Dexmethylphenidate hydrochloride

1 INDICATIONS AND USAGE Dexmethylphenidate hydrochloride tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies (14) ] . Dexmethylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorders (ADHD) ( 1 ).

2 DOSAGE AND ADMINISTRATION • Administer orally twice daily, 4 hours apart with or without food ( 2 ). • For patients new to methylphenidate: Recommend starting dose of 5 mg once daily (2.5 mg twice daily) ( 2.2 ). • For patients currently taking methylphenidate: Initiate dexmethylphenidate hydrochloride tablets therapy with half (1/2) the current total daily dose of methylphenidate ( 2.2 ). • Titrate weekly in increments of 2.5 to 5 mg to a maximum of 20 mg/day (10 mg twice daily) ( 2.2 ). 2.1 Pretreatment Screening Prior to treating patients with dexmethylphenidate hydrochloride 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 dexmethylphenidate hydrochloride tablets [see Warnings and Precautions (5.10) ] . 2.2 Recommended Dosage Patients New to Methylphenidate The recommended starting dose of dexmethylphenidate hydrochloride tablets for pediatric patients who are not currently taking racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg daily (2.5 mg twice daily) with or without food. Patients Currently on Methylphenidate The recommended starting dose of dexmethylphenidate hydrochloride tablets for pediatric patients currently using methylphenidate is half (1/2) the total daily dose of racemic methylphenidate. Titration Schedule The dose may be titrated weekly in increments of 2.5 to 5 mg to a maximum of 20 mg daily (10 mg twice daily). The dose should be individualized according to the needs and response of the patient. 2.3 Administration Instructions Dexmethylphenidate hydrochloride tablets are administered orally twice daily, at least 4 hours apart. 2.4 Dosage Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue dexmethylphenidate hydrochloride tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

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 dexmethylphenidate hydrochloride tablets, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing dexmethylphenidate hydrochloride 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: Careful observation for digital changes is necessary during dexmethylphenidate hydrochloride 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 ). • Acute Angle Closure Glaucoma: Dexmethylphenidate hydrochloride tablets -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 dexmethylphenidate hydrochloride 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 ( 5.9 ). • Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating dexmethylphenidate hydrochloride 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 ( 5.10 ). 5.1 Abuse, Misuse and Addiction Dexmethylphenidate hydrochloride tablets have a high potential for abuse and misuse. The use of dexmethylphenidate hydrochloride tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Dexmethylphenidate hydrochloride tablets can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2) ]. Misuse and abuse of CNS stimulants, including dexmethylphenidate hydrochloride 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 dexmethylphenidate hydrochloride 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 dexmethylphenidate hydrochloride tablets in a safe place, preferably locked, and instruct patients to not give dexmethylphenidate hydrochloride tablets to anyone else. Throughout dexmethylphenidate hydrochloride 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 are treated with CNS stimulants at the recommended ADHD dosage. Avoid dexmethylphenidate hydrochloride tablets use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease,…

4 CONTRAINDICATIONS • Hypersensitivity to methylphenidate or other components of dexmethylphenidate hydrochloride tablets. Hypersensitivity reactions, such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions (6.1) ]. • Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions (7.1) ]. • Known hypersensitivity to methylphenidate or other components of dexmethylphenidate hydrochloride tablets ( 4 ). • Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days ( 4 ).

Antihypertensive Drugs : Monitor blood pressure. Adjust dosage of antihypertensive drug as needed ( 7.1 ). 7.1 Clinically Important Drug Interactions With Dexmethylphenidate Hydrochloride Tablets Table 2 presents clinically important drug interactions with dexmethylphenidate hydrochloride tablets. Table 2 : Clinically Important Drug Interactions with Dexmethylphenidate Hydrochloride Tablets Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including dexmethylphenidate hydrochloride tablets, 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 dexmethylphenidate hydrochloride tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Antihypertensive Drugs Clinical Impact Dexmethylphenidate hydrochloride tablets may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3) ]. Intervention Adjust the dosage of the antihypertensive drug as needed. Halogenated Anesthetics Clinical Impact Concomitant use of halogenated anesthetics and dexmethylphenidate hydrochloride tablets may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Monitor blood pressure and avoid use of dexmethylphenidate hydrochloride 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

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including dexmethylphenidate hydrochloride tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/. Risk Summary Dexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. 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 during pregnancy (see Clinical Considerations ). Embryo-fetal development studies in rats showed delayed fetal skeletal ossification at doses up to 5 times the maximum recommended human dose (MRHD) of 20 mg/day given to adults based on plasma levels. A decrease in pup weight in males was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 5 times the MRHD of 20 mg/day given to adults based on plasma levels. Plasma levels in adults were comparatively similar to plasma levels in adolescents (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 dexmethylphenidate hydrochloride 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 embryo-fetal development studies conducted in rats and rabbits, dexmethylphenidate was administered orally at doses of up to 20 and 100 mg/kg/day, respectively, during the period of organogenesis. No evidence of malformations was found in either the rat or rabbit study; however, delayed fetal skeletal ossification was observed at the highest dose level in rats. When dexmethylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 20 mg/kg/day, post-weaning body weight gain was decreased in male offspring at the highest dose, but no other effects on postnatal development were observed. At the highest doses tested, plasma levels [area under the curves (AUCs)] of dexmethylphenidate in pregnant rats and rabbits were approximately 5 and 1 times, respectively, those in adults dosed with the MRHD of 20 mg/day. Racemic methylphenidate has been shown to cause malformations (increased incidence of fetal spina bifida) in rabbits when given in doses of 200 mg/kg/day throughout organogenesis.

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 dexmethylphenidate hydrochloride tablets [see Contraindications (4) ] • Hypertensive crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4) , Drug Interactions (7.1) ] • Risk 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) ] The most common adverse reactions (greater than or equal to 5% and twice the rate of placebo) in pediatric patients 6 to 17 years were abdominal pain, fever, nausea, and anorexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Nivagen Pharmaceuticals, Inc. at 1-877-977-0687 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions in Studies with Dexmethylphenidate Hydrochloride Tablets in Pediatric Patients with ADHD The safety data in this section is based on data related to dexmethylphenidate hydrochloride tablets exposure during the premarketing development program in a total of 696 participants in clinical trials (684 patients, 12 healthy adult subjects). These participants received dexmethylphenidate hydrochloride tablets 5, 10, or 20 mg/day. The 684 ADHD patients (ages 6 to 17 years) were evaluated in 2 controlled clinical studies, 2 clinical pharmacology studies, and 2 open-label long-term safety studies. Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): abdominal pain, fever, anorexia, and nausea Adverse Reactions Leading to Discontinuation: Overall, 50 of 684 (7.3%) pediatric patients treated with dexmethylphenidate hydrochloride tablets experienced an adverse reaction that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each). Table 1 enumerates adverse reactions for two, placebo-controlled, parallel group studies in pediatric patients with ADHD taking dexmethylphenidate hydrochloride tablets doses of 5, 10, and 20 mg/day. The table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride tablets for which the incidence was at least 5% and twice the incidence among placebo-treated patients. Table 1 : Common Adverse Reactions in Pediatric Patients (6 to 17 years of age) With ADHD System organ class Adverse reactions Dexmethylphenidate hydrochloride tablets (N = 79) Placebo (N = 82) Body as a whole Abdominal Pain 15 % 6 % Fever 5 % 1 % Digestive system Anorexia 6 % 1 % Nausea 9 % 1 % Abbreviation: ADHD, attention deficit hyperactivity disorder. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always po…