” imprinted in black ink 54 mg: pink with “TL709” imprinted in black ink 63 mg: orange with “TL700” imprinted in black ink and 72 mg: blue with “TL710” imprinted in black ink. Extended-release tablets:18 mg, 27 mg, 36 mg, 45 mg, 54 mg, 63 mg, and 72 mg ( 3 )

Methylphenidate Hydrochloride Methylphenidate hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE HYPROMELLOSES PHOSPHORIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED SILICON DIOXIDE SODIUM CHLORIDE MAGNESIUM STEARATE SUCCINIC ACID FERROSOFERRIC OXIDE TITANIUM DIOXIDE FD&C RED NO. 40 CELLULOSE ACETATE LACTOSE MONOHYDRATE POLYETHYLENE OXIDE 200000 POLYETHYLENE OXIDE 5000000 TRIACETIN TL711 Methylphenidate Hydrochloride Methylphenidate hydrochloride METHYLPHENIDATE HYDROCHLORIDE METHYLPHENIDATE HYPROMELLOSES PHOSPHORIC ACID POLYETHYLENE GLYCOL, UNSPECIFIED SILICON DIOXIDE SODIUM CHLORIDE MAGNESIUM STEARATE SUCCINIC ACID FERROSOFERRIC OXIDE TITANIUM DIOXIDE TRIACETIN CELLULOSE ACETATE LACTOSE MONOHYDRATE POLYETHYLENE OXIDE 200000 POLYETHYLENE OXIDE 5000000 FERRIC OXIDE YELLOW FERRIC OXIDE RED TL700

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the MRHD of methylphenidate hydrochloride extended-release tablets on a mg/m 2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 6 times the MRHD of methylphenidate hydrochloride extended-release tablets on a mg/m 2 basis, respectively. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 11-fold the MRHD of methylphenidate hydrochloride extended-release tablets on a mg/m 2 basis, respectively.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 4 times the MRHD of methylphenidate hydrochloride extended-release tablets on a mg/m 2 basis, respectively. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown. Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 6 times the MRHD of methylphenidate hydrochloride extended-release tablets on a mg/m 2 basis, respectively. In a 24-week carcinogenicity study in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate. Mutagenesis Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of Fertility Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 11-fold the MRHD of methylphenidate hydrochloride extended-release tablets on a mg/m 2 basis, respectively.

NDA216117

Methylphenidate Hydrochloride

Methylphenidate hydrochloride

13811-700

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL PRINCIPAL DISPLAY PANEL PRINCIPAL DISPLAY PANEL - Methylphenidate Hydrochloride Extended-release Tablets CII 45 mg Tablet Label NDC 13811-711-30 30 tablets Rx only Please see the Medication Guide provided by your pharmacist. Methylphenidate 45 mg 30ct BL 200306-1 Rev. 06/2022

RECENT MAJOR CHANGES Boxed Warning 10/2023 Dosage and Administration ( 2.1 , 2.3 ) 10/2023 Warnings and Precautions ( 5.1 , 5.2 , 5.9 , 5.10 , 5.11 ) 10/2023

17 PATIENT COUNSELING INFORMATION 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 hydrochloride extended-release 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 ), and Overdosage ( 10 )] . 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. Administration Instructions Instruct patients to swallow methylphenidate hydrochloride extended-release tablets whole with the aid of liquids, and not to chew, divide, or crush the tablets. Advise patients that the medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; advise patients not to be concerned if they occasionally notice in their stool something that looks like a tablet [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.8 )] . 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 hydrochloride extended-release 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 [see Warnings and Precautions ( 5.2 )] . Increased Blood Pressure and Heart Rate Advise patients and their caregivers that methylphenidate hydrochloride extended-release tablets can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions ( 5.3 )] . Psychiatric Adverse Reactions Advise patients and their caregivers that methylphenidate hydrochloride extended-release tablets, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions ( 5.4 )] . Priapism Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions ( 5.5 )] . Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including Raynaud’s Phenomenon] (see Warnings and Precautions ( 5.6 )] . Instruct patients beginning treatment with methylphenidate hydrochloride extended-release tablets about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their healthcare provider any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride extended-release tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Long-Term Suppression of Growth in Pediatric Patients Advise patients, families and caregivers that methylphenidate hydrochloride extended-release tablets may cause slowing of growth and weight loss [see Warnings and Precautions ( 5.7 )] . Increased Intraocular Pressure (IOP) and Glaucoma Advise patients that IOP and glaucoma may occur during treatment with methylphenidate hydrochloride extended-release tablets [see Warnings and Precautions ( 5.10 )] . Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with methylphenidate hydrochloride extended-release tablets. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see Warnings and Precautions ( 5.11 ] . Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to methylphenidate hydrochloride extended-release tablets during pregnancy [see Use in Specific Populations ( 8.1 )] . Manufactured for: Trigen Laboratories, LLC Alpharetta, GA 30005 1-800-444-5164 www.trigenlab.com 200320-3 Patent numbers: US 9,855,258 US 9,827,234 US 9,707,217 US 10,265,308 US 10,695,336 Trigen Logo

