Dexmethylphenidate Hydrochloride Extended-Release

1 INDICATIONS AND USAGE Dexmethylphenidate Hydrochloride Extended-release Capsules is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies (14) ] . Dexmethylphenidate Hydrochloride Extended-release Capsules is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients aged 6 years and older

2 DOSAGE AND ADMINISTRATION Dexmethylphenidate Hydrochloride Extended-release Capsules is for oral administration once daily in the morning. Dexmethylphenidate Hydrochloride Extended-release Capsules may be swallowed as whole capsules or alternatively may be administered by sprinkling the capsule contents on a small amount of applesauce (see specific instructions below). Dexmethylphenidate Hydrochloride Extended-release Capsules and/or their contents should not be crushed, chewed, or divided. The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Dosage should be individualized according to the needs and responses of the patient. Patients new to methylphenidate: Recommended starting dose is 5 mg once daily for pediatric patients and 10 mg once daily for adults with or without food in the morning ( 2.2 ). Patients currently on methylphenidate: Dexmethylphenidate Hydrochloride Extended-release Capsules dosage is half the current total daily dosage of methylphenidate ( 2.2 ). Patients currently on dexmethylphenidate immediate-release tablets: Give the same daily dose of Dexmethylphenidate Hydrochloride Extended-release Capsules ( 2.2 ) Titrate weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients ( 2.2 ). Maximum recommended daily dose: 30 mg in pediatric patients and 40 mg in adults ( 2.2 ). Capsules may be swallowed whole or opened and the entire contents sprinkled on applesauce ( 2.3 ). 2.1 Pretreatment Screening Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants including Dexmethylphenidate Hydrochloride Extended-release Capsules, assess for the presence of cardiac disease (i.e., perform a careful history including family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions (5.2) ] . Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for Dexmethylphenidate Hydrochloride Extended-release Capsules use [see Boxed Warning , Warnings and Precautions (5.1) , Drug Abuse and Dependence (9) ] . 2.2 Treatment of ADHD Patients New to Methylphenidate The recommended starting dosage of Dexmethylphenidate Hydrochloride Extended-release Capsules for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate are: Pediatric patients: Start with 5 mg orally once daily in the morning with or without food. Adult patients: Start with 10 mg orally once daily in the morning with or without food. Patients Currently on Methylphenidate The recommended starting dose of Dexmethylphenidate Hydrochloride Extended-release Capsules for patients currently using methylphenidate is half the total daily dose of racemic methylphenidate. Patients currently using dexmethylphenidate immediate-release tablets may be given the same daily dose of Dexmethylphenidate Hydrochloride Extended-release Capsules. Titration Schedule The dose may be titrated weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients. The dose should be individualized according to the needs and response of the patient. Daily doses above 30 mg in pediatrics and 40 mg in adults have not been studied and are not recommended. Maintenance/Extended Treatment Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of Dexmethylphenidate Hydrochloride Extended-release Capsules and adjust dosage as needed. 2.3 Administration Instructions Dexmethylphenidate Hydrochloride Extended-release Capsules is administered orally and may be take…

5 WARNINGS AND PRECAUTIONS Serious Cardiovascular Events: Sudden death has been reported in association with CNS stimulant treatment at usual doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke, and myocardial infarction have been reported Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm arrhythmias, or coronary artery disease ( 5.2 ). Blood Pressure and Heart Rate Increases: Monitor blood pressure and pulse. Consider the benefits and risk in patients for whom an increase in blood pressure or heart rate would be problematic ( 5.3 ). Psychiatric Adverse Reactions: Use of stimulants may cause psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with preexisting psychiatric illness. Evaluate for existing psychotic or bipolar disorder prior to Dexmethylphenidate Hydrochloride Extended-release Capsules use ( 5.4 ). Priapism: Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of prolonged penile erections or priapism are observed ( 5.5 ). Peripheral Vasculopathy, Including Raynaud’s Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants ( 5.6 ). Long-Term Suppression of Growth: Monitor height and weight at appropriate intervals in pediatric patients ( 5.7 ). 5.1 Potential for Abuse and Dependence CNS stimulants, including Dexmethylphenidate Hydrochloride Extended-release Capsules, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning , Drug Abuse and Dependence ( 9.2 , 9.3 )] . 5.2 Serious Cardiovascular Reactions Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Dexmethylphenidate Hydrochloride Extended-release Capsules treatment. 5.3 Blood Pressure and Heart Rate Increases CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia. 5.4 Psychiatric Adverse Reactions Exacerbation of Preexisting Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating treatment, screen patients for risk factors for developing manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing Dexmethylphenidate Hydrochloride Extended-release Capsules. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stim…

