Methylphenidate Hydrochloride

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 a higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of methylphenidate hydrochloride extended-release tablets, 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 (9.1, 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 methylphenidate hydrochloride extended-release tablets, 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.

5 WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. (5.2) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. (5.3) Psychiatric Adverse Reactions: Prior to initiating methylphenidate hydrochloride extended-release tablets, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets. (5.4) Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention (5.5) Peripheral Vasculopathy, including Raynaud’s Phenomenon: Carefully assess for digital changes during methylphenidate hydrochloride extended-release tablets treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy (5.6) Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (5.7) Risk of Gastrointestinal (GI) Obstruction in Patients with GI Narrowing: Only use in patients able to swallow the extended-release tablet whole, and should not ordinarily be used in patients with pre-existing severe GI narrowing. (5.8) Acute Angle Closure Glaucoma: Methylphenidate hydrochloride extended-release tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. (5.9) Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe methylphenidate hydrochloride extended-release tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma. (5.10) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. (5.11) 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride extended-release tablets have a high potential for abuse and misuse. The use of methylphenidate hydrochloride extended-release tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction [see Drug Abuse and Dependence (9.1, 9.2)] . Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride extended-release tablets, can result in overdose and death [see Overdosage (10)] , and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection. Before prescribing methylphenidate hydrochloride extended-release tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store methylphenidate hydrochloride extended-release tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride extended-release tablets to anyone else. Throughout methylphenidate hydrochloride extended-release tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride extended-release tablets use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute) [see Adverse Reactions (6)]. Some patients may have larger increases. Monitor all methylphenidate hydrochloride extended-release tablets-treated patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Psychosis in Patients with a Psychotic Disorder CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may exacerbate behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants, including methylphenidate hydrochloride extended-release tablets, may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating methylphenidate hydrochloride extended-release tablets treatment, screen patients for risk factors for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms in Patients without a History of a Bipolar or Psychotic Disorder CNS stimulants (including methylphenidate hydrochloride extended-release tablets), at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing methylphenidate hydrochloride extended-release tablets. 5.5 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in adult and pediatric male patients [see Adverse Reactions (6)]. Although priapism was not reported with methylphenidate initiation, priapism occurred in patients treated with methylphenidate after some time, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation). Methylphenidate hydrochloride extended-release tablets-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention. 5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including methylphenidate hydrochloride extended-release tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon [see Adverse Reactions (6.2)] . Signs and symptoms of these cases of peripheral vasculopathy were usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms of peripheral vasculopathy generally improved after CNS stimulant dosage reduction or discontinuation. During methylphenidate hydrochloride extended-release tablets treatment, carefully assess for digital changes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for methylphenidate hydrochloride extended-release tablets-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Long-Term Suppression of Growth in Pediatric Patients Methylphenidate hydrochloride extended-release tablets are not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4)]. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Pediatric patients 7 to 13 years of age who received methylphenidate for 7 days per week for over 14 months to over 36 months had a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this development period. Closely monitor growth (weight and height) in methylphenidate hydrochloride extended-release tablets -treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.8 Risk of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing Because methylphenidate hydrochloride extended-release tablets are nondeformable and do not appreciably change in shape in the gastrointestinal (GI) tract, methylphenidate hydrochloride extended-release tablets should not ordinarily be administered to patients with pre-existing severe pathologic or iatrogenic GI narrowing. There have been rare reports of obstructive GI symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable modified-release dosage forms. Methylphenidate hydrochloride extended-release tablets should be used only in patients who are able to swallow the extended-release tablets whole [see Dosage and Administration (2.2)]. 5.9 Acute Angle Closure Glaucoma There have been reports of angle closure glaucoma associated with methylphenidate hydrochloride extended-release tablets treatment. Although the mechanism is not clear, methylphenidate hydrochloride extended-release tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. 5.10 Increased Intraocular Pressure and Glaucoma There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6)]. Prescribe methylphenidate hydrochloride extended-release tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor methylphenidate hydrochloride extended-release tablets-treated patients with a history of abnormally increased IOP or open angle glaucoma. 5.11 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics [see Adverse Reactions (6)]. Worsening of Tourette’s syndrome has also been reported. Before initiating methylphenidate hydrochloride extended-release tablets, assess the family history for tics or Tourette’ syndrome and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor methylphenidate hydrochloride extended-release tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue methylphenidate hydrochloride extended-release tablets treatment if clinically appropriate.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2)] Hypersensitivity Reactions [see Contraindications (4)] Monoamine Oxidase Inhibitors [see Contraindications (4), Drug Interactions (7)] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)] Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)] Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)] Priapism [see Warnings and Precautions (5.5)] Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.6)] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.7)] Risks of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing [see Warnings and Precautions (5.8)] Acute Angle Closure Glaucoma [see Warnings and Precautions (5.9)] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.10)] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.11)] The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients 6 to 17 years: upper abdominal pain. (6.1) Adults up to 65 years of age: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The data below is based on a total of 3,906 patients in clinical studies who received methylphenidate hydrochloride extended-release tablets. Patients aged 6 up to 65 years old with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies [see Table 3]. Table 3: Methylphenidate Hydrochloride Extended-Release Tablets-treated Patients in Double-Blind and Open-Label Clinical Studies Patient Population N Dosage Range Pediatric patients 6 to 12 years of age 2,216 18 to 54 mg once daily Adolescents 502 18 to 72 mg once daily Adults up to 65 years of age 1,188 18 to 108 mg once daily The most common adverse reactions (≥5%) in double-blind clinical trials were: Pediatric patients: upper abdominal pain [see Table 4]. Adults: decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, tachycardia, and hyperhidrosis [see Table 5]. The most common adverse reactions associated with methylphenidate hydrochloride extended-release tablets discontinuation (≥1%) from the pediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure. Most Common Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations. Adverse Reactions in Pediatric Patients Aged 6 years and Older Table 4 displays adverse reactions reported in 2% or more of methylphenidate hydrochloride extended-release tablets -treated pediatric patients ages 6 and older with ADHD in 4 placebo-controlled, double-blind clinical trials. Table 4: Most Common Adverse Reactions 1 in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials Methylphenidate Hydrochloride Extended-Release Tablets (n=321) Placebo (n=318) Upper abdominal pain 6% 4% Insomnia 2 3% 1% Nasopharyngitis 3% 2% Vomiting 3% 2% Pyrexia 2% 1% 1 Reported in ≥ 2% of methylphenidate hydrochloride extended-release tablets-treated patients 2 Initial insomnia (methylphenidate hydrochloride extended-release tablets =0.6%) and insomnia (methylphenidate hydrochloride extended-release tablets =2.2%) terms were combined into Insomnia. Adverse Reactions in Adults Table 5 lists the adverse reactions reported in 2% or more of methylphenidate hydrochloride extended-release tablets-treated adults with ADHD in 2 placebo-controlled, double-blind clinical trials. Table 5: Most Common Adverse Reactions1 in Adults with ADHD in 2 Placebo-Controlled, Double-Blind Clinical Trials 1 Reported in ≥ 2% of methylphenidate hydrochloride extended-release tablets -treated patients 2 Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage). Other Adverse Reactions Observed in Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets The following adverse reactions occurred in less than 2% of methylphenidate hydrochloride-treated patients ages 6 to 65 years of age in the double-blind and open-label clinical ADHD trials. • Blood and Lymphatic System Disorders: Leukopenia • Cardiac Disorders: Cardiac murmur, Hypertension, Heart rate increased • Ear and Labyrinth Disorders : Vertigo • Eye Disorders: Accommodation disorder, Dry eye, Vision blurred • Gastrointestinal Disorders : Abdominal discomfort/pain, Constipation, Diarrhea, Vomiting • General Disorders and Administration Site Conditions : Asthenia, Fatigue, Feeling jittery, Thirst • Hepatobiliary Disorders: Hepatic enzymes increased • Infections and Infestations: Sinusitis • Metabolism and Nutrition Disorders: Anorexia • Musculoskeletal and Connective Tissue Disorders: Muscle spasms, Muscle tightness • Nervous System Disorders: Lethargy, Paresthesia, Psychomotor hyperactivity, Sedation, Somnolence, Tension headache • Psychiatric Disorders: Affect lability, Aggression, Anger, Bruxism, Confusional state, Depression, Hypervigilance, decreased libido, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tension, Tic • Reproductive System and Breast Disorders: Erectile dysfunction • Respiratory, Thoracic and Mediastinal Disorders: Cough, Dyspnea, Oropharyngeal pain • Skin and Subcutaneous Tissue Disorders : Rash • Vascular Disorders: Hot flush Discontinuation Due to Adverse Reactions In the 2 placebo-controlled studies in adults with ADHD, 25 (6%) methylphenidate hydrochloride extended-release tablets -treated patients and 6 (3%) placebo-treated patients discontinued due to an adverse reaction. In the methylphenidate hydrochloride extended-release tablets group, adverse reactions leading to discontinuation with an incidence of >0.5% were anxiety (1.7%), irritability (1.4%), increased blood pressure (1%), and nervousness (0.7%). In the placebo group, adverse reactions leading to discontinuation with an incidence of >0.5% were increased blood pressure (0.9%) and depressed mood (0.9%). In the 11 open-label studies in patients 6 to 65 years of age with ADHD, 266 (7%) methylphenidate hydrochloride extended-release tablets-treated patients discontinued due to an adverse reaction including insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%). Blood Pressure and Heart Rate Increases • In the 1-week treatment, controlled trials in pediatric patients 6 to 12 years of age with ADHD (Studies 1 and 2) [see Clinical Studies (14.2)], both the methylphenidate hydrochloride extended-release tablets once daily group and the methylphenidate three times daily group increased resting pulse by an average of 2 to 6 beats per minute (bpm) and increased the average systolic and diastolic blood pressure roughly 1 to 4 mm Hg during the day, relative to placebo. • In the randomized withdrawal portion of the double-blind, placebo-controlled trial with pediatric patients 13 to 17 years of age with ADHD (Study 4) [see Clinical Studies (14.3)], mean increases from baseline in resting pulse rate were observed with methylphenidate hydrochloride extended-release tablets and placebo at the end of the double-blind phase (5 and 3 beats/minute (bpm), respectively). At the end of four weeks of treatment, mean increases from baseline in blood pressure for methylphenidate hydrochloride extended-release tablets and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. • In the 7-week dose-titration, placebo-controlled study in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (14.4)], mean changes from baseline in resting pulse rate were 3.6 in methylphenidate hydrochloride extended-release tablets -treated patients and -1.6 for placebo-treated patients after 7 weeks of treatment. Mean changes from baseline in blood pressure after 7 weeks of treatment in methylphenidate hydrochloride extended-release tablets-treated and placebo-treated patients were –1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.3)]. • In the 5-week fixed-dose, placebo-controlled trial in adults 18 to 65 years of age with ADHD (Study 5) [see Clinical Studies (14.4)], dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with methylphenidate hydrochloride extended-release tablets -treated patients and 2.7 bpm with placebo-treated patients at the end of 5 weeks. Mean changes from baseline in standing blood pressure after 5 weeks of treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for methylphenidate hydrochloride extended-release tablets-treated patients and 1.1 mm Hg (systolic) and 1.8 mm Hg (diastolic) for placebo-treated patients. table 5 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of methylphenidate hydrochloride extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency: • Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura • Cardiac Disorders: Angina pectoris, Bradycardia, Supraventricular tachycardia, Ventricular extrasystoles • Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis • General Disorders and Administration Site Conditions: Chest pain, Drug effect decreased, Hyperpyrexia • Hepatobiliary Disorders: Hepatocellular injury, Acute hepatic failure, Blood bilirubin increased • Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Exanthemas NEC • Investigations: Blood alkaline phosphatase increased, Platelet count decreased • Musculoskeletal and Connective Tissue Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis • Nervous System Disorders: Convulsion, Grand mal convulsion, Stroke in pediatric patients, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics • Psychiatric Disorders: Disorientation, Hallucination, Mania, Logorrhea • Reproductive System and Breast Disorders : Priapism • Skin and Subcutaneous Tissue Disorders: Alopecia, Bullous conditions, Erythema, Exfoliative conditions, Pruritus, Urticarias • Vascular Disorders: Raynaud’s phenomenon

<table border="10"><tbody><tr><td><content styleCode="bold">Patient Population</content></td><td><content styleCode="bold">N</content></td><td><content styleCode="bold">Dosage Range</content></td></tr><tr><td>Pediatric patients 6 to 12 years of age</td><td>2,216</td><td>18 to 54 mg once daily</td></tr><tr><td>Adolescents</td><td>502</td><td>18 to 72 mg once daily</td></tr><tr><td>Adults up to 65 years of age</td><td>1,188</td><td>18 to 108 mg once daily</td></tr></tbody></table>

<table border="10"><tbody><tr><td/><td><content styleCode="bold">Methylphenidate Hydrochloride Extended-Release Tablets (n=321) </content></td><td><content styleCode="bold">Placebo (n=318) </content></td></tr><tr><td>Upper abdominal pain</td><td>6%</td><td>4%</td></tr><tr><td>Insomnia ²</td><td>3%</td><td>1%</td></tr><tr><td>Nasopharyngitis</td><td>3%</td><td>2%</td></tr><tr><td>Vomiting</td><td>3%</td><td>2%</td></tr><tr><td>Pyrexia</td><td>2%</td><td>1%</td></tr></tbody></table>