MEDICATION GUIDE MEDICATION GUIDE Methylphenidate hydrochloride extended-release tablets (METH-il-FEN-i-date) for oral use, CII What is the most important information I should know about methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets may cause serious side effects, including: Abuse, misuse, and addiction. Methylphenidate hydrochloride extended-release tablets have a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of methylphenidate hydrochloride extended-release tablets, other methylphenidate containing medicines, and amphetamine containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of methylphenidate hydrochloride extended-release tablets or when it is used in ways that are not approved, such as snorting or injection. Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with methylphenidate hydrochloride extended-release tablets and will monitor you or your child during treatment. Methylphenidate hydrochloride extended-release tablets may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. Do not give methylphenidate hydrochloride extended-release tablets to anyone else. See “ What are methylphenidate hydrochloride extended-release tablets? ” for more information. Keep methylphenidate hydrochloride extended-release tablets in a safe place and properly dispose of any unused medicine. See “ How should I store methylphenidate hydrochloride extended-release tablets? ” for more information. Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting treatment with methylphenidate hydrochloride extended-release tablets. Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Call your healthcare provider or go to the nearest hospital emergency room right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with methylphenidate hydrochloride extended-release tablets. Increased blood pressure and heart rate. Your healthcare provider should check your or your child's blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride extended-release tablets. Mental (psychiatric) problems, including: new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with methylphenidate hydrochloride extended-release tablets, especially hearing voices, seeing or believing things that are not real, or new manic symptoms. What are methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets are a central nervous system (CNS) stimulant prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults less than 65 years of age and children 6 years of age and older . Methylphenidate hydrochloride extended-release tablets may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. It is not known if methylphenidate hydrochloride extended-release tablets are safe and effective in children under 6 years of age. Methylphenidate hydrochloride extended-release tablets have not been studied in adults older than 65 years of age. Methylphenidate hydrochloride extended-release tablets are a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep methylphenidate hydrochloride extended-release tablets in a safe place to protect it from theft. Never give your methylphenidate hydrochloride extended-release tablets to anyone else because it may cause death or harm them. Selling or giving away methylphenidate hydrochloride extended-release tablets may harm others and is against the law. Do not take methylphenidate hydrochloride extended-release tablets if: you or your child are: allergic to methylphenidate or any of the ingredients in methylphenidate hydrochloride extended-release tablets. See the end of this Medication Guide for a complete list of ingredients in methylphenidate hydrochloride extended-release tablets. taking, or have stopped taking within the past 14 days, a medicine called a monoamine oxidase inhibitor (MAOI). Before taking methylphenidate hydrochloride extended-release tablets tell your healthcare provider about all your medical conditions, including if you or your child: have heart problems, heart disease, heart defects, or high blood pressure have mental problems including psychosis, mania, bipolar illness, or depression, or a family history of suicide, bipolar illness, or depression have circulation problems in fingers and toes have eye problems, including increased pressure in your eye, glaucoma, or problems with your close-up vision (farsightedness) have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome are pregnant or plan to become pregnant. It is not known if methylphenidate hydrochloride extended-release tablets will harm the unborn baby. Pregnancy Exposure Registry: There is a pregnancy registry for women who are exposed to methylphenidate hydrochloride extended-release tablets during pregnancy. The purpose of the registry is to collect information about the health of women exposed to methylphenidate hydrochloride extended-release tablets and their baby. If you or your child becomes pregnant during treatment with methylphenidate hydrochloride extended-release tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. are breastfeeding or plan to breastfeed. Methylphenidate hydrochloride extended-release tablets passes into breast milk. Talk to your healthcare provider about the best way to feed the baby during treatment with methylphenidate hydrochloride extended-release tablets. Tell your healthcare provider about all of the medicines that you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride extended-release tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with methylphenidate hydrochloride extended-release tablets. Your healthcare provider will decide whether methylphenidate hydrochloride extended-release tablets can be taken with other medicines. Especially tell your healthcare provider if you or your child takes: blood pressure medicines (anti-hypertensive) Know the medicines that you take or your child take. Keep a list of your medicines with you to show