4 CONTRAINDICATIONS Hypersensitivity to methylphenidate or other components of Dexmethylphenidate Hydrochloride Extended-release Capsules. 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 Extended-release Capsules ( 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 ). Halogenated Anesthetics: Avoid use of Dexmethylphenidate Hydrochloride Extended-release Capsules on the day of surgery if halogenated anesthetics will be used ( 7.1 ). 7.1 Clinically Important Interactions with Dexmethylphenidate Hydrochloride Extended-Release Capsules Table 5 presents clinically important drug interactions with Dexmethylphenidate Hydrochloride Extended-release Capsules. Table 5: Clinically Important Drug Interactions with Dexmethylphenidate Hydrochloride Extended-Release Capsules Monoamine Oxidase Inhibitors (MAOI) Clinical Impact Concomitant use of MAOIs and CNS stimulants, including Dexmethylphenidate Hydrochloride Extended-Release Capsules, 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 Extended-Release Capsules with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Antihypertensive Drugs Clinical Impact Dexmethylphenidate Hydrochloride Extended-Release Capsules 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. Examples Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists Halogenated Anesthetics Clinical Impact Concomitant use of halogenated anesthetics and Dexmethylphenidate Hydrochloride Extended-Release Capsules may increase the risk of sudden blood pressure and heart rate increase during surgery. Intervention Avoid use of Dexmethylphenidate Hydrochloride Extended-Release Capsules in patients being treated with anesthetics on the day of surgery. Examples halothane, isoflurane, enflurane, desflurane, sevoflurane

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 Extended-release Capsules, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy registry for ADHD medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhdmedications/. Risk Summary Dexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. 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 may be risks to the fetus associated with the use of CNS stimulants use 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 ( 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 Extended-release Capsules, 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. 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, postweaning 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 curve (AUCs)] of dexmethylphenidate in pregnant rats and rabbits were approximately 5 and 1 times, respectively, those in adults dosed with 20 mg/day. Plasma levels in adults were comparatively similar to plasma levels in adolescents. 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 and Dependence [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 Extended-release Capsules [see Contraindications (4) ] Hypertensive Crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4) , Drug Interactions (7.1) ] Serious Cardiovascular Reactions [see Warnings and Precautions (5.2) ] Blood Pressure and Heart Rate Increases [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 [see Warnings and Precautions (5.7) ] The most common adverse reactions (greater than or equal to 5% and twice the rate of placebo): Pediatric patients 6 to 17 years: dyspepsia, decreased appetite, headache, and anxiety ( 6.1 ). Adults: dry mouth, dyspepsia, headache, pharyngolaryngeal pain, and anxiety ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 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. Clinical Trials Experience with Dexmethylphenidate Hydrochloride Extended-Release Capsules in Pediatric Patients with ADHD The safety data in this section is based on data from a 7-week controlled clinical study of dexmethylphenidate hydrochloride extended-release capsules in 100 (103 randomized) pediatric patients with ADHD ages 6 to 17 years (ages 6 to 12, n = 86; ages 13 to 17, n = 17). This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the time of onset, duration of efficacy, tolerability, safety of dexmethylphenidate hydrochloride extended-release capsules 5 mg to 30 mg/day who met DSM-IV criteria for ADHD [ see Clinical Studies (14.1) ] . Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): dyspepsia, decreased appetite, headache and anxiety. Adverse Reactions Leading to Discontinuation : 50 of 684 (7.3%) pediatric patients treated with dexmethylphenidate immediate-release 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 the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible dexmethylphenidate hydrochloride extended-release capsules doses of 5–30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride extended-release capsules and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release capsules was at least twice the incidence in placebo-treated patients. Table 1: Common Adverse Reactions in Pediatric Patients (6 to 17 years of age) with ADHD Abbreviation: attention deficit hyperactivity disorder. System Organ Class Adverse Reaction Dexmethylphenidate HCl ER Capsules N=53 Placebo N=47 Gastrointestinal Disorders 38% 19% Dyspepsia 8% 4% Metabolism and Nutrition Disorders 34% 11% Decreased Appetite 30% 9% Nervous System Disorders 30% 13% Headache 25% 11% Psychiatric Disorders 26% 15% Anxiety 6% 0% Table 2 below enumerates the incidence of dose-related adverse reactions that occurred during a fixed-dose, double-blind, placebo-controlled trial in pediatri…