Methylphenidate Hydrochloride

1 INDICATIONS AND USAGE Methylphenidate Hydrochloride Chewable Tablets is indicated for the treatment of: Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years of age and older Narcolepsy Methylphenidate Hydrochloride Chewable Tablets are a central nervous system (CNS) stimulant indicated for the treatment of: Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years of age and older ( 1 ) Narcolepsy ( 1 )

2 DOSAGE AND ADMINISTRATION Pediatric Patients 6 Years and Older: Start with 5 mg twice daily (before breakfast and lunch); titrate the dose in weekly increments of 5 mg to 10 mg. Daily dosages above 60 mg are not recommended. ( 2.2 ) Adults: Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum recommended daily dosage is 60 mg. ( 2.2 ) Administer with at least 8 ounces (a full glass) of water or other fluid. ( 2.2 ) 2.1 Pretreatment Screening Prior to treating patients with Methylphenidate Hydrochloride Chewable 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 Chewable Tablets [ see Warnings and Precautions ( 5.10 ) ]. 2.2 Recommended Dosage and Administration Information Pediatric Patients 6 years and Older The recommended starting dosage is 5 mg orally twice daily before breakfast and lunch (preferably 30 to 45 minutes before meals). Increase the dosage gradually, in increments of 5 mg to 10 mg weekly. Daily dosage above 60 mg is not recommended. Adults Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. The maximum recommended dosage is 60 mg daily. The average dosage is 20 to 30 mg daily. For adult patients who are unable to sleep if medication is taken late in the day, administer the last dose before 6 p.m. Administer Methylphenidate Hydrochloride Chewable Tablets with at least 8 ounces (a full glass) of water or other fluid. Do not swallow whole. Taking this product without enough liquid may cause choking [ see Warnings and Precautions ( 5.11 ) ] 2.3 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage, or, if necessary, discontinue Methylphenidate Hydrochloride Chewable Tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue Methylphenidate Hydrochloride Chewable Tablets.

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, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing methylphenidate hydrochloride. ( 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: Careful observation for digital changes is necessary during methylphenidate hydrochloride 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 ) Acute Angle Closure Glaucoma: methylphenidate hydrochloride-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. ( 5.8 ) Increased Intraocular Pressure (IOP) and Glaucoma: Prescribe methylphenidate hydrochloride 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. ( 5.9 ) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating methylphenidate hydrochloride, 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. ( 5.10 ) Risk of Choking: Taking this product without enough liquid may cause choking. Discontinue Methylphenidate Hydrochloride Chewable Tablets and seek immediate medical attention if chest pain, vomiting, difficulty in swallowing, or difficulty in breathing occur after administration. ( 5.11 ) 5.1 Abuse, Misuse, and Addiction Methylphenidate hydrochloride has a high potential for abuse and misuse. The use of methylphenidate hydrochloride exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. methylphenidate hydrochloride can be diverted for non-medical use into illicit channels or distribution [ see Drug Abuse and Dependence ( 9.2 , 9.3 ) ]. Misuse and abuse of CNS stimulants, including methylphenidate hydrochloride, 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, 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 chewable tablets in a safe place, preferably locked, and instruct patients to not give methylphenidate hydrochloride to anyone else. Throughout methylphenidate hydrochloride 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 taking CNS stimulants at the recommended ADHD dosage. Avoid methylphenidate hydrochloride u…

4 CONTRAINDICATIONS Methylphenidate Hydrochloride Chewable Tablets is contraindicated in patients: with a known hypersensitivity to methylphenidate or other components of Methylphenidate Hydrochloride Chewable Tablets. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions ( 6 )] . 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 chewable tablets ( 4 ) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days ( 4 )

7 DRUG INTERACTIONS Antihypertensive Drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. ( 7.1 ) 7.1 Clinically Important Drug Interactions Table 1 presents clinically important drug interactions with methylphenidate hydrochloride. Table 1: Drugs Having Clinically Important Interactions with methylphenidate hydrochloride Monoamine Oxidase Inhibitors (MAOI) Clinical Impact: Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride, 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: Concomitant use of methylphenidate hydrochloride with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact: Methylphenidate hydrochloride 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 may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention: Avoid use of methylphenidate hydrochloride 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.

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, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting online at www.womensmentalhealth.org/research/pregnancyregistry/adhd-medications/. Risk Summary Published studies and postmarketing 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 may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations) . No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 12 and 19 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adults on a mg/m 2 basis. However, spina bifida was observed in rabbits at a dose 65 times the MRHD given to adults. A decrease in pup body weight was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 7 times the MRHD given to adults (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions CNS stimulants, such as methylphenidate hydrochloride, 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 embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 65 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (19 times the MRHD given to adults on a mg/m 2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (12 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the MRHD on a mg/m 2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (7 times the MRHD of 60 mg/day given to adults on a mg/m 2 basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (approximately 2 times the MRHD given to adults on a mg/m 2 basis).

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 , 9.3 )] Known hypersensitivity to methylphenidate or other ingredients of methylphenidate hydrochloride chewable tablets [see Contraindications ( 4 )] Hypertensive crisis when used concomitantly with 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 )] Acute Angle Closure Glaucoma [see Warnings and Precautions ( 5.8 )] Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions ( 5.9 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.10 )] Risk of Choking [see Warnings and Precautions ( 5.11 )] The following adverse reactions associated with the use of methylphenidate containing products were identified in other clinical studies, postmarketing reports, or literature. Because some of these reactions were 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. Infections and infestations: nasopharyngitis Blood and the lymphatic system disorders: leukopenia, thrombocytopenia, anemia, pancytopenia Immune system disorders: hypersensitivity reactions, including angioedema and anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas Metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients Psychiatric disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood, affect lability, mania, disorientation, libido changes Nervous system disorders: headache, dizziness, tremor, dyskinesia including choreoathetoid movements, drowsiness, convulsions, cerebral arteritis and/or occlusion, serotonin syndrome in combination with serotonergic drugs, migraine, motor and verbal tics Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, mydriasis, increased intraocular pressure Cardiac disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris, sudden cardiac death, myocardial infarction, bradycardia, extrasystole Respiratory, thoracic and mediastinal disorders: cough, pharyngolaryngeal pain, dyspnea Gastrointestinal disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia, diarrhea General disorders: fatigue, hyperpyrexia Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura, angioneurotic edema, erythema, fixed drug eruption Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, rhabdomyolysis, myalgia, muscle twitching Renal and urinary disorders: hematuria Reproductive system and breast disorders: gynecomastia Urogenital disorders: priapism Vascular disorders: peripheral coldness, Raynaud’s phenomenon Investigations: weight loss Common adverse reactions: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-746…