your healthcare provider and pharmacist. Do not start any new medicine during treatment with methylphenidate hydrochloride extended-release tablets without first talking to your healthcare provider. How should methylphenidate hydrochloride extended-release tablets be taken? Take methylphenidate hydrochloride extended-release tablets exactly as prescribed by your healthcare provider. Your healthcare provider may change the dose or tell you to stop taking methylphenidate hydrochloride extended-release tablets if needed. Take methylphenidate hydrochloride extended-release tablets 1 time each day in the morning with or without food. Swallow methylphenidate hydrochloride extended-release tablets whole with water or other liquids. Do not chew, crush, or divide the tablets. Tell your healthcare provider if you or your child cannot swallow methylphenidate hydrochloride extended-release tablets whole. A different medicine may need to be prescribed. Methylphenidate hydrochloride extended-release tablets does not dissolve completely in the body after all the medicine has been released. You or your child may sometimes notice the empty tablet in a bowel movement. This is normal. If you or your child take too much methylphenidate hydrochloride extended-release tablets, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of methylphenidate hydrochloride extended-release tablets? Methylphenidate hydrochloride extended-release tablets may cause serious side effects, including: See "What is the most important information I should know about methylphenidate hydrochloride extended-release tablets?" Painful and prolonged erections (priapism). Priapism that may require surgery has happened in males who take products that contain methylphenidate. If you or your child develop priapism, get medical help right away. Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon): Signs and symptoms may include: fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you or your child have numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes, or if you or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with methylphenidate hydrochloride extended-release tablets. Slowing of growth (height and weight) in children. Children should have their height and weight checked often during treatment with methylphenidate hydrochloride extended-release tablets. Methylphenidate hydrochloride extended-release tablets treatment may be stopped if your child is not growing or gaining weight. Possible blockage of the intestine. Because the methylphenidate hydrochloride extended-release tablet does not change in shape in the intestines (GI tract), methylphenidate hydrochloride extended-release tablets should not be taken by people with severe intestinal problems (preexisting severe gastrointestinal narrowing). Eye problems (increased pressure in the eye and glaucoma). Call your healthcare provider right away if you or your child develop changes in your vision or eye pain, swelling, or redness. New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with methylphenidate hydrochloride extended-release tablets. The most common side effects of methylphenidate hydrochloride extended-release tablets in adults include: decreased appetite • headache dry mouth • nausea trouble sleeping (insomnia) • anxiety dizziness • weight loss irritability • increased sweating The most common side effects of methylphenidate hydrochloride extended-release tablets in children 6 to 17 years of age was stomach pain. These are not all the possible side effects of methylphenidate hydrochloride extended-release tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store methylphenidate hydrochloride extended-release tablets? Store methylphenidate hydrochloride extended-release tablets at room temperature between 68°F to 77°F (20°C to 25°C). Store methylphenidate hydrochloride extended-release tablets in a safe place, like a locked cabinet. Protect from light and moisture. Dispose of remaining, unused, or expired methylphenidate hydrochloride extended-release tablets by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix methylphenidate hydrochloride extended-release tablets with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away methylphenidate hydrochloride extended-release tablets in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep methylphenidate hydrochloride extended-release tablets and all medicines out of the reach of children. General information about the safe and effective use of methylphenidate hydrochloride extended-release tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use methylphenidate hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give methylphenidate hydrochloride extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about methylphenidate hydrochloride extended-release tablets that was written for healthcare professionals. What are the ingredients in methylphenidate hydrochloride extended-release tablets? Active Ingredient: methylphenidate hydrochloride Inactive Ingredients: cellulose acetate, colloidal silicon dioxide, ferrosoferric oxide, hypromellose, iron oxide black, lactose monohydrate, magnesium stearate, phosphoric acid, polyethylene glycol, polyethylene oxide, sodium chloride, succinic acid, titanium dioxide, and triacetin. 27 mg tablets contain: FD&C Yellow #6 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake 45 mg tablets contain: FD&C Red #40 Aluminum Lake 54 mg tablets contain: FD&C Yellow #6 Aluminum Lake, FD&C Red #40 Aluminum Lake, FD&C Blue #2 Aluminum Lake 63 mg tablets contain: iron oxide red, iron oxide yellow 72 mg tablets contain: FD&C Blue #1 Aluminum Lake Manufactured for: Trigen Laboratories, LLC Alpharetta, GA 30005 For more information, go to www.trigenlab.com or call 1-800-444-5164 200320-3 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 10/2023 Trigen Logo

14 CLINICAL STUDIES The efficacy of methylphenidate hydrochloride extended-release tablets for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients (6 to 17 years) and adult patients is based upon adequate and well-controlled studies of another formulation of methylphenidate hydrochloride extended-release tablets (referred to as “methylphenidate hydrochloride extended-release tablets” in the section below). The results of these adequate and well-controlled studies are presented below. Methylphenidate hydrochloride extended-release tablets was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in four randomized, double-blind, placebo-controlled studies in pediatric patients 6 to 17 years and two double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4 th edition (DSM-IV) criteria for ADHD. Pediatric Patients 6 to 12 Years Three double-blind, active- and placebo-controlled studies were conducted in 416 pediatric patients 6 to 12 years. The controlled studies compared methylphenidate hydrochloride extended-release tablets given once daily (18 mg, 36 mg, or 54 mg), methylphenidate given three times daily over 12 hours (15 mg, 30 mg, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was methylphenidate hydrochloride extended-release tablets versus placebo. Symptoms of ADHD were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for methylphenidate hydrochloride extended-release tablets. Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at Week 4. The scores for methylphenidate hydrochloride extended-release tablets and placebo for the three studies are presented in Figure 2. Error bars represent the mean plus standard error of the mean. Figure 2: Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with Methylphenidate Hydrochloride Extended-Release Tablets Once Daily (18 mg, 36 mg, or 54 mg) and Placebo (Studies 1, 2, and 3) In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the Swanson, Kotkin, Agler, M-Fynn, and Pelham (SKAMP) laboratory school rating scale. The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with methylphenidate hydrochloride extended-release tablets versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory schoolteacher SKAMP ratings for methylphenidate hydrochloride extended-release tablets and placebo. Figure 3: Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2) Pediatric Patients 13 to 17 years In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving 177 patients, methylphenidate hydrochloride extended-release tablets was demonstrated to be effective in the treatment of ADHD in pediatric patients aged 13 to 18 years at doses up to 72 mg once daily (1.4 mg/kg/day). Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg once daily) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dose of methylphenidate hydrochloride extended-release tablets (18 mg to 72 mg once daily, n=87) or placebo (n=90) during a two-week double-blind phase. At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that methylphenidate hydrochloride extended-release tablets was statistically significantly superior to placebo. Adults Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared methylphenidate hydrochloride extended-release tablets administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 mg to 108 mg once daily) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18 mg, 36 mg, and 72 mg once daily). Study 5 demonstrated the effectiveness of methylphenidate hydrochloride extended-release tablets in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg once daily to 108 mg once daily based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7-week trial, 110 were randomized to methylphenidate hydrochloride extended-release tablets and 116 were randomized to placebo. Treatment was initiated at 36 mg once daily and patients continued with incremental increases of 18 mg once daily (36 mg to 108 mg once daily) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated methylphenidate hydrochloride extended-release tablets was statistically significantly superior to placebo. Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed-dose groups (18 mg, 36 mg, and 72 mg). Patients were randomized to receive methylphenidate hydrochloride extended-release tablets administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg once daily (n=102), or placebo (n=96). All three doses of methylphenidate hydrochloride extended-release tablets were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD. Figure 2 Figure 3

8.5 Geriatric Use Methylphenidate hydrochloride extended-release tablets have not been studied in patients greater than 65 years of age.

8.2 Lactation 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. However, 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 infant from methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, 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 to 17 years. The safety and effectiveness of methylphenidate hydrochloride extended-release tablets in pediatric patients less than 6 years have not been established. The long-term efficacy of methylphenidate in pediatric patients have not been established. Long Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.1 )] . Juvenile Animal Toxicity Data 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 4 times the MRHD of 54 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (9 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (equal to the MRHD given to children on a mg/m 2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388. Risk Summary Published studies and post-marketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There 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 development studies with oral administration of methylphenidate to pregnant rats at doses up to 4 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. However, malformations were observed in rabbits at a dose 54 times the MRHD given to adults. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as 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 therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine‑dependent mothers. Data Animal Data In development studies conducted in rats and rabbits, methylphenidate was administered at doses up to 30 and 200 mg/kg/day, respectively. Methylphenidate has been shown to cause malformations in rabbits when given in doses of 200 mg/kg/day, which is approximately 54 times the MRHD on a mg/m 2 basis, respectively. A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 4-fold the MRHD on a mg/m 2 basis.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate hydrochloride extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388. Risk Summary Published studies and post-marketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There 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 development studies with oral administration of methylphenidate to pregnant rats at doses up to 4 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m 2 basis. However, malformations were observed in rabbits at a dose 54 times the MRHD given to adults. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as 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 therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine‑dependent mothers. Data Animal Data In development studies conducted in rats and rabbits, methylphenidate was administered at doses up to 30 and 200 mg/kg/day, respectively. Methylphenidate has been shown to cause malformations in rabbits when given in doses of 200 mg/kg/day, which is approximately 54 times the MRHD on a mg/m 2 basis, respectively. A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 4-fold the MRHD on a mg/m 2 basis. 8.2 Lactation 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. However, 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 infant from methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, 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 to 17 years. The safety and effectiveness of methylphenidate hydrochloride extended-release tablets in pediatric patients less than 6 years have not been established. The long-term efficacy of methylphenidate in pediatric patients have not been established. Long Term Suppression of Growth Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.7 ) and Adverse Reactions ( 6.1 )] . Juvenile Animal Toxicity Data 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 4 times the MRHD of 54 mg/day given to children on a mg/m 2 basis) or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (9 times the MRHD given to children on a mg/m 2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (equal to the MRHD given to children 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 have not been studied in patients greater than 65 years of age.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methylphenidate hydrochloride extended-release tablets are available as: 18 mg yellow tablets with “TL706” imprinted in black ink NDC 13811-706-10 in 100-count bottle 27 mg gray tablets with “TL707” imprinted in black ink NDC 13811-707-10 in 100-count bottle 36 mg white tablets with “TL708” imprinted in black ink NDC 13811-708-10 in 100-count bottle 45 mg pink tablets with “TL711” imprinted in black ink NDC 13811-711-30 in 30-count bottle 54 mg pink tablets with “TL709” imprinted in black ink NDC 13811-709-10 in 100-count bottle 63 mg orange tablets with “TL700” imprinted in black ink NDC 13811-700-30 in 30-count bottle 72 mg blue tablets with “TL710” imprinted in black ink NDC 13811-710-30 in 30-count bottle Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from humidity.

WARNING: ABUSE, MISUSE, AND ADDICTION 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. 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. 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, proper storage of the drug, and proper disposal of any unused drug. 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 [see Warnings and Precautions ( 5.1 ) and Drug Abuse and Dependence ( 9.2 )] . WARNING: ABUSE, MISUSE, AND ADDICTION See full prescribing information for complete boxed warning. 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. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death ( 5.1 , 9.2 , 10 ): 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, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient’s